A 42-year-old woman presented with a 1-week history of swelling and pain in the fifth finger of her left hand. She reported no related trauma. She had systemic lupus erythematosus, treated with mycophenolate mofetil and prednisone. Physical examination of the affected finger revealed soft-tissue swelling, with erythema and warmth, that was most prominent between the proximal and distal interphalangeal joints, sparing the fingertip. The patient’s husband had recently traveled to China and developed a cough soon after his return home. What is the cause of the patient’s finger swelling?

Acute gout The answer is extrapulmonary manifestation of Flare of systemic lupus erythematosus tuberculosis. Examination of a biopsy specimen of the deep dermis after Fite staining revealed Septic arthritis numerous acid-fast bacilli. Culture of a tissue sample grew Mycobacterium tuberculosis. Extrapulmonary manifestation of Although infection of the finger is a rare tuberculosis extrapulmonary manifestation of tuberculosis, it is an important consideration in Osteoarthritis immunosuppressed patients. This patient was treated with a four-drug antituberculosis regimen for a total of 9 months and had complete resolution of her symptoms. Oxycodon wurde 1916 von Martin Freund (1863–1920) und Edmund Speyer (1878–1942) an der Universität Frankfurt/Main entwickelt und ein Jahr später von Merck in Darmstadt unter dem Namen Eukodal als schmerz- und hustenstillendes Mittel auf den Markt gebracht. Seit 1919 wurde es als Analgetikum therapeutisch genutzt. Eukodal war bis 1990 in Deutschland im Handel und wurde wegen des sehr hohen Sucht- und Missbrauchspotentials vom Markt genommen. Die ersten Fälle von Oxycodon-Missbrauch, der in Analogie zum Morphinismus Eukodalismus genannt wird, wurden zu Beginn der 1920er Jahre geschildert. Der US- amerikanische Pharmakonzern Purdue Pharma L.P. wurde im Jahr 2007 zu 634,5 Mio. US-Dollar Strafe verurteilt, weil er in der Packungsbeilage nicht ausreichend gekennzeichnet hatte, dass Oxycodon wie andere Opioide ein hohes Abhängigkeitspotenzial besitzt. 2010 lag Oxycontin, das seit den 1990er Jahren aggressiv beworben worden war, in den Vereinigten Staaten auf Platz fünf der umsatzstärksten Medikamente. Der Umsatz betrug über 3,5 Mrd. US- Dollar. Der US-Staat Florida kämpft seit 2010 gegen sog. pill mills, Schmerzkliniken, in denen Opioide wie Oxycontin verschrieben werden. Durch staatliche Regulierung wurde die Verfügbarkeit seither verringert. Allerdings ist dafür ein illegaler Handel mit der Substanz aufgeblüht, und viele Oxycontin-Abhängige sind überdies auf Heroin umgestiegen, da es inzwischen günstiger und teilweise auch besser verfügbar ist. https://www.newyorker.com/magazine/2017/10/30/the- family-that-built-an-empire-of-pain

Within five years of its introduction, OxyContin was generating a billion dollars a year. “There is no sign of it slowing down,” Richard Sackler told a team of company representatives in 2000. The sales force was heavily incentivized to push the drug. In a memo, a sales manager in Tennessee wrote, “$$$$$$$$$$$$$ It’s Bonus Time in the Neighborhood!” May, who was assigned to the Virginia area, was astonished to learn that especially skillful colleagues were earning hundreds of thousands of dollars in commissions. One year, May’s own sales were so brisk that Purdue rewarded him with a trip to Hawaii. As prescriptions multiplied, Purdue executives—and the Sackler family members on the company’s board—appeared happy to fund such blandishments. Internal budget plans described the company’s sales force as its “most valuable resource.” In 2001, Purdue Pharma paid forty million dollars in bonuses. The Tobacco Master Settlement Agreement — Strategic Lessons for Addressing Public Health Problems

The 1998 Master Settlement Agreement (MSA) between the tobacco industry and 46 state attorneys general (AGs), five U.S. territories, and Washington, D.C., remains the largest legal settlement ever executed in the United States. The MSA achieved important public health objectives, including substantially reduced smoking rates and lives saved.1 Given its success, the agreement has enormous promise as a model for similar litigation or settlements that could hold industries accountable when they knowingly deceive and injure consumers with their products. Most opioid prescription deaths occur among people with common conditions for which prescribing risks outweigh benefits. General psychological insights offer an explanation: People may judge risk to be low without available personal experiences, may be less careful than expected when not observed, and may falter without an injunction from authority. To test these hypotheses, we conducted a randomized trial of 861 clinicians prescribing to 170 persons who subsequently suffered fatal overdoses. Clinicians in the intervention group received notification of their patients’ deaths and a safe prescribing injunction from their county’s medical examiner, whereas physicians in the control group did not. Milligram morphine equivalents in prescriptions filled by patients of letter recipients versus controls decreased by 9.7% (95% confidence interval: 6.2 to 13.2%; P < 0.001) over 3 months after intervention. We also observed both fewer opioid initiates and fewer high-dose opioid prescriptions by letter recipients.

Decedent characteristics.OTC, over the counter; n, number of clinicians.

Prescriber characteristics. Adjusted daily average milligram morphine equivalents (MMEs) dispensed per prescriber among persons randomized to the intervention or control groups.

Transthyretin (TTR) is a transport protein in the serum and cerebrospinal fluid that carries the thyroid hormone thyroxine (T4) and retinol-binding protein bound to retinol. This is how transthyretin gained its name: transports thyroxine and retinol. The liver secretes transthyretin into the blood, and the choroid plexus secretes TTR into the cerebrospinal fluid. TTR was originally called prealbumin (or thyroxine-binding prealbumin) because it ran faster than albumin on electrophoresis gels. Tafamidis (trade name Vyndaqel) is a drug used to delay loss of peripheral nerve function in adults with familial amyloid polyneuropathy (FAP), an orphan disease. It works by stabilizing the protein, transthyretin, which is normally made up of four strands. In people with FAP these strands separate and form clumps that harm nerves. Tafamidis functions as a chaperone that stabilizes the correctly folded tetrameric form of the transthyretin (TTR) protein by binding in one of the two thyroxine-binding sites of the tetramer. In people with FAP, the individual monomers fall away from the tetomer, misfold, and aggregate; the aggregates harm nerves. The maximum plasma concentration is achieved around 2 hours after dosing; in plasma it is almost completely bound to proteins. Based on preclinical data, it appears to be metabolized by glucuronidation and excreted via bile; in humans, around 59% of a dose is recovered in feces, and approximately 22% in urine. Tafamidis Treatment for Patients with Transthyretin Amyloid Cardiomyopathy

Transthyretin amyloid cardiomyopathy is caused by the deposition of transthyretin amyloid fibrils in the myocardium. The deposition occurs when wild-type or variant transthyretin becomes unstable and misfolds. Tafamidis binds to transthyretin, preventing tetramer dissociation and amyloidogenesis. In a multicenter, international, double-blind, placebo-controlled, phase 3 trial, we randomly assigned 441 patients with transthyretin amyloid cardiomyopathy in a 2:1:2 ratio to receive 80 mg of tafamidis, 20 mg of tafamidis, or placebo for 30 months. In the primary analysis, we hierarchically assessed all-cause mortality, followed by frequency of cardiovascular-related hospitalizations according to the Finkelstein–Schoenfeld method. Key secondary end points were the change from baseline to month 30 for the 6-minute walk test and the score on the Kansas City Cardiomyopathy Questionnaire– Overall Summary (KCCQ-OS), in which higher scores indicate better health status. Primary Analysis and Components. Panel A shows the results of the primary analysis as determined with the use of the Finkelstein– Schoenfeld method. Panel B shows an analysis of all-cause mortality for pooled tafamidis and for placebo, a secondary end point. Panel C shows the frequency of cardiovascular- related hospitalizations, also a secondary end point. Overall and Subgroup Results as Calculated with the Use of the Finkelstein–Schoenfeld Method, All-Cause Mortality, and Cardiovascular-Related Hospitalizations. All-cause mortality was evaluated with the use of a Cox proportional-hazards model, with treatment and stratification factors treated as covariates. The survival analysis interaction terms are based on a post hoc analysis. The frequency of cardiovascular-related hospitalizations was assessed with the use of a Poisson regression model. ATTRm denotes disease that results from an inherited autosomal dominant trait that is caused by pathogenic mutations in TTR, ATTRwt disease that results from the deposition of wild-type transthyretin protein, and NYHA New York Heart Association. Key Secondary End Points. Panel A shows the least-squares (LS) mean (±SE) change from baseline to month 30 in the distance walked in the 6-minute walk test in the pooled tafamidis group as compared with the placebo group. Panel B shows the LS mean (±SE) change from baseline for both groups in the Kansas City Cardiomyopathy Questionnaire–Overall Summary (KCCQ- OS) score, in which higher scores indicate better health status. I bars indicated standard errors. Safety and Adverse Effects The safety profiles of tafamidis and placebo were similar. There was no meaningful difference in the safety of the two doses of tafamidis. Adverse events that emerged during treatment were generally mild to moderate in severity, and permanent discontinuation of tafamidis or placebo as a result of adverse events was less common in the tafamidis groups than in the placebo group

ATTR-ACT showed that tafamidis is superior to placebo in reducing the combination of all-cause mortality and cardiovascular-related hospitalizations. The evidence also supports the assertion that the risk of each component, when analyzed independently of the other, is reduced. Tafamidis was also associated with a significant reduction in the decline in functional capacity (as measured by the 6-minute walk test) and the decline in quality of life (as measured by the KCCQ-OS) at month 30, with differences first observed at 6 months. In contrast, the effect on overall survival emerged after approximately 18 months. This dissociation between the effect on symptoms and survival has also been observed with other therapies for systolic heart failure in which ventricular remodeling takes months to achieve. Sphingosin-1-phosphat hat als Signalmolekül vielfältige intra- wie extrazelluläre Funktionen. Besonders hervorzuheben ist seine Bedeutung für: • die Zellproliferation: S1P steigert die Zellproliferation und ist Schutzfaktor im Falle toxischer Ereignisse. Im Sinne des Sphingolipid rheostat führt eine vermehrte Bildung von S1P zur Verringerung von Sphingosin und Ceramid, welche dem endogenen Zelltod, der Apoptose, förderlich sind. • die Zellmigration: S1P bewirkt als Gewebshormon eine Verstärkung des gerichteten Wanderverhaltens einzelner Zellen (Stichwort Chemotaxis) durch Aktivitätssteigerung zytoskeletaler Bewegungsfunktionen (Aktivierung des S1P1-Rezeptors) und innergeweblicher Verankerungen (Aktivierung des S1P2-Rezeptors, Stichwort stress fiber). Die Rezirkulation von Lymphozytenwird gehemmt. • die Gefäßpermeabilität: Durch Aktivierung des VE-Cadherin-Systems/adherens junction und durch unbekannte Effekte auf die vesikuläre Transzytose wird die Durchlässigkeit des Endothels für große Moleküle und ggf. Zellen deutlich reduziert. Die Wirkung des VEGF wird gehemmt. • die Angiogenese: Viele Vorgänge der Angiogenese werden unterstützt: Induktion der endothelialen NO- Synthase (eNOS), Proliferation und Migration von Endothelzellen, Röhrenbildung (tube formation), Gefäßreifung durch glatte Muskelzellen und Perizyten. • die Funktion von Thrombozyten: S1P wird in den Blutplättchen gebildet, gespeichert und bei Aktivierung sezerniert. Es findet sich in den Plättchen kein abbauender Stoffwechselweg. • Stimulation der Cyclooxygenase 2 zur Produktion von PGE2. Synergistische Induktion der cytosolischen Phospholipase A2 (cPLA2) durch Ceramid-1-phosphat.

S1P-Rezeptoren sind typischerweise an G-proteine gekoppelt und werden durch Ligandenbindung und Autophosphorylierung oder durch ligandenunabhängige Phosphorylierung durch andere Kinasen (z. B. akt/PI3K, Stichwort Transaktivierung) aktiviert. Die Rezeptoren wurden zunächst edg*, später s1p* benannt. 2nd messenger sind alle Zweige der MAP Kinasen, PI3k, PLC/IP3/Calcium, rho kinase. Fingolimod (früher FTY720) wirkt als Sphingosin-1- phosphat-Analogon. Es hält eine wichtige Untergruppe der weißen Blutkörperchen, die Lymphozyten, in den Lymphknoten zurück und senkt so die Zahl von Lymphozyten, die in das Zentralnervensystem einwandern und dort Nervenbahnenvon Patienten mit MS schädigen könnten. Im Gegensatz zu vielen bisher verfügbaren immunsuppressiven Medikamenten werden durch Fingolimod die Immunzellen nicht abgetötet oder an der Vermehrung gehindert. Stattdessen hemmt Fingolimod die Wanderung von Lymphozyten aus den lymphoiden Organen ins Blut und senkt so die Zahl entzündungsfördernder Lymphozyten, die im Zentralnervensystem schädigend wirken könnten. Fingolimod wird nach Einnahme durch das Enzym Sphingosin-Kinase-2 zu FTY720-Phosphat (FTY720-P) umgebaut, das dann an die auf Zelloberflächen vorhandenen Sphingosin-1-phosphat- (S1P)-Rezeptoren S1P1, S1P3, S1P4, und S1P5 binden kann. Wesentlich für den Wirkmechanismus von FTY720-P ist vor allem der S1P1-Rezeptor auf T- und B-Lymphozyten. S1P1-Rezeptoren werden von FTY720-P 'internalisiert', das heißt, aus der Zellmembran ins Innere der Zelle verlagert und abgebaut. Dieser Abbau ist für die Hemmung der S1P1- abhängigen Auswanderung der Lymphozyten aus den Lymphknoten ins Blut[18] und die infolgedessen verminderte Einwanderung entzündungsfördernder Zellen in periphere Organe und ins Zentralnervensystem verantwortlich. Trial of Fingolimod versus Interferon Beta-1a in Pediatric Multiple Sclerosis (5%)

Treatment of patients younger than 18 years of age with multiple sclerosis has not been adequately examined in randomized trials. We compared fingolimod with interferon beta-1a in this population. In this phase 3 trial, we randomly assigned patients 10 to 17 years of age with relapsing multiple sclerosis in a 1:1 ratio to receive oral fingolimod at a dose of 0.5 mg per day (0.25 mg per day for patients with a body weight of ≤40 kg) or intramuscular interferon beta-1a at a dose of 30 μg per week for up to 2 years. The primary end point was the annualized relapse rate.

Time to the First Confirmed Relapse and Percentage of Patients Free of Relapse. The time to the first confirmed relapse was significantly longer in the fingolimod group than in the interferon beta-1a group (P<0.001). The Kaplan–Meier estimate of the percentage of patients free of relapse at month 12 and month 24 was higher in the fingolimod group (87.7% and 85.7%, respectively) than in the interferon beta-1a group (54.7% and 38.8%, respectively), with an 82% risk difference up to month 24 as calculated with a Cox proportional-hazards model (rate ratio, 0.18; P<0.001). Censored data are indicated by circles (in the fingolimod group) and squares (in the interferon beta-1a group). Six patients receiving fingolimod and one patient receiving interferon beta-1a had a seizure during the trial. Seizures may be a more important side effect in pediatric patients receiving fingolimod than in adults and may need to be monitored in subsequent trials. There were no reports of skin carcinomas, an increased risk of which has been associated with fingolimod among adults, but longer monitoring may be necessary to assess dermatologic risks. This double-blind, active-comparator trial showed superior efficacy of fingolimod over interferon beta-1a in reducing relapses in children and adolescents with multiple sclerosis who received treatment for a median of 1.61 years. Relapse rates with fingolimod in our trial were similar to those seen among adults in phase 3 trials of fingolimod. In contrast, the annualized relapse rate in the interferon beta-1a group was approximately twice that seen among adult patients who received interferon beta-1a in TRANSFORMSand was more than 1.5 times that seen among adults who received placebo in the FTY720 Research Evaluating Effects of Daily Oral Therapy in Multiple Sclerosis (FREEDOMS) trials. In our trial, relapse frequencies were similar in the two treatment groups before randomization, and at randomization, the percentage of patients who were free of gadolinium-enhancing lesions was higher in the interferon beta-1a group than in the fingolimod group.

Fewer patients prematurely discontinued fingolimod than interferon beta-1a; about half of those discontinuing interferon beta-1a did so because their physicians, who were unaware of the trial-group assignments, judged the therapeutic effect to be unsatisfactory. Longer-duration trials are needed to determine the durability and the safety of fingolimod in the pediatric population with multiple sclerosis. An open-label 5- year extension trial involving the population in the current trial is ongoing. Unter dem Begriff Myelodysplastisches Syndrom (MDS, Myelodysplasie oder Myelodysplastisc he Syndrome) wird eine Gruppe von Erkrankungen des Knochenmarks zusammengefasst, bei denen die Blutbildung nicht von gesunden, sondern von genetisch veränderten Ursprungszellen (Stammzellen) ausgeht (PRV, Thrombozytose, Myelofibrose Jak2 Mut) Das Knochenmark von Patienten, die an myelodysplastischen Syndromen leiden, ist nicht mehr in der Lage, aus diesen Stammzellen vollständig reife und funktionstüchtige Blutzellen zu bilden. Übersicht, nicht sehr zellreich In fortgeschrittenen Stadien dieser Erkrankungen werden immer mehr unreife Blutzellen produziert. Der Blutbildungsprozess ist also nachhaltig gestört und kann bei manchen Patienten zu einem späteren Zeitpunkt auch zu einer akuten myeloischen Leukämie (AML) führen. Die myelodysplastischen Syndrome treten vor allem in höherem Alter – ab ca. 60 Jahre – auf und verlaufen von Patient zu Patient sehr unterschiedlich. Die Behandlungsmöglichkeiten haben sich in den letzten Jahren entscheidend verbessert, sind aber angesichts der Einzelne Megakaryozyten in der Übersicht komplexen Krankheitsentstehung sehr differenziert und berücksichtigen vor allem die Unterscheidung in Niedrigrisiko- und Hochrisiko-MDS. An mehreren Hochschulen, zum Beispiel an der Universität Düsseldorf, laufen Forschungsprogramme zur Bekämpfung dieser Krankheit. Das MDS-Register Düsseldorf verfolgt das Ziel, die Krankheit biologisch so gut wie möglich zu charakterisieren, den Krankheitsverlauf so gut wie möglich vorherzusagen und für die Patienten die am besten geeigneten Therapien zu ermitteln. Thrombozytenhaufen, passend zum hohen Thrombozytenwert von 433000 µ/l Mutation Clearance after Transplantation for Myelodysplastic Syndrome

Allogeneic hematopoietic stem-cell transplantation is the only curative treatment for patients with myelodysplastic syndrome (MDS). The molecular predictors of disease progression after transplantation are unclear. We sequenced bone marrow and skin samples from 90 adults with MDS who underwent allogeneic hematopoietic stem-cell transplantation after a myeloablative or reduced-intensity conditioning regimen. We detected mutations before transplantation using enhanced exome sequencing, and we evaluated mutation clearance by using error-corrected sequencing to genotype mutations in bone marrow samples obtained 30 days after transplantation. In this exploratory study, we evaluated the association of a mutation detected after transplantation with disease progression and survival. Distribution of Mutations before Allogeneic Hematopoietic Stem-Cell Transplantation in Patients with and Patients without Disease Progression. Shown is the distribution of mutations in genes and pathways of interest detected by means of enhanced exome sequencing at initial sampling and grouped according to patients with and without disease progression after transplantation. PTPs denotes protein tyrosine phosphatases, Ser–Thr serine–threonine, and Tyr tyrosine. Decreases in Variant Allele Frequencies after Allogeneic Hematopoietic Stem-Cell Transplantation in Patients with and Patients without Disease Progression. Shown is the maximum variant allele frequency (VAF) detected per patient as measured by means of error-corrected sequencing at initial sampling and at day 30 and day 100 after transplantation in patients with no disease progression (green, Panels A and B) and with disease progression (orange, Panels C and D). Plots are further divided according to pretransplantation conditioning regimen (reduced-intensity conditioning in Panels A and C and myeloablative conditioning in Panels B and D). Shading represents the range of observed values (first two quartiles shown). The inset plots show the interval in the VAF from 0% to 3%; the bold line represents the median value of the maximum VAF observed in each patient. The numbers of patients with samples sequenced at each time point are indicated. Association of Mutation Clearance with Outcomes. The VAF on day 30 after transplantation was determined with the use of error-corrected sequencing interrogating single-nucleotide variant mutations identified by enhanced exome sequencing of samples before transplantation. Patients are grouped according to the presence of positive (+) or negative (−) results for at least one mutation VAF of at least 0.5% (red lines) or all VAFs less than 0.5% (blue lines) and according to whether the patient received a reduced-intensity conditioning regimen (RIC, solid lines) or myeloablative conditioning (MAC, dashed lines). The rates of disease progression (Panel A) and disease progression or death (Panel B) are shown. Association of Outcomes with Mutation Clearance Determined with the Use of a 40-Gene Panel. Only the VAFs of 40 genes recurrently mutated in myeloid cancers were used to assess mutation clearance at day 30 after transplantation. VAFs were determined with the use of error-corrected sequencing interrogating single- nucleotide variants identified by enhanced exome sequences of samples before transplantation. Patients are grouped according to the presence of at least one VAF of at least 0.5% (red lines) or all VAFs less than 0.5% (blue lines) and according to whether they received a reduced-intensity conditioning regimen (RIC, solid lines) or myeloablative conditioning (MAC, dashed line). The rates of disease progression (Panel A) and disease progression or death (Panel B) are shown. In this exploratory study involving patients with MDS, the risk of disease progression was higher and the rate of progression-free survival was lower among patients in whom persistent mutations were detected in bone marrow samples obtained 30 days after allogeneic hematopoietic stem-cell transplantation than among those in whom these mutations were not detected. The risk of progression was higher among patients with detectable mutations who had received a reduced-intensity conditioning regimen than among those who had received a myeloablative regimen. These findings suggest that sequencing bone marrow samples at early clinical time points after transplantation could be used as an individualized risk-assessment biomarker for disease progression in patients with MDS. The prognostic usefulness of monitoring measurable residual disease after treatment for MDS and AML has been studied with the use of a variety of approaches, including morphologic analysis, assessment of chimerism, quantitative PCR, and multiparameter flow cytometry. Essential Role of BRCA2 in Ovarian Development and Function

BRCA2 ist ein Protein in den Zellkernen der meisten Eukaryoten, das als Untereinheit mehrerer Proteinkomplexe eine Schlüsselrolle bei der DNA- Reparatur und der homologen Rekombination einnimmt. Beim Menschen wird BRCA2 hauptsächlich in Brust- und Thymusdrüse, sowie in der Lunge, den Eierstöcken und der Milz produziert. Homozygote Mutationen im BRCA2-Gen sind für erhöhtes Risiko für Bauchspeicheldrüsenkrebs, Brust- und Eierstockkrebs sowie heterozygote(rezessiv) Mutationen für die Fanconi-AnämieGruppe D Typ 1 verantwortlich. Das Gen wird daher zur (veralteten) Klasse der Tumorsuppressorgene gezählt. Das BRCA2-Protein bindet an RAD51 und PALB2. Der Komplex mit RAD51 bindet mit Hilfe von PALB2 an DNA-Doppelstrangbrüche und leitet die DNA-Reparatur ein. BRCA2 wird für die Bildung der RAD51- Nukleofilamente benötigt, indem es RPA vom resektierten DNA-Abschnitt entfernt und durch Rad51 ersetzt. BRCA2 ist daher essenziell für die genomische Stabilität einer eukaryotischen Zelle. Summary The causes of ovarian dysgenesis remain incompletely understood. Two sisters with XX ovarian dysgenesis carried compound heterozygous truncating mutations in the BRCA2 gene that led to reduced BRCA2 protein levels and an impaired response to DNA damage, which resulted in chromosomal breakage and the failure of RAD51 to be recruited to double- stranded DNA breaks. The sisters also had microcephaly, and one sister was in long-term remission from leukemia, which had been diagnosed when she was 5 years old. Drosophila mutants that were null for an orthologue of BRCA2 were sterile, and gonadal dysgenesis was present in both sexes. These results revealed a new role for BRCA2 and highlight the importance to ovarian development of genes that are critical for recombination during meiosis. Two sisters, 20 and 15 years of age, from a Gene Discovery and Characterization. Panel A shows the pedigree nonconsanguineous family of Ethiopian of the family; the arrow indicates the proband. Circles indicate ancestry presented with short stature, primary female family members, and squares male family members; the amenorrhea, and absence of spontaneous number 3 inside the square and circle indicates the numbers of pubertal development brothers and sisters, respectively. The current ages are shown below the circles or squares. The slash denotes a deceased family member. Asterisks indicate the family members who were enrolled in the study, from whom the samples were obtained. Solid circles indicate the two sisters who had a normal female karyotype (46,XX), ovarian dysgenesis, microcephaly (head circumferences of 48.7 cm in family member III-2 when she was 19 years of age and 47.5 cm in family member III-4 when she was 14 years of age), and café au lait spots. The older sister (III-2) also had received a diagnosis of leukemia at 5 years of age. The half-solid square indicates the brother who died from acute promyelocytic leukemia at 13 years of age. The gray circle indicates fetal death. V1 denotes the BRCA2 c.7579delG variant, V2 the BRCA2 c.9693delA variant, and N normal. Panel B is a depiction of the BRCA2 protein. The RAD51- binding domain includes eight repeated motifs called BRC repeats (blue). The DNA-binding domain contains a helical domain (H, green), three oligonucleotide binding folds (OB, purple), and a tower domain (T, orange). The nuclear localization signal (NLS) is near the C-terminal of the protein (red). The red arrow indicates the position of V1 and the blue arrow the position of V2 on the BRCA2 protein. BRCA2 p.V2527X is predicted to lack most of the DNA-binding domain and the NLS. BRCA2 p.S3231fs16*, with a predicted truncation of 171 residues, retains these domains. Panel C shows chromosomal breakage in the peripheral lymphocytes obtained from the proband (III-2 [V1/V2]), the mother (II-1 [V1/N]), and an unrelated control (N/N). Representative chromosomal breaks (Br) are marked by red arrows. Triradial (Tra), quadriradial (Qra), and complex rearrangements (cRa) are marked by dashed red arrows. Panel D shows the effect of increasing exposure to mitomycin C on chromosomal breaks in the cells of the two affected sisters (III-2 and III-4), the mother (II-1), a healthy sister (III-3), and an unrelated control (N/N). Characterization of the Effect of BRCA2 Mutations in the Cells from the Enrolled Persons. Panel A shows the results of the quantitative real-time reverse- transcriptase–polymerase-chain-reaction (RT-PCR) assays of BRCA2 transcripts. The bars represent the mean levels of BRCA2 RNA expression (shown as the percentage of wild-type) for each genotype from six RT-PCR assays performed in each person; T bars indicate the standard deviations. The results show that BRCA2 expression was significantly lower in the cells of the affected sisters (III-2 and III-4 [V1/V2]) than in those of their unaffected relatives (II-1 and III-3 [V1/N] and II-2 and III-5 [V2/N]) and of unrelated controls (N/N). NS denotes not significant. Panel B shows the quantification of Western blots of BRCA2 protein, with the use of the ImageJ image processing program from the National Institutes of Health. Drosophila Model of the BRCA2-Null Genotype. Panel A shows that homozygous deletion of the drosophila orthologue of BRCA2 leads to sterility in female and male flies. Female and male Dmbrca2−/− flies were crossed with wild-type controls to evaluate egg and progeny production. The results are presented as the mean daily number of eggs and progeny produced by each of the crosses indicated below the x axis (as averaged across three to five replicates per cross); T bars indicate the standard deviations. Eggs and progeny were counted daily for 3 days. The mean daily number of eggs laid by Dmbrca2-null female flies (−/− female) crossed with wild-type control male flies (yw male) was lower than the mean daily number of eggs laid by wild-type female flies (yw female) crossed with wild-type male flies (yw male) by a factor of more than 20 (mean daily number, 22 vs. 428, P=0.001). In comparison with the mean daily number of eggs hatched when wild-type female flies were crossed with wild-type male flies (388 of 428 eggs hatched [91%]), only 1 of a total of 214 eggs hatched among the Dmbrca2-null female flies that were crossed with wild-type male flies and 1 of a total of 2116 eggs hatched among the Dmbrca2-null male flies that were crossed with wild-type female flies. Panel B shows the percentages of abnormal ovary and testes phenotypes in Dmbrca2-null flies. Among 62 female flies tested, most ovarioles (69%) were severely dysgenic, 27% were moderately abnormal, and 4% were mildly abnormal. Among 59 male flies tested, nearly all testes (92%) were severely or moderately abnormal; 8% were mildly abnormal. Panel C shows the morphologic features and immunostaining of the drosophila ovaries and testes. The panels on the left for the wild-type control flies show normal, healthy morphologic features of both the ovaries and testes, as compared with the panels on the left for the Dmbrca2-null flies that show shrunken, underdeveloped ovaries and testes. The panels on the right for both the wild-type control flies and the Dmbrca2-null flies show the results of immunostaining. Nuclear DNA is green, actin is blue, and cleaved caspase-3 (indicating apoptosis) is red. We report that loss of BRCA2 function in the two sisters caused XX ovarian dysgenesis, which manifested as the absence of spontaneous pubertal development and as primary amenorrhea. The loss of BRCA2 function led to reduced recruitment of RAD51 to double- stranded breaks in DNA. Recruitment of RAD51 to double-stranded breaks in DNA is necessary both for the repair of breaks that occur during recombination in meiosis and for the repair of DNA in mitotic cells. Complete loss of function of BRCA2 causes early embryonic lethality in humans and in mice. Biallelic damaging mutations in BRCA2 that are not both fully null are compatible with life but result in Fanconi’s anemia D1, which is characterized by chromosomal instability, as reflected by extreme hypersensitivity to cross-linking agents. Most patients with Fanconi’s anemia have developmental abnormalities including microcephaly, short stature, skeletal malformations, abnormal skin pigmentation, early bone marrow failure, and acute myelocytic leukemia and are at higher risk for some solid tumors. However, the patients in our study presented primarily with isolated XX ovarian dysgenesis.

Our results indicate that ovarian development depends on the normal repair of double- stranded DNA breaks that occur at recombination during meiosis. These results highlight an emerging concept of a critical role for DNA repair genes (e.g., MCM-8, MCM-9, and, as we report here, BRCA2) in ovarian development and function. This concept has implications for the clinical evaluation of gonadal dysgenesis. In particular, assays for chromosomal breaks are a useful screening tool in the evaluation of patients who present with ovarian dysgenesis, since they may indicate in some patients that defects in DNA repair are the underlying genetic basis for gonadal dysgenesis and that these patients have a predisposition for cancer that warrants surveillance. Primary Hyperparathyroidism A 57-year-old woman has a fasting serum calcium level of 10.8 mg per deciliter (2.70 mmol per liter; reference range, 9.0 to 10.2 mg per deciliter [2.24 to 2.56 mmol per liter]) detected on routine laboratory testing. On repeat testing a week later, the level is 10.5 mg per deciliter (2.62 mmol per liter). The serum phosphorus level is 2.4 mg per deciliter (0.75 mmol per liter), the estimated glomerular filtration rate (eGFR) more than 60 ml per minute, the total serum protein level 7.0 g per liter, and the albumin level 4.0 g per liter. The parathyroid hormone (PTH) level is 95 pg per milliliter (reference range, 20 to 65). The patient’s last menstrual period occurred at 54 years of age. She has no history of fracture or renal stones and no family history of hypercalcemia. Her mother fractured her hip slipping on ice at 70 years of age. How should this patient’s condition be evaluated and treated? Approximately 80% of patients with primary hyperparathyroidism have a single parathyroid adenoma, 10 to 11% have more than one adenoma, and less than 10% have hyperplasia of all four glands. Parathyroid carcinoma causes less than 1% of cases of hyperparathyroidism. Computed Tomographic (CT) Scan Showing a Parathyroid Adenoma. Shown is a dynamic (4D) CT scan of a left-inferior-pole parathyroid adenoma in a 43- year-old woman with a serum calcium level of more than 13 mg per deciliter (3.24 mmol per liter) and severe pancreatitis. The parathyroid hormone level was 408 pg per milliliter. At surgery, a single 900-mg parathyroid adenoma was removed. Noncontrast coronal CT imaging (Panel A) reveals a hypodense nodule relative to the thyroid gland, inferior to the left thyroid lobe (red arrowhead). The postcontrast coronal CT image (Panel B) shows diffuse enhancement of the left inferior nodule (red arrowhead). A fused CT and sestamibi image (Panel C) shows increased sestamibi uptake in the left lower parathyroid adenoma (red arrowhead).

Parathyroid Hormone Measurements before and after Parathyroid Resection. Shown are the intraoperative parathyroid hormone measurements in a 59-year-old woman with osteoporosis who was found to have a serum calcium level of 10.4 mg per deciliter (2.60 mmol per liter), a serum phosphorus level of 2.4 mg per deciliter (0.75 mmol per liter), a parathyroid hormone level of 122 pg per milliliter, a serum creatinine level of 0.8 mg per deciliter (70 μmol per liter), a 25- hydroxyvitamin D level of 37 ng per milliliter, and a urine calcium level of 241 mg per day (6.0 mmol per day). After resection of the left inferior parathyroid adenoma, the intraoperative parathyroid hormone level did not drop appropriately. Resection of the right inferior parathyroid adenoma resulted in normalization of the intraoperative parathyroid hormone level. Nine days after surgery, the serum calcium level was 8.9 mg per deciliter (2.22 mmol per liter) and the parathyroid hormone level was 15 pg per milliliter. Conclusions and Recommendations The patient described in the vignette appears to have mild hyperparathyroidism, given her mild hypercalcemia, normal eGFR, and absence of complications, but further evaluation is warranted. The maternal history of fragility fracture increases her risk of fracture. She is early in menopause and may have accelerated bone loss because of both estrogen deficiency and parathyroid disease. If a bone densitometric study shows a T score of −2.5 or less at any site, I would recommend surgery. Sonographic evidence of renal stones or a urine calcium level of more than 400 mg per day, particularly if accompanied by hyperoxaluria or hypocitraturia, would prompt a surgical referral. If the patient does not have indications for surgery now or prefers medical management, I would advise a calcium-sufficient diet (1000 mg per day) and use a vitamin D supplement if necessary to maintain her serum 25- hydroxyvitamin D level in the range of 20 to 30 ng per milliliter. I would stress the importance of hydration and encourage regular exercise. If her urine calcium level was higher than 400 mg per day, I would consider using a thiazide. If her bone density was in the osteoporotic range, I would discuss antiresorptive therapy. I would see her annually to reassess her symptoms and biochemical profile and would repeat the renal ultrasound examination if symptoms developed that suggested the presence of a renal stone. Depending on her baseline bone mineral density and whether antiresorptive therapy was initiated, I would repeat the bone densitometric study in 2 years. Aspirin-Exacerbated Respiratory Disease

Salicylic acid is found in an extract prepared from the bark of white willow trees and has been used for thousands of years for the relief of fever and pain.1 In 1897, Felix Hoffmann, a young chemist employed by Friedrich Bayer and Company, acetylated salicylic acid to produce acetylsalicylic acid. By 1899, Bayer had patented the drug, named it “aspirin,” and begun selling it around the world. Consumption skyrocketed, with aspirin then used for controlling pain, fever, headache, arthritis, and other diseases. It was not until 1922, in a case report by Widal et al., that respiratory disease exacerbated by aspirin was first described. After an oral challenge with aspirin, a female volunteer with all the hallmarks of underlying respiratory disease had an asthma attack, profuse rhinorrhea, and urticaria. The same reactions occurred after oral challenges with antipyrine, which had been synthesized in 1883 and was the only other available nonsteroidal antiinflammatory drug (NSAID) at that time. In 1967, Max Samter, an immunologist in the United States who was unaware of the 1922 French report, believed that he had discovered this disease and named it “Samter’s Triad” (nasal polyps, asthma, and sensitivity to aspirin). Mechanisms Underlying Respiratory Reactions to Cyclooxygenase 1 (COX-1) Inhibitors. At baseline, inflammation of the respiratory tract is already ongoing in patients with aspirin- exacerbated respiratory disease (AERD). With COX-1 inhibition by any nonsteroidal antiinflammatory drug (NSAID), the loss of prostaglandin E2 (PGE2) inhibitory control leads to massive release of histamine and generation of cysteinyl leukotrienes by mast cells, an event that is unique to AERD. (Prostaglandin D2 [PGD2] is pharmacologically inhibited with COX-1 inhibition, but the level greatly increases during reactions through mast-cell and eosinophil activation.) COX-1 inhibition does not block this alternative pathway, which continues unchecked. Red arrows represent abnormal baseline conditions in patients with AERD, and blue arrows indicate changes after COX-1 inhibition. The number of arrows indicates the magnitude of change. ASA denotes acetylsalicylic acid, EP2R prostaglandin E2 receptor, 5-HPETE 5- hydroperoxyeicosatetraenoic acid, LT leukotriene

(types A4, C4, D4, and E4), 5-LO 5-lipoxygenase, PG prostaglandin (types G2, H2, I2, and F2), and TXA2 thromboxane A2. Inflammatory Pathways in AERD. Type 2 inflammation has a circular path in patients with AERD (Panel A). Allergens, viral infection, and environmental factors are all capable of initiating epithelial injury and release of alarmins, interleukin- 33, thymic stromal lymphopoietin (TSLP), and interleukin-25. These upstream cytokines have multiple effects focusing on type 2 inflammatory responses. Type 2 innate lymphoid cells (ILC2) and mast cells in AERD both amplify the responses, leading to eosinophilia and potential feed-forward mechanisms. Leukotrienes enhance these pathways and can control ILC2 responses. Platelet–adherent neutrophils (Panel B) further increase the leukotriene burden in AERD. Despite COX-1 inhibition of prostaglandins, a paradoxical oversynthesis of prostaglandin D2 (PGD2) occurs as a result of mast-cell and eosinophil activation through thromboxane (TP) receptors. PGD2 receptors stimulate the recruitment of type 2 helper

T (Th2) cells. Cysteinyl leukotrienes C4 (LTC4) and D4 (LTD4) act on both cysteinyl leukotriene receptor 1 (CysLT1) and cysteinyl leukotriene receptor 2 (CysLT2). Leukotriene E4 (LTE4) has minimal function at CysLT1 and CysLT2 but binds G protein– coupled receptor 99 (GPR99), leading to mucin release and submucosal swelling. CRTH2 denotes chemoattractant receptor-homologous molecule expressed on Th2 cells.

Medical Treatment AERD is treated medically in a stepwise fashion according to established guidelines for the management of asthma and chronic sinusitis. Management usually progresses through the use of controller inhaler medications and leukotriene-modifier drugs, with the possible use of biologic agents as indicated for asthma. The upper airways are similarly treated with topical glucocorticoids, and if this treatment fails, it is necessary to add antihistamines, leukotriene modifiers, and systemic glucocorticoids. Zileuton, an inhibitor of 5-lipoxygenase, merits attention, since it partially blocks the formation of all cysteinyl leukotrienes, including

LTE4, and has proved to be effective in the treatment of AERD. LTE4 would not be markedly affected by the CysLT1 receptor antagonists montelukast, zafirlukast, and pranlukast. Most patients with AERD have difficulty managing airway inflammation and are therefore candidates for aspirin desensitization and daily aspirin therapy. In fact, the only unique treatment for AERD that is currently available is aspirin desensitization.

Aspirin Desensitization and Treatment with Aspirin Drug desensitization, also called induction of drug tolerance, can be used for selected medications. Aspirin desensitization is achieved by starting at low oral doses of aspirin (approximately 40.5 mg) and gradually increasing the dose over a period of 1 to 3 days, during which drug-induced reactions become milder and shorter and then disappear. When the target dose of 325 mg is achieved, any additional doses of aspirin or other COX-1– inhibiting NSAIDs do not induce hypersensitivity reactions. Awareness of AERD continues to be overshadowed by the false assumption that it is a rare, esoteric disease. This misperception is combined with unfounded safety concerns about diagnostic oral aspirin challenges. Clinicians should realize that aspirin desensitization, followed by daily aspirin therapy, is a disease-specific treatment that offers a benefit for the majority of patients with AERD. Now that phenotyping in asthma and sinus disease can guide treatment decisions, AERD is a diagnosis worth considering. 39-Year-Old Man with Epistaxis, Pain and Erythema of the Forearm, and Pancytopenia The patient had been in his usual state of good health until 6 months before admission, when episodes of spontaneous, prolonged epistaxis developed. Two months before admission, the patient noticed spontaneous bruising of the arms and legs. Four days before admission, pain, swelling, and erythema of the dorsal aspect of the distal right forearm developed, without any preceding trauma; the pain was worse with extension of the fourth and fifth fingers. The same day, fevers, chills, and night sweats developed, along with nausea and frontal headache. The patient took naproxen and acetaminophen, and he had relief of symptoms except for the pain, swelling, and erythema of the right forearm. The patient presented to an urgent care center for evaluation. The temperature was 36.8°C, the blood pressure 140/88 mm Hg, the pulse 76 beats per minute, the respiratory rate 20 breaths per minute, and the oxygen saturation 99% while he was breathing ambient air. There was pain in the dorsal aspect of the distal right forearm, with resistance to extension of the wrist and fourth and fifth fingers. There was a resolving ecchymosis on the left medial proximal calf. Laboratory testing reportedly revealed pancytopenia. Ceftriaxone was administered, and the patient was asked to present to an emergency department for further evaluation. The hematology service was consulted. Examination of a peripheral-blood smear revealed evidence of anisocytosis, hypochromia, and a few large platelets and no evidence of blasts or hemolysis. Blood cultures showed no growth. A diagnostic procedure was performed. Imaging Studies. CT of the chest, abdomen, and pelvis was performed after the administration of intravenous and oral contrast material (Panels A and B). There is evidence of mediastinal lymphadenopathy, including enlarged subcarinal, right hilar, and diaphragmatic pericaval (Panel A, arrow) lymph nodes. The spleen is enlarged, measuring up to 18.3 cm (Panel B, arrows). Enlarged retroperitoneal lymph nodes are present, including portacaval (Panel B, arrowhead), superior pancreatic, and aortocaval lymph nodes. A CT scan of the forearm, obtained after the administration of intravenous contrast material (Panel C), shows a low-attenuation fluid collection, measuring up to 3.1 cm, in the extensor compartment (arrow). An ultrasound image of the forearm, obtained on the day after admission (Panel D), again shows the fluid collection, which was subsequently aspirated with the use of ultrasonographic guidance and an 18-gauge needle (arrowheads). Nutritional Deficiency and Toxin-Mediated Disease This patient was born and raised in the United States and had limited recent international travel. He had a normal diet and no known exposures to toxins, either at work or at home. His history appears to be reliable; he reported no clinically significant alcohol or drug use and had been prescribed no medications. Thus, the cause of his pancytopenia is unlikely to be nutritional deficiency or toxin exposure. Infection Infectious agents are known to have a variety of effects on bone marrow function, ranging from bone marrow suppression or failure (seen in HIV infection) to bone marrow infiltration or replacement (seen in fungal or mycobacterial disease). In effect, infection is a frequent cause of pancytopenia in adults. This patient did not report having a recent viral prodrome, and he had negative screening tests for HIV and hepatitis B and C viruses and had no known risk factors for these viruses; therefore, a viral cause is unlikely. He had a negative interferon- gamma release assay for M. tuberculosis and was at low risk for acquisition of invasive fungal disease. In New England, tickborne diseases such as anaplasmosis and ehrlichiosis are associated with leukopenia and thrombocytopenia, features that were seen in this case. However, this patient’s presentation with prolonged epistaxis, easy bruising, and normal results on liver-function tests is not consistent with a diagnosis of tickborne disease. Autoimmune Disorders A variety of mechanisms of autoimmune disease commonly lead to pancytopenia, with possibilities ranging from drug-induced autoimmune disease to systemic lupus erythematosus (SLE) and lupus-associated hemophagocytic lymphohistiocytosis. However, this patient did not meet the criteria that would establish a diagnosis of lupus or have long-standing systemic symptoms that would suggest other autoimmune causes. Could this patient have aplastic anemia? The recurrent epistaxis that had occurred 6 months before presentation and the recent bruising are consistent with this diagnosis. The fever and pain in the right forearm are most consistent with cellulitis and a deeper loculated bacterial infection, with the site of minor skin breakdown probably serving as a portal of entry for bacteria. Clonal Causes of Pancytopenia In a retrospective case series involving adults in the United States who presented with pancytopenia (without a history of receiving cytotoxic chemotherapy), the most common diagnoses were myeloid disorders, with 26% presenting with acute myeloid leukemia and 17% presenting with myelodysplasia. In this patient, the absolute neutrophil count on presentation was 358 per cubic millimeter, a finding consistent with a clonal disease process. Furthermore, lymphadenopathy and splenomegaly are features of several clonal disorders, particularly lymphomas and indolent leukemias. Non-Hodgkin’s Lymphoma This patient presented with subacute symptoms of cytopenia, but he did not have the classic B symptoms (i.e., prolonged fevers, night sweats, and weight loss) that are often associated with clonal disorders. The clinical presentation of non-Hodgkin’s lymphoma varies substantially. Patients with aggressive forms tend to present with B symptoms and an elevated lactate dehydrogenase level, whereas patients with indolent forms (e.g., follicular lymphoma and small lymphocytic lymphoma) may have an insidious presentation with signs that are due to cellular infiltration, such as cytopenia and the slow development of lymphadenopathy or splenomegaly, but without overt B symptoms. Hairy-Cell Leukemia Hairy-cell leukemia is a rare chronic B-cell lymphoproliferative disorder, with only 1000 new cases diagnosed in the United States annually. Affected patients are most commonly middle-aged men who seek medical attention when they have symptoms related to massive splenomegaly or cytopenia. Patients often do not have palpable lymphadenopathy but may present with fatigue, bleeding, or infection due to compromised cell counts. The leukemic cells of hairy-cell leukemia are known to release pathogenic cytokines that cause bone marrow fibrosis and suppression, which are manifested by cytopenia in up to 85% of patients. Could this patient have hairy-cell leukemia? His overall presentation with subacute symptoms, cytopenia, splenomegaly, and infection due to immunocompromise would be consistent with this diagnosis. He also had an absolute monocytopenia, a feature often seen in hairy-cell leukemia. Hairy cells are detected on examination of a peripheral-blood smear in approximately 90% of patients who eventually receive a diagnosis of hairy-cell leukemia, but they are often present in small numbers, and an experienced observer may be needed to identify them. In this patient, no hairy cells were identified on examination of the initial peripheral-blood smear. Examination of the initial peripheral-blood smear revealed pancytopenia with absolute monocytopenia. Of note, although the relative monocyte percentage was normal (7.0%), the absolute monocyte count was low (80.5 per cubic millimeter; reference range, 200 to 1200). At higher magnification, nondysplastic granulocytes and reactive lymphocytes were visible. There was evidence of hypochromia and anisocytosis, but the red cells were otherwise morphologically unremarkable. No atypical lymphoid cells were identified. Specimens of Bone Marrow and Peripheral Blood. Hematoxylin and eosin staining of a biopsy specimen of the bone marrow (Panel A) shows markedly hypercellular marrow with minimal normal trilineage hematopoiesis and a diffuse interstitial infiltrate of atypical lymphoid cells. The atypical lymphoid cells have well-defined cellular borders, abundant pink cytoplasm, and bean-shaped nuclei. Wright–Giemsa staining of a peripheral-blood smear (Panel B) shows very rare circulating medium-sized lymphocytes with pale cytoplasm and irregular, circumferential cytoplasmic projections. On immunohistochemical staining, the atypical lymphoid cells are positive for B- cell markers CD20 and PAX5 (Panels C and D, respectively), as well as CD123 and cyclin D1 (Panels E and F, respectively). On flow cytometry analysis (Panel G), the atypical lymphoid cells (in blue) are brightly positive for CD20 and coexpress the hairy-cell marker CD103. On staining with the use of a BRAF V600E–specific antibody (Panel H), the lymphoid cells are highlighted. The diagnostic armamentarium has taken a great leap forward with the discovery that the BRAF V600E mutation is virtually ubiquitous in patients with hairy-cell leukemia (i.e., present in >97% of patients). In contrast with this patient, up to 25% of patients with hairy-cell leukemia are asymptomatic at the time of presentation, and the diagnosis is made incidentally. Because the disease is indolent, some patients with hairy-cell leukemia can be followed closely without intervention, often for years. In this case, we elected to treat the patient because he had a clinically significant infection in the context of neutropenia. The purine analogues cladribine and pentostatin are first-line chemotherapeutic agents; they are associated with complete response rates of up to 75%, overall response rates of up to 95%, and median relapse-free survival of at least 16 years. The two drugs are equally efficacious as well as highly immunosuppressive and myelosuppressive. In this patient, the fluid collection in the right forearm that was aspirated eventually grew methicillin-susceptible Staphylococcus aureus. The infection was controlled with antibiotic agents, abscess drainage, and white-cell growth factors. Then, cladribine was administered by means of continuous infusion for a single 7-day course, to allow for a shorter duration of treatment; in contrast, pentostatin is administered for up to 6 months. Precautions against the tumor lysis syndrome were not necessary in this patient, since his Ki-67 proliferation index was generally low and thus the tumor lysis syndrome was unlikely to occur. Longevity in elite athletes: the first 4-min milers

Potential adverse consequences of physical overexertion have been periodically debated since the legend of Pheidippides, who was said to have collapsed and died after running 26 miles from Marathon to Athens, Greece, in 490 BC. Concerns about the dangers of extreme physical endurance have extended to modern long distance running (including marathons), rowing, swimming, and cycling. High-sensitivity troponin in the evaluation of patients with suspected acute coronary syndrome: a stepped-wedge, cluster-randomised controlled trial

High-sensitivity cardiac troponin assays permit use of lower thresholds for the diagnosis of myocardial infarction, but whether this improves clinical outcomes is unknown. We aimed to determine whether the introduction of a high-sensitivity cardiac troponin I (hs-cTnI) assay with a sex-specific 99th centile diagnostic threshold would reduce subsequent myocardial infarction or cardiovascular death in patients with suspected acute coronary syndrome.

We evaluated the implementation of an hs-cTnI assay in consecutive patients who had been admitted to the hospitals' emergency departments with suspected acute coronary syndrome. Patients were eligible for inclusion if they presented with suspected acute coronary syndrome and had paired cardiac troponin measurements from the standard care and trial assays. During a validation phase of 6–12 months, results from the hs-cTnI assay were concealed from the attending clinician, and a contemporary cardiac troponin I (cTnI) assay was used to guide care. Hospitals were randomly allocated to early (n=5 hospitals) or late (n=5 hospitals) implementation, in which the high-sensitivity assay and sex-specific 99th centile diagnostic threshold was introduced immediately after the 6-month validation phase or was deferred for a further 6 months. Patients reclassified by the high-sensitivity assay were defined as those with an increased hs-cTnI concentration in whom cTnI concentrations were below the diagnostic threshold on the contemporary assay. The primary outcome was subsequent myocardial infarction or death from cardiovascular causes at 1 year after initial presentation. Schematic of the High-STEACS trial design and linkage of electronic patient record data sources

(A) Diagram illustrating how screening, enrolment, adjudication, and follow-up were done by use of linked routine health-care data in Scotland. The Community Health Index is a population health-care register that includes all individuals resident in Scotland. The Community Health Index number, date and time of presentation, and study inclusion and exclusion criteria were extracted from the TrakCare software application and linked to the ARCHITECT assay platform to identify eligible patients. This number was also used to link all data sources, which are held securely within the NHS safe haven of each Health Board. Eligible patients were assigned a unique study ID and all identifiable data were removed. Anonymised data were transferred to a national analytical platform in the Farr Institute of Health Informatics Research (Edinburgh Bioquarter) for analysis and reporting. (B) Study design, in which sites were separated into early and late implementation designs. ICD-10=International Classification of Diseases, tenth edition. PIS=Prescribing Information System. SIMD=Scottish Index of Multiple Deprivation.

Incidence of myocardial infarction or death from cardiovascular causes at 1 year, stratified by troponin concentration and phase

Data are Kaplan-Meier time-to- event curves. Paired log-rank test results are p=0·047 for no myocardial injury, p=0·131 for those reclassified by the hs- cTnI assay, and p=0·019 for those already identified by the contemporary cTnI assay. hs- cTnI=high-sensitivity cardiac troponin I. cTnI=contemporary cardiac troponin I. Primary and secondary outcomes in patients reclassified by the high-sensitivity cardiac troponin I assay before and after implementation.

Data are the number and percentage of patients with each outcome in the validation phase and implementation phase and the odds ratio for implementation versus validation. The intra-cluster correlation coefficient from the generalised linear mixed effects model was 0.

Non-invasive detection of coronary inflammation using computed tomography and prediction of residual cardiovascular risk (the CRISP CT study): a post-hoc analysis of prospective outcome data Coronary artery inflammation inhibits adipogenesis in adjacent perivascular fat. A novel imaging biomarker—the perivascular fat attenuation index (FAI)—captures coronary inflammation by mapping spatial changes of perivascular fat attenuation on coronary computed tomography angiography (CTA). However, the ability of the perivascular FAI to predict clinical outcomes is unknown. In the Cardiovascular RISk Prediction using Computed Tomography (CRISP-CT) study, we did a post-hoc analysis of outcome data gathered prospectively from two independent cohorts of consecutive patients undergoing coronary CTA in Erlangen, Germany (derivation cohort) and Cleveland, OH, USA (validation cohort). Perivascular fat attenuation mapping was done around the three major coronary arteries—the proximal right coronary artery, the left anterior descending artery, and the left circumflex artery. We assessed the prognostic value of perivascular fat attenuation mapping for all-cause and cardiac mortality in Cox regression models, adjusted for age, sex, cardiovascular risk factors, tube voltage, modified Duke coronary artery disease index, and number of coronary CTA-derived high-risk plaque features.

Perivascular FAI analysis around epicardial coronary vessels

(A) Perivascular FAI phenotyping of the proximal segments of all three major epicardial coronary vessels, with corresponding FAI colour maps. (B) Example of perivascular FAI phenotyping around the proximal RCA. Perivascular fat was defined as fat within a radial distance equal to the diameter (d) of the vessel. FAI=fat attenuation index. HU=Hounsfield unit. LAD=left anterior descending artery. LCx=left circumflex artery. RCA=right coronary artery. Kaplan-Meier curves of all-cause mortality and cardiac mortality with high versus low perivascular FAI High values for the perivascular FAI were ≥–70·1 HU and low perivascular FAI values were <–70·1 HU. Mortality curves show risk of all-cause mortality in the derivation cohort (A) and validation cohort (C) and cardiac mortality in the derivation cohort (B) and validation cohort (D). HRs are adjusted for age, sex, hypertension, hypercholesterolaemia, diabetes mellitus, smoker status, epicardial adipose tissue volume, tube voltage, extent of coronary artery disease (Duke coronary artery disease index), and number of high-risk plaque features. FAI=fat attenuation index. HR=hazard ratio. HU=Hounsfield unit. Incremental prognostic value of the perivascular FAI beyond current coronary CTA-based risk stratification

Comparison of time-dependent ROC curves (at 6 years) and respective AUC of two nested models for discrimination of cardiac mortality in the (A) derivation and (B) validation cohorts. Model 1 represents the current state-of-the-art in risk assessment and consisted of age, sex, risk factors (hypertension, hypercholesterolaemia, diabetes mellitus, smoker status, epicardial adipose tissue volume), modified Duke coronary artery disease index, and number of high-risk plaque features on coronary CTA. Model 2 incorporates perivascular FAI values (≥–70·1 HU vs <–70·1 HU) into model 1. AUC=area under the curve. CTA=computed tomography angiography. FAI=fat attenuation index. HU=Hounsfield unit. ROC=receiver operating characteristic. Subgroup analysis of the prognostic value of the perivascular FAI in patients with and without coronary artery disease

Plots show adjusted HRs for high versus low perivascular FAI values (≥–70·1 HU vs <–70·1 HU) as a prognostic biomarker for (A) all-cause mortality and (B) cardiac mortality in different patient subgroups, with or without cardiac CTA-derived features of coronary artery disease. HRs are adjusted for age, sex, and epicardial adipose tissue volume. CTA=computed tomography angiography. FAI=fat attenuation index. HU=Hounsfield unit. HR=hazard ratio.

Ticagrelor plus aspirin for 1 month, followed by ticagrelor monotherapy for 23 months vs aspirin plus clopidogrel or ticagrelor for 12 months, followed by aspirin monotherapy for 12 months after implantation of a drug-eluting stent: a multicentre, open-label, randomised superiority trial

We hypothesised that ticagrelor, in combination with aspirin for 1 month, followed by ticagrelor alone, improves outcomes after percutaneous coronary intervention compared with standard antiplatelet regimens. GLOBAL LEADERS was a randomised, open-label superiority trial at 130 sites in 18 countries. Patients undergoing percutaneous coronary intervention with a biolimus A9-eluting stent for stable coronary artery disease or acute coronary syndromes were randomly assigned (1:1) to 75–100 mg aspirin daily plus 90 mg ticagrelor twice daily for 1 month, followed by 23 months of ticagrelor monotherapy, or standard dual antiplatelet therapy with 75–100 mg aspirin daily plus either 75 mg clopidogrel daily (for patients with stable coronary artery disease) or 90 mg ticagrelor twice daily (for patients with acute coronary syndromes) for 12 months, followed by aspirin monotherapy for 12 months. Randomisation was concealed, stratified by centre and clinical presentation (stable coronary artery disease vs acute coronary syndrome), and blocked, with randomly varied block sizes of two and four. The primary endpoint at 2 years was a composite of all-cause mortality or non-fatal centrally adjudicated new Q-wave myocardial infarction as assessed by a core lab in a blinded manner. The key secondary safety endpoint was site-reported bleeding assessed according to the Bleeding Academic Research Consortium criteria (grade 3 or 5).

Cumulative incidence of all-cause mortality at 2 years Subgroup analyses of all-cause mortality or non-fatal centrally adjudicated new Q-wave myocardial infarction at 2 years Type of reference treatment strategy was a post-hoc criterion for subgroup analysis. Rate ratios and 95% CIs were estimated with the Mantel-Cox method with two-sided p-values from the log-rank test. All events were 2 censored beyond 730 days. pinteraction values were calculated with approximate χ tests for unequal rate ratios in the subgroups. Assumed no risk in case of missing data: diabetes (n=11), renal failure (n=85), peripheral vascular disease (n=146).

Sir William Boog Leishman (* 6. November 1865 in Glasgow; † 2. Juni 1926 ebenda) war ein schottischer Militärarzt, Tropenarzt und Pathologe. William Boog Leishman, Sohn des schottischen Gynäkologen William Leishman (1834–1894), besuchte die Westminster School in Glasgow und studierte anschließend an der Universität Glasgow. Nach dem Abschluss trat er in den Medizinischen Dienst der Armee ein. Er wurde in Indien eingesetzt und untersuchte dort Typhus und die später nach ihm benannte Leishmaniose. Er kehrte 1897 nach Großbritannien zurück und wurde 1900 zum Assistenzprofessor für Pathologie an der Army Medical School ernannt. Er forschte besonders auf dem Gebiet der Humanparasiten und entwickelte die nach ihm benannte Leishman-Färbung zum Sir William Boog Leishman Nachweis von Malariaerregern und anderen Parasiten im Blut. Gleichzeitig mit Charles Donovan beschrieb er 1901 Leishmania donovani, den nach beiden benannten Erreger der Leishmaniose, und veröffentlichte die Ergebnisse 1903. Zuvor hatte bereits im Jahr 1898 der russische Militärarzt Peter Borowski den Erreger der Orientbeule („Leishmania tropicalis“) entdeckt. Leishman war Mitglied und langjähriger Präsident der Royal Society of Tropical Medicine and Hygiene. Leishmans Name bekam durch Ronald Ross einen Platz in der Geschichte der Parasitologie, der die von Leishman identifizierten Erreger „Leishmania“ Charles Donovan genannt hatte. Charles Donovan MD (19 September 1863 – 29 October 1951) was an Irish medical officer in the Indian Medical Service. He is best remembered for his discoveries of Leishmania donovani as the causative agent of visceral leishmaniasis, and Klebsiella granulomatis as that of donovanosis. The son of a judge in India, he was born in Calcutta and completed his primary education in India, and continued secondary school in Cork City, Ireland. He graduated in medicine from Trinity College, Dublin and joined the Indian Medical Service. He participated in British expeditions to Mandalay in Burma, Royapuram and Mangalore in India, Afghanistan, and finally Madras (now Chennai), where he spent the rest of his service. He was professor at Madras Medical College from 1898 until his retirement in 1919. A fatal infectious disease called visceral leishmanis (kala-azar as it was called in Hindi) was widespread in India just after the Indian Rebellion of 1857. The first epidemic was reported in 1870 by British medical officers from Assam. In 1900 William Boog Leishman first discovered the protozoan parasite from an English soldier who was stationed at Dum Dum, West Bengal, and died at the Army Medical School in Netley, England. But he mistook the parasite to be degenerate trypanosomes, already known protozoan parasites in Africa and South America. In 1903 Leishman published his discovery in the British Medical Journal, which appeared on 11 May. It was titled "On the possibility of the occurrence of trypanosomiasis in India." On 17 June 1903 Donovan found the parasites (by then known as "Leishman bodies") from the spleen tissue and in the blood of an infected young boy who was admitted to the Government General Hospital. Donovan identified the Leishman bodies as the causative agents of kala-azar. At the time the disease was believed to be a quinine-resistant malaria. He wrote a commentary of his discovery in relation to that of Leishman in the same journal (using the same title as Leishman's), which appeared on 11 July 1903. Soon a controversy arose as to whom such monumental discovery should be credited. Donovan sent some of his slides to Ronald Ross, who was in Liverpool, and to Alphonse Laveran at the Pasteur Institute in Paris. Laveran and his colleague Félix Mesnil identified the protozoan (and yet wrongly) to be members of Piroplasmida, and gave the scientific name Piroplasma donovanii. It was Ross who resolved the conflict of priority in the discovery and correctly identified the species as member of the novel genus Leishmania. He gave the popular name "Leishman- Donovan bodies", and subsequently the valid binomial Leishmania donovani, thereby equally crediting the two rivals. But the reconciliation was not embraced by Londoners, who still wanted to remove Donovan's name. Donovan's continued works on the biology of L. donovani however established him as the leading authority on kala-azar. Leishmaniasis

Summary Leishmaniasis is a poverty-related disease with two main clinical forms: visceral leishmaniasis Leishmania life cycle and cutaneous leishmaniasis. An estimated 0·7–1 million new cases of leishmaniasis per year are reported from nearly 100 endemic countries. The number of reported visceral leishmaniasis cases has decreased substantially in the past decade as a result of better access to diagnosis and treatment and more intense vector control within an elimination initiative in Asia, although natural cycles in transmission intensity might play a role. In east Africa however, the case numbers of this fatal disease continue to be sustained. Increased conflict in endemic areas of cutaneous leishmaniasis and forced displacement has resulted in a surge in these endemic areas as well as clinics across the world. WHO lists leishmaniasis as one of the neglected tropical diseases for which the development of new treatments is a priority. Major evidence gaps remain, and new tools are needed before leishmaniasis can be definitively controlled.

Status of endemicity of visceral leishmaniasis worldwide in 2016 Cyclical epidemiological patterns of visceral leishmaniasis in south Asia Recrudescence of Old World cutaneous leishmaniasis in conflict areas of the Middle East

A patient with a severely debilitating lesion due to post- kala-azar dermal leishmaniasis A female patient (A) and child (B) with erythematous maculopapular rash and a patient with hypopigmented macula (C) due to post-kala-azar dermal leishmaniasis Severe oronasal mucocutaneous leishmaniasis in a 73-year-old German man with a history of travel to Panama.

A male patient with cutaneous leishmaniasis contracted in Bolivia. An infected macrophage with several amastigotes PKDL=post-kala-azar dermal leishmaniasis. VL=visceral leishmaniasis. *As soon as an effective and safe regimen is identified. Reproduced from WHO, by permission of the World Health Organization. Melanoma Summary Cutaneous melanoma causes 55 500 deaths annually. The incidence and mortality rates of the disease differ widely across the globe depending on access to early detection and primary care. Once melanoma has spread, this type of cancer rapidly becomes life-threatening. For more than 40 years, few treatment options were available, and clinical trials during that time were all unsuccessful. Over the past 10 years, increased biological understanding and access to innovative therapeutic substances have transformed advanced melanoma into a new oncological model for treating solid cancers. Treatments that target B-Raf proto-oncogene serine/threonine-kinase (BRAF)V600 (Val600) mutations using selected BRAF inhibitors combined with mitogen-activated protein kinase inhibitors have significantly improved response and overall survival. Furthermore, advanced cutaneous melanoma has developed into a prototype for testing checkpoint-modulating agents, which has increased hope for long-term tumour containment and a potential cure. These expectations have been sustained by clinical success with targeted agents and antibodies that block programmed cell-death protein 1 in locoregional disease, which induces prolongation of relapse- free, distant-metastasis-free, and overall survival times.

Worldwide, about 232 100 (1·7%) cases of all newly diagnosed primary malignant cancers (excluding non-melanoma skin cancer) are cases of cutaneous melanoma, and about 55 500 cancer deaths (0·7% of all cancer deaths) are due to cutaneous melanoma annually. The incidence and mortality rates of cutaneous melanoma differ widely by country. In 2012, the age-standardised (world standard population) incidence of cutaneous melanoma ranged from 0·2 per 100 000 person- years in southeast Asia to 7·7 per 100 000 person-years in the Americas. Incidences were highest in New Zealand (35·8 per 100 000 person-years) and Australia (34·9 per 100 000 person-years). Estimated age-standardised worldwide incidence of cutaneous melanoma in both men and women in 2012 Trends in age-standardised incidence of cutaneous melanoma for men and women in selected countries, 1970–2007

All rates are age-standardised (world standard population) and expressed as the number of cases per 100 000 person-years. Selected key signalling pathways and therapeutic targets in melanoma

(A) MAPK, PI3K-AKT signalling, and cell-cycle regulation under normal conditions permits balanced control of basic cell functions. (B) In melanomas, genetic alterations lead to constitutive pathway activation with loss of cellular homeostasis. (C) The PD- 1-PD-L1 immune checkpoint is primarily regulated by interferon-γ signalling. AKT=protein kinase B. BRAFV600E=B-Raf proto-oncogene serine/threonine- kinase (Val600Glu). CDK=cyclin-dependent kinase. ERK=extracellular signal-regulated kinase. IFNR= interferon receptor. IFNγ=interferon γ. MAPK=mitogen- activated protein kinase. MDM2=mouse double-minute- 2 homologue. MEK=mitogen-activated protein kinase kinase. NF1=neurofibromin 1. NRAS=NRAS proto- oncogene GTPase. P=phosphorylated. PD- 1=programmed cell-death protein 1. PDK1=phosphoinositide-dependent protein kinase. PD- L1=programmed cell-death ligand 1. PIP=phosphatidylinositol phosphate. PI3K=phosphoinositide-3 kinase. pRB=retinoblastoma protein. PTEN=phosphate and tensin homologue. RTK=receptor tyrosine kinase. STAT1=signal transducer and activator of transcription 1. Distribution of activating mutations in different melanoma subtypes

Genetic classification with distribution of tumour types according to the activating gene mutation. Mutations with a frequency of more than 5% are shown.

Frequencies are as reported for cutaneous, acral, mucosal, conjunctival, and uveal melanoma. BRAF=B-Raf proto-oncogene serine/threonine kinase.

Conclusion Prevention, early detection, and the arrival of effective adjuvant treatment strategies in stage-3 melanoma will increase overall survival and cure rates for patients with melanoma. Using PD-1- based treatment algorithms and targeted agents in BRAFv600-mutant melanoma, 5-year overall survival rates for metastatic melanoma have increased substantially from less than 10% to up to 40–50% today in countries that have access to these innovations. Patients with high tumour burden, brain metastasis, and elevated lactate dehydrogenase still have a poor prognosis (3-year survival <10%). There is considerable interest in combining active agents independent of their mode of action. One strategy is combining MEK-inhibitors with or without BRAF-inhibitors and checkpoint inhibitors (PD-1-blocking or PD-L1-blocking antibodies) in clinical phase-3 registration studies. Another strategy is to focus on applying PD-1 antibodies as a standard of care and adding other immune-modulating or microenvironment-modulating agents such as LAG3 antibodies, which are also being tested in phase 3 studies. Particularly with checkpoint inhibition, the optimal duration of treatment is unknown in the adjuvant and metastatic setting. Furthermore, numerous clinical trials are investigating other molecules usually with a standard of care of PD-1 antibodies or BRAF- MEK inhibition. Additionally, further questions include whether a full combination is always needed as a first-line treatment (with all its inherent toxicity) or whether giving one drug after the other (ie, the sequencing approach) could lead to a comparable overall survival. Several main challenges to treating the metastatic stage remain, which include establishing the most reliable study endpoint (median PFS, median overall survival, or PFS or overall survival at defined landmarks) to judge whether relevant progress has been made after initial release of clinical study results leading to a changing standard of care. Lastly, developing treatment options for patients who do not initially respond to systemic therapy will be crucial to increase the number of long-term survivors.

A 40-year-old woman presented to our hospital with a 4-year history of recurrent central chest pain. The patient had no medical history of diabetes, hypertension, hypercholesterolaemia or hypothyroidism. She did, however, give a history of having a prolonged fever for about 3 months accompanied by arthralgia at the age of 13 years. She said that at the time she had extensive investigations for infections and possible malignancies—but the fever resolved gradually without any cause being identified. She said that she had had no further problems until the current complaint began 4 years ago. On clinical examination, her blood pressure was 130/90 mm Hg in both upper limbs, pulses were easily palpable, and there were no bruits or murmurs heard on auscultation. A chest x-ray showed calcification of the wall of the aortic arch and descending thoracic aorta, with narrowing at the level of the diaphragmatic hiatus. Full blood count, erythrocyte sedimentation rate, C-reactive protein, lipid profile, and parathyroid hormone levels were normal. MRI angiograms showed narrowing of the aorta in the post-subclavian area, in the descending thoracic aorta at the level of the diaphragm, and at the level just above the origin of the left renal artery. CT angiogram showed extensive calcification.. Taken together these findings led us to making a diagnosis of aorta arteritis type III with active disease. Takayasu arteritis or aorto- arteritis is a large vessel vasculitis of the aorta and its branches. The disease may manifest itself with only non-specific features like fever, myalgia, arthritis, and malaise during the acute phase, which can last for several months. In the chronic phase, in the absence of clinical features secondary to vessel occlusion or ischaemia, the diagnosis maybe further delayed. However, disease activity may persist in the aortic wall despite the patient being asymptomatic and all inflammatory markers remaining within normal limits. A high index of suspicion is required to make the diagnosis during the acute phase, and regular monitoring is necessary to avoid serious long-term complications. The disease takes its name from Mikito Takayasu, who described the first case in 1908 at the Annual Meeting of the Japan Ophthalmology Society.