A 30-year-old man presented with a 15-month history of intermittent discomfort in the right upper quadrant of the abdomen. He lived in a rural area of Morocco and had occasional contact with dogs. The physical examination revealed hepatomegaly with a palpable hepatic mass. Laboratory tests showed a normal white- cell count and a normal absolute eosinophil count. Ultrasonography and computed tomography of the abdomen revealed a large cyst in the right lobe of the liver. What is the diagnosis?

Primary Hepatic Carcinoma

Autoimmune Hepatitis

Primary Biliary Cholangitis

Amebiasis

Cystic Echinococcosis The correct answer is cystic echinococcosis. Dogs are the definitive host for the Echinococcus granulosus tapeworm. The infection is transmitted when eggs shed in their stool are ingested by humans or other animals. Die Amöbenruhr (Amöbiasis) ist eine Infektion des Darmes mit dem 1883 von Stephanos Kartulis entdeckten Erreger Entamoeba histolytica. Sie wird von einer Amöbe (Wechseltierchen) der Art Entamoeba histolytica verursacht. Die Krankheitserreger leben im Nahrungsbrei des menschlichen Dickdarms und vermehren sich ungeschlechtlich durch Zellteilung. Als sehr widerstandsfähige Dauerformen kann der Erreger Zysten bilden und in dieser Form im Dickdarm verbleiben – unter Umständen jahrelang ohne jegliche Krankheitsanzeichen zu verursachen – und wird auch mit dem Stuhl ausgeschieden („Minutaform“). Der Infizierte ist also gleichzeitig Überträger. Die ausgeschiedene Dauerform kann in der Außenwelt monatelang infektiös bleiben. Aus noch unbekannten Gründen können sich diese Erreger verändern, man kann dann eine veränderte DNA und ein verändertes Enzymmuster beobachten. Durch verschiedene Pathogenitätsfaktoren der „Magnaform“ (pathogene Form abzugrenzen von der Minutaform, die nicht zum Bild der Amöbenruhr führt), Amobaphore, porenbildende Enzyme sowie Zysteinproteasen, die die extrazelluläre Matrix des Colons zersetzen, kommt es zu sogenannten geschwulstartigen Amöbom. Dies führt zum Vollbild der Amöbenruhr. Amöbenleberabszeß Typisch für den Amöbenleberabszeß sind akut auftretende, zunächst dumpfe, dann heftige Schmerzen im rechten Oberbauch und Fieber. Es handelt sich um ein akutes, bedrohliches Krankheitsbild mit Abgeschlagenheit und schwerem Krankheitsgefühl, seltener entwickelt sich die Symptomatik schleichend. Die Schmerzen im rechten Oberbauch können in den Rücken und zur rechten Schulter und Skapula ausstrahlen, die Schmerzen sind manchmal atemabhängig. In anderen Fällen können Bauchschmerzen mit Abwehrspannung vorhanden sein, gelegentlich kann der Amöbenleberabszeß als akutes Abdomen imponieren. Als Echinokokkose bezeichnet man in der Human- und Veterinärmedizin verschiedene durch die Infektion mit einem Bandwurm der Gattung Echinococcus hervorgerufene Erkrankungen. Im Hauptwirt, verschiedenen Raubtieren, leben die Erreger als Darmparasiten, wobei sie dem Tier selbst nur geringfügig schaden, so dass es zu einer hohen Wurmlast kommen kann. Im Zwischenwirt kommt es zur Bildung von Hydatiden durch das Finnenstadium, die das Tier stark schwächen, so dass es bald erbeutet wird oder der Infektion erliegt. Echinokokken sind in verschiedenen Arten weltweit verbreitet. Echinokokkose bezeichnet folgende Erkrankungen: Die Übertragung des Hundebandwurms erfolgt meist per Kontaktinfektion bzw. Schmierinfektion vom Hundekot, dem Fell oder der Schnauze über die danach kontaminierten (mit Erregeranhaftungen versehenen) Hände mit dem Mund. Auch indirekte Ansteckungen sind möglich, zum Beispiel durch Nahrungsmittel oder Trinkwasser, die mit Echinococcus-Eiern verunreinigt sind. Die Erkrankung kann hauptsächlich mit bildgebenden Verfahren wie Sonographie, Röntgen, und Computertomographie (CT) sowie Magnetresonanztomographie (MRT) nachgewiesen werden, die mit serologischen Methoden (IFT, PHA) kombiniert werden sollten. Eine serologische Unterscheidung von E. granulosus und E. multilocularis (Fuchsbandwurm) ist mittels ELISA möglich. Zusätzlich sind Kreuzreaktionen auch mit anderen Bandwürmern zur eindeutigen Erregerbestimmung möglich und angezeigt. Multiple hydatid cysts in the liver are a very rare occurrence in childhood. We present a similar case in a nine-year-old girl, a resident in a rural community, who presented with two hydatid cysts in her liver. The cysts were operated upon by a pediatric surgeon. The laboratory findings of this patient showed peripheral blood eosinophilia, elevated white blood cells, and liver enzymes. The serology was positive. The ultrasonography showed cystic masses in the liver, and the diagnosis of hydatid cysts was eventually confirmed by computed tomography (CT) of the abdomen. In the early ‘90s, the American Pain Society opined that there was a national epidemic of untreated pain in our nation’s hospitals and announced that pain should be classified as the fifth vital sign. This assertion is riddled with many problems. Vital signs are clinical measurements, specifically: pulse rate, temperature, respiration rate and blood pressure, that all indicate the state of a patient's essential body functions.

These clinical measures are very objective in character and include an assortment of relevant numerical values. Pain is a subjective feeling that is impossible to accurately and consistently quantify across patient populations. Therefore, in order for providers to assess pain as a vital sign, they must ascribe a numerical value for it, such as zero to ten based on the Universal Numeric Pain Scale.

As a result of equating pain as a vital sign, medical practitioners must come up with a reliable and effective treatment if and when a patient subjectively rates their pain high on the scale. In 1998, the Federation of American Medical Boards issued a policy reassuring physicians that “in the course of treatment,” large doses of opioids were acceptable. In 2001, the Joint Commission mandated that hospitals across the country assess pain on each patient they treat. Oxycodon (auch Dihydroxycodeinon) ist ein stark wirkendes Opioid der Stufe III im WHO-Stufenschema (Klassifizierung der Schmerztherapie), das als Schmerzmittel bei starken bis sehr starken Schmerzen angewendet wird. Unter dem neuen Markennamen Oxygesic wurde es 2003 vom Hersteller Mundipharma wieder auf den deutschen Markt gebracht. Seit 2007 ist es als Generikum erhältlich. 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, wurde im Jahr 2007 zu 634,5 Mio. US-Dollar Strafe verurteilt, weil er in der Packungsbeilage nicht Bekannter Eukodal (iv.) Patient ausreichend gekennzeichnet hatte, dass Oxycodon wie andere Opioide ein hohes Abhängigkeitspotenzial besitzt. Buprenorphin ist ein stark wirksames Schmerzmittel (Analgetikum) aus der Gruppe der Opioide, das zur Behandlung ausgeprägter Schmerzen eingesetzt wird. Es gilt im höheren Alter aufgrund seines guten Sicherheitsprofils als Mittel der ersten Wahl zur Behandlung starker chronischer Schmerzen. Darüber hinaus wird Buprenorphin hochdosiert seit circa Mitte der 1990er Jahre als Substitutionsmittel in der Therapie einer Abhängigkeit von Opioiden verwendet, 2006 wurde es für diese Anwendung in die Liste der unentbehrlichen Arzneimittel der Weltgesundheitsorganisation aufgenommen.

Methadon ist ein vollsynthetisch hergestelltes Opioid mit starker schmerzstillender Wirksamkeit. Methadon ist reiner Agonist am μ-Opioid-Rezeptor. Es hat als Heroin- Ersatzstoff im Rahmen von Substitutionsprogrammen seine Wirksamkeit bewiesen[5] und wurde deshalb 2005 von der Weltgesundheitsorganisation (WHO) in die Liste der unentbehrlichen Arzneimittel der Weltgesundheitsorganisation aufgenommen. Die später Methadon benannte Substanz wurde 1937 von Max Bockmühl und Gustav Ehrhart, zwei Mitarbeitern der zum I.G. Farben-Konzern gehörenden Hoechster Farbwerke, mit der Synthesenummer VA 10820 entwickelt und 1938 zum Patent angemeldet. Seit den 1960er Jahren wird Methadon (zuerst in den USA) als Substitutionsmittel bei Heroinabhängigkeit eingesetzt, wobei in den ersten Jahren ausschließlich mit sehr hohen Dosen in hochstrukturierten Programmen mit dem Ziel einer Dauersubstitution gearbeitet wurde. Primary Care and the Opioid-Overdose Crisis — Buprenorphine Myths and Realities Despite widespread awareness of the opioid-overdose crisis, the epidemic continues to worsen. In 2016, there were 42,249 opioid-overdose deaths in the United States, a 28% increase from the previous year. According to the National Center for Health Statistics, life expectancy in the United States dropped in 2016 for the second consecutive year, partly because of an increase in deaths from unintentional injuries, including overdoses. It was the first 2-year decline since the 1960s. How can we be making so little progress? We believe there’s a realistic, scalable solution for reaching the millions of Americans with opioid use disorder: mobilizing the primary care physician (PCP) workforce to offer office-based addiction treatment with Each point represents the percentage change in buprenorphine, as other countries have done. As of absolute volume of buprenorphine or methadone 2017, according to the Kaiser Family Foundation, there dispensed from all sources in the United States were more than 320,000 PCPs, plus a broad workforce (including retail pharmacies, hospitals, and outpatient of nurse practitioners and physician assistants, treating methadone treatment facilities) as compared with the prior year, measured in grams dispensed. The U.S. adults. In contrast, there are just over 3000 earliest year with data available for buprenorphine diplomates of the American Board of Addiction was 2005, so 2006 is the first year we could estimate Medicine, and only 16% of 52,000 active psychiatrists growth. Because of data irregularities for methadone had a waiver to prescribe buprenorphine in 2015 in 2005, we began tracking methadone growth (moreover, 60% of U.S. counties have no starting with 2006–2007. psychiatrists).3 Training enough addiction medicine or psychiatric specialists would take years, and most methadone treatment programs are already operating at 80% of capacity or greater

The first step toward debunking this myth would be to scale back these federal regulations. Training in appropriate buprenorphine treatment optimizes outcomes and minimizes risks, but such training could be incorporated into existing medical education. All physicians could be trained during medical school and residency, so that both PCPs and other specialists would be equipped to offer this treatment — and, more generally, would be comfortable in caring for patients with opioid use disorder.

The second myth is that buprenorphine is simply a “replacement” and that patients become “addicted” to it — a belief still held by some physicians. But addiction is defined not by physiological dependence but by compulsive use of a drug despite harm. If relying on a daily medication to maintain health were addiction, then most patients with chronic health conditions such as diabetes or asthma would be considered addicted.

A closely related myth is that abstinence-based treatment, usually implying short-term detoxification and rehabilitation, is more effective than medication for addiction treatment. This belief underpins widespread advocacy for more substance use treatment “beds” as a key solution for the overdose crisis. But whereas there’s a strong evidence base for buprenorphine and methadone treatment, no study has shown that detoxification or 30-day rehabilitation programs are effective at treating opioid use disorder. Moving Addiction Care to the Mainstream — Improving the Quality of Buprenorphine Treatment More than 40,000 Americans died from opioid overdoses in 2016 — more than the number killed in motor vehicle accidents. The stunning increase in overdose deaths since the 1990s has revealed a pervasive lack of capability to meet the need for treatment in the 2.1 million Americans who have an opioid use disorder. Since less than one fifth of people with opioid use disorder receive addiction treatment,1 recent national initiatives have understandably focused on increasing access to care, and especially access to medications, for addiction treatment. Even when patients do obtain treatment, however, they often experience care as fragmented and difficult to navigate. These challenges exist worldwide but are particularly acute in the United States, given the magnitude of opioid-related injury and death rates in this country and the historical marginalization and underfunding of addiction care. Payers and health systems can help move treatment to the mainstream, and increase the proportion of patients who recover, by expanding the pool of clinicians who treat opioid use disorder, improving measurement of treatment quality, and linking payment to outcomes. Expanding buprenorphine provision could have population-wide benefits, but as currently delivered, this treatment is not fully living up to its promise.

Buprenorphine Treatment Duration and Coprescribing with Opioid Analgesics among 10 Patients Randomly Selected from a Multistate Database. Methadone in Primary Care — One Small Step for Congress, One Giant Leap for Addiction Treatment

The opioid-overdose epidemic has had a devastating impact throughout the United States and currently claims an average of 115 lives a day. Federal, state, and local public health officials, health care agencies, and community partners are working hard to stem the tide of deaths. Opioid use disorder, the major driver of overdose deaths, is a complex chronic medical condition that can be successfully treated — yet treatment is out of reach for many people. One of the oldest and most effective of such medications, methadone, is available for prescription in primary care clinics in Great Britain, Canada, and Australia, but it is not approved for the treatment of opioid use disorder in primary care settings in the United States.

By the 1970s, a system of methadone delivery had been developed in the United States that requires patients to visit a designated clinic site that is organizationally and often physically separate from the general medical care system. Such “methadone clinics” provide specialized, highly structured care. Medication is typically administered daily under observation, and patients periodically take urine drug tests, which can distinguish methadone from substances of abuse, and receive counseling.

The last act of Congress that expanded access to effective medications for opioid use disorder in primary care, the Drug Addiction Treatment Act of 2000, enabled buprenorphine to become available to thousands of patients in the United States. Expanding access to methadone in primary care will require more than legislation. Transthyretin ist ein spezialisiertes Transportprotein, das bei sämtlichen bekannten Wirbeltieren vorkommt. Es ist auf den Transport von Schilddrüsenhormonen im Serum spezialisiert. Seine Bildung findet vorwiegend in der Leber und dem Plexus choroideus statt. Bei Transthyretin handelt sich um ein Polypeptid, welches sich aus 127 Aminosäuren zusammensetzt. Strukturell stellt Transthyretin ein Homotetramer dar. In der Serumelektrophorese erscheint das Transthyretin vor dem Albuminpeak, daher der alternative Name Präalbumin. Die molare Masse des Transportproteins beträgt rund 55 kDa. Die zentrale biologische Bedeutung von Transthyretin ist der Transport von Thyroxin sowie, durch Komplexbildung mit Retinol- bindendem Protein, auch von Retinol. Transthyretin wird bei Entzündungsreaktionen reduziert. Es ist somit ein Anti-Akute-Phase-Protein. Liegt in dem für Transthyretin kodierenden Gen eine Mutation vor, so besteht ein chronischer Mangel des Transportproteins. Folge sind nicht selten Störungen wie die Amyloidose (meistens Typ 1). Des Weiteren scheint Transthyretin im fortgeschrittenen Alter beim Menschen für die Entstehung und Aufrechterhaltung der ATTR-Amyloidose (senile Amyloidose) verantwortlich zu sein. Eine andere, seltene genetische Variante führt zu einer erhöhten Affinität von Transthyretin und Thyroxin. Dies wird als dystransthyretinämische Hyperthyroxinämie bezeichnet, da der Spiegel von Gesamtthyroxin im Blut erhöht ist. Freies Thyroxin ist dabei normal und die Patienten sind euthyreot. Transthyretin-Amyloidose Bei der familiären, autosomal-dominant vererbten Amyloidose entsteht das Amyloid aufgrund struktureller Veränderungen des Eiweißes infolge einer Schädigung des Erbguts. Am häufigsten liegen Veränderungen des Bluteiweißes Transthyretin vor. Die Transthyretin-Amyloidose ist eine Erkrankung des Erwachsenenalters mit begrenzter bzw. sehr invasiver Behandlungsmöglichkeit. Transthyretin dient im Blut als Transporteiweiß für das Schilddrüsenhormon (Thyroxin) und wird überwiegend in der Leber gebildet. Es besteht aus vier strukturellen Einzelbausteinen und weist zwei Bindungsstellen für Thyroxin auf. Durch die Bindung von Thyroxin wird diese Konformation stabilisiert. Bereits in der unveränderten Form besitzt Transthyretin eine Tendenz zur Ablagerung als Amyloid im Gewebe. Klinisch zeigt sich dieses in der Alters-Amyloidose des Herzens. In Folge unterschiedlicher sogenannter amyloidogener Mutationen wird die Transthyretin-Struktur instabiler. Hierdurch wird die Ablagerung von mutiertem Transthyretin im Gewebe begünstigt (Transthyretin-Amyloidose). Eine Erbanlage (Heterozygotie) für eine amyloidogene Mutation reicht dabei aus. Die Klinik hängt von der spezifischen Erbveränderung ab und wird vor allem durch eine Nervenbeschwerden (sensible und autonome Polyneuropathie) und eine Herzmuskelschwäche (Kardiomyopathie) geprägt. Derzeit sind mehr als 100 verschiedene Genveränderungen bekannt. Neben bislang unbekannten Umweltfaktoren sind das Manifestationsalter und der Schweregrad der Herzbeteiligung ebenfalls von der spezifischen Erbveränderung abhängig. Am häufigsten sind bisher Mutationen an der Position 30 des Transthyretins mit einem Austausch von zwei bestimmten Eiweißbausteinen (Valin durch Methionin = Val30Met) beschrieben. Diese Patienten entwickeln eine rasch fortschreitende Polyneuropathie, eine Kardiomyopathie und Magen- Darm-Beschwerden. Andere Genveränderungen, wie z. B. der Austausch von den Bausteinen Valin durch Isoleucin an der Position 20 des Transthyretins (Val20Ile) scheint typischerweise zu einer isolierten Kardiomyopathie ohne Polyneuropathie im Alter von 50 bis 60 Jahren zu führen. Inotersen Treatment for Patients with Hereditary Transthyretin Amyloidosis Hereditary transthyretin amyloidosis is caused by pathogenic single-nucleotide variants in the gene encoding transthyretin (TTR) that induce transthyretin misfolding and systemic deposition of amyloid. Progressive amyloid accumulation leads to multiorgan dysfunction and death. Inotersen, a 2′-O-methoxyethyl– modified antisense oligonucleotide, inhibits hepatic production of transthyretin. We conducted an international, randomized, double-blind, placebo-controlled, 15-month, phase 3 trial of inotersen in adults with stage 1 (patient is ambulatory) or stage 2 (patient is ambulatory with assistance) hereditary transthyretin amyloidosis with polyneuropathy. Patients were randomly assigned, in a 2:1 ratio, to receive weekly subcutaneous injections of inotersen (300 mg) or placebo. The primary end points were the change in the modified Neuropathy Impairment Score+7 (mNIS+7; range, −22.3 to 346.3, with higher scores indicating poorer function; minimal clinically meaningful change, 2 points) and the change in the score on the patient-reported Norfolk Quality of Life–Diabetic Neuropathy (QOL-DN) questionnaire (range, −4 to 136, with higher scores indicating poorer quality of life). A decrease in scores indicated improvement. Change from Baseline in Primary End Points. Brackets indicate the difference in the least-squares mean change from baseline between the inotersen group and the placebo group. Composite scores on the modified Neuropathy Impairment Score+7 (mNIS+7) scale range from −22.3 to 346.3 (the higher the score, the poorer the function), and total scores on the Norfolk Quality of Life–Diabetic Neuropathy (QOL-DN) questionnaire range from −4 to 136 (the higher the score, the poorer the quality of life). A decrease in score indicated an improvement on each scale. A 2-point change in the NIS+7 has been defined as the minimal clinically meaningful change detectable.14,18 Changes in the patient-reported Norfolk QOL-DN score have been shown to be proportional to changes in the Neuropathy Impairment Score (range, 0 to 244, with a higher score indicating poorer function). One patient in the inotersen group had a fatal intracranial hemorrhage in association with a platelet count of less than 10,000 per cubic millimeter that occurred before the introduction of frequent platelet monitoring. A higher proportion of patients in the inotersen group (60 of 112, 54%) had a confirmed decrease in the postbaseline platelet count to less than 140,000 per cubic millimeter than in the placebo group (8 of 60, 13%).

Glomerulonephritis occurred in three patients (3%) in the inotersen group. Each of these three patients carried the Val30Met mutation. Two had shown a decline in the estimated glomerular filtration rate. In all three cases, the renal biopsy showed complex pathologic features, consistent with crescentic glomerulonephritis superimposed on a background of amyloidosis and (in two cases) interstitial fibrosis. One patient was successfully treated with glucocorticoids and cyclophosphamide and regained clinically significant renal function.

Another patient did not receive immunosuppressive therapy owing to delayed diagnosis, and permanent hemodialysis was initiated. A third patient was identified as having clinically significant proteinuria after the implementation of more frequent renal monitoring of every 2 to 3 weeks; this patient did not show a decline in renal function. Urinary protein excretion returned to baseline levels after treatment with glucocorticoids. Patisiran, an RNAi Therapeutic, for Hereditary Transthyretin Amyloidosis

Patisiran, an investigational RNA interference therapeutic agent, specifically inhibits hepatic synthesis of transthyretin. In this phase 3 trial, we randomly assigned patients with hereditary transthyretin amyloidosis with polyneuropathy, in a 2:1 ratio, to receive intravenous patisiran (0.3 mg per kilogram of body weight) or placebo once every 3 weeks. The primary end point was the change from baseline in the modified Neuropathy Impairment Score+7 (mNIS+7; range, 0 to 304, with higher scores indicating more impairment) at 18 months. Other assessments included the Norfolk Quality of Life–Diabetic Neuropathy (Norfolk QOL-DN) questionnaire (range, −4 to 136, with higher scores indicating worse quality of life), 10-m walk test (with gait speed measured in meters per second), and modified body-mass index (modified BMI, defined as [weight in kilograms divided by square of height in meters]×albumin level in grams per liter; lower values indicated worse nutritional status). Panel A shows the percentage change in serum transthyretin levels from baseline over time in the patisiran group and the placebo group. The nadirs in transthyretin reduction at 9 and 18 months correspond to the predose and postdose assessments. Panel B shows the least-squares mean change in the modified Neuropathy Impairment Score+7 (mNIS+7). At baseline, the mean mNIS+7 was 80.9 (range, 8.0 to 165.0) in the patisiran group and 74.6 (range, 11.0 to 153.5) in the placebo group. Panel C shows the least-squares mean change in Norfolk Quality of Life–Diabetic Neuropathy (QOL-DN) scores (range, −4 to 136; with higher scores indicating worse quality of life). At baseline, the mean Norfolk QOL-DN score was 59.6 (range, 5.0 to 119.0) in the patisiran group and 55.5 (range, 8.0 to 111.0) in the placebo group. In Panels A through C, � bars indicate standard errors. Panel D shows the percentage of patients with an improvement (decrease from baseline) in the mNIS+7 or the Norfolk QOL-DN score from baseline after 18 months. A post hoc analysis was used to calculate the odds ratio for improvement in the Norfolk QOL-DN score. Correlation of Reduction in Transthyretin Levels with Change in mNIS+7 from Baseline at 18 Months. The analysis included 188 patients with nonmissing mNIS+7 assessments at month 18. Secondary and Exploratory End Points. Adverse events leading to discontinuation of the trial regimen occurred more frequently with placebo (14%) than with patisiran (5%); adverse events that led to discontinuation of the trial regimen in two or more patients were cardiac failure (two patients [1%] in the patisiran group) and acute kidney injury (two patients [3%] in the placebo group). Death occurred in seven patients (5%) in the patisiran group and in six patients (8%) in the placebo group. The causes of death were primarily cardiovascular in nature and consistent with those expected in patients with hereditary transthyretin amyloidosis Oligonucleotide Drugs for Transthyretin Amyloidosis Transthyretin proteins form a homotetramer; tetramers containing at least one mutant subunit are kinetically or thermodynamically unstable and dissociate under physiologic conditions to release monomers. Once released, the monomers are no longer constrained by the tetrameric structure and misfold into aggregation-prone polypeptides that form toxic oligomers and amyloid fibrils Current Therapies for Autosomal Dominant Hereditary Amyloidotic Polyneuropathy Caused by Mutations in the Gene Encoding Transthyretin (TTR). As shown in Panel A, the genome of patients with hereditary amyloidotic polyneuropathy contains one copy of wild-type TTR and one copy containing a base substitution resulting in a change in the amino acid sequence. In hepatocytes, both copies appear to be equally transcribed and translated. Patisiran and inotersen bind to wild-type and mutant transthyretin RNA transcripts, resulting in their degradation either in the nucleus by ribonuclease H (inotersen) or by the cytoplasmic Dicer small interfering RNA mechanism (patisiran), both of which substantially reduce the amount available for translation. As shown in Panel B, in the presence of adequate wild-type or mutant transthyretin messenger RNA (mRNA) transcripts, transthyretin is synthesized on membrane-bound polyribosomes and transported into the endoplasmic reticulum. Noncovalent tetramer formation appears to occur either in the endoplasmic reticulum or the Golgi apparatus, probably through a transient dimer intermediate, close to the time of secretion. Tetramerization stabilizes even mutant monomers; however, it is possible that the translated mutant transthyretin monomer is less stable than the wild-type monomer and a greater proportion is directed to the endoplasmic reticulum–associated degradation pathway. Tetramers may contain one to four mutant monomers. As shown in Panel C, circulating transthyretin is predominantly tetrameric, but mutant or wild- type monomers may also be found in the circulation as a consequence of tetramer dissociation, which is enhanced by the presence of one or more mutant monomers. The first approach (on which the trials by Adams et al. and Benson et al. are based) is to reduce or halt the amount of mutant transthyretin that is synthesized by the liver. The results in approximately 2000 liver- transplant recipients in whom a liver producing mutant transthyretin was replaced by one synthesizing only the wild-type protein indicate a slowing of disease: 80% of the patients survived for at least 10 years, and arrest of progression of the neuropathy was achieved in the majority. However, recovery of organ function did not seem to occur.4 The second strategy is to stabilize the mutant tetramers so that amyloidogenic monomers are not released. Randomized, controlled trials of small-molecule transthyretin tetramer stabilizers (tafamidis and diflunisal) have shown clinical efficacy.

In both trials, the patients who received the active drug had a lower mean rate of progression of the manifestations of the neuropathy (as determined by the modified Neuropathy Impairment Score+7 [NIS+7]) than did the patients who received placebo. The frequency of adverse events was similar among patients who received patisiran and those who received placebo. However, inotersen appeared to systematically reduce circulating platelet levels, with mean platelet counts being significantly lower in the drug-recipient cohort than in the placebo group; one patient who received inotersen had a fatal intracranial hemorrhage. The mechanism of the thrombocytopenia, for which patients were monitored once its association with inotersen became apparent, is not known.

It seems likely that, over the course of 18 months and given the clinical metrics available, a response in 60% of patients is the best that can be obtained with current interventions. The development of more sensitive, dynamic measures to serve as predictors of response seems feasible and desirable, preferably in the form of a noninvasive biomarker related to the pathophysiology of the disease that reflects the effect of an intervention of short duration on both transthyretin availability and tissue deposition. Measuring the reduction in total transthyretin level or the stabilization of the tetramer, although adequate to compare treated with untreated populations, may not be sufficient to define the therapeutic response in a single patient. Perhaps a better approach could be established by carefully examining the features of the disease or physiological or molecular characteristics of the patients who have the best response in comparison with those who do not have a response to define potentially predictive indicator molecules. Platelet Counts during Pregnancy

Platelet counts of less than 150,000 per cubic millimeter during uncomplicated pregnancies are described as gestational thrombocytopenia if no alternative cause is identified. Platelet counts may be even lower in women with pregnancy-related complications. However, the occurrence and severity of thrombocytopenia throughout pregnancy are not defined. We evaluated platelet counts throughout pregnancy in women who delivered at Oklahoma University Medical Center between 2011 and 2014. These platelet counts were compared with those of nonpregnant women who were included in the National Health and Nutrition Examination Survey from 1999 through 2012.

Mean Platelet Counts over Time. Panel A shows the mean platelet counts of the women who had uncomplicated pregnancies and of the nonpregnant women. � bars denote 95% confidence intervals. The mean platelet count in the 8885 nonpregnant women is designated by N on the x axis. The mean platelet counts of the 4568 women who had uncomplicated pregnancies are shown at each trimester (with the mean time of gestation when they were measured indicated on the x axis), at the time of delivery (designated by D on the x axis), and during the postpartum period (designated by PP on the x axis). The mean platelet counts of the 336 women with uncomplicated pregnancies who had platelet counts at each trimester and at the time of delivery are also shown in Panel A. The difference in the mean platelet count between the women who had no missing platelet counts and the 4232 women who had missing platelet counts during one or more trimesters was not significant (P=0.79). Panel B shows the mean platelet counts of the women who had uncomplicated pregnancies, the women who had pregnancy-related complications, and the women who had preexisting disorders that were associated with thrombocytopenia. The platelet counts of all three groups of women decreased significantly throughout pregnancy (P<0.001). The mean platelet counts of the 2586 women who had pregnancy-related complications were higher than those of the 4568 women who had uncomplicated pregnancies during the first and second trimester (P<0.001) but were not significantly different during the third trimester (P=0.38) or at the time of delivery (P=0.09). The mean platelet counts of the 197 women who had preexisting disorders associated with thrombocytopenia were lower than those of the women who had uncomplicated pregnancies at all trimesters and at the time of delivery (P<0.03 for all comparisons).

Platelet Count Distribution. Shown are the distribution of the mean platelet counts of the nonpregnant women and the distribution of the mean platelet counts during the first trimester (mean gestation, 8.7 weeks) and at the time of delivery in the women who had uncomplicated pregnancies. The distributions of the mean platelet counts for all three curves were symmetric, with a slight skew toward higher platelet counts that was consistent across all three curves. The mean and median platelet count values for each of the three distribution curves differed by less than 3%. Platelet Counts during Pregnancy and at the Time of Delivery. Although gestational thrombocytopenia has been recognized for more than 25 years, the course of platelet counts throughout pregnancy and the potential severity of gestational thrombocytopenia have not been defined. Our data showed that among the women who had uncomplicated pregnancies, the decline in platelet counts began in the first trimester and continued throughout pregnancy, with the nadir occurring at the time of delivery, when 9.9% of the women had platelet counts of less than 150,000 per cubic millimeter. At a mean of 7.1 weeks after delivery, platelet counts in the women who had uncomplicated pregnancies recovered to the level of platelet counts in the nonpregnant women. Assuming that platelet counts measured in the women during the postpartum period were similar to their platelet counts before pregnancy, mean platelet counts decreased by an estimated 17% during pregnancy. Oral Tecovirimat for the Treatment of Smallpox Smallpox was declared eradicated in 1980, but variola virus (VARV), which causes smallpox, still exists. There is no known effective treatment for smallpox; therefore, tecovirimat is being developed as an oral smallpox therapy. Because clinical trials in a context of natural disease are not possible, an alternative developmental path to evaluate efficacy and safety was needed. We investigated the efficacy of tecovirimat in nonhuman primate (monkeypox) and rabbit (rabbitpox) models in accordance with the Food and Drug Administration (FDA) Animal Efficacy Rule, which was interpreted for smallpox therapeutics by an expert advisory committee. We also conducted a placebo- controlled pharmacokinetic and safety trial involving 449 adult volunteers.

On day 0, nonhuman primates (Panels A and B) and rabbits (Panels C and D) were infected with a lethal dose of monkeypox virus or rabbitpox virus, respectively. Survival was monitored for 18 to 42 days after infection, indicated on the horizontal axis labels. Tecovirimat was administered by oral gavage at doses ranging from 0.3 to 20 mg per kilogram of body weight in nonhuman primates and from 20 to 120 mg per kilogram in rabbits. Tecovirimat was administered for 14 consecutive daily doses starting on day 4 after infection, after the onset of clinical signs (pock lesions in nonhuman primates and fever and viremia in rabbits) in each study. Comparison of the exposures required for efficacy in rabbits and nonhuman primates showed that the nonhuman primate was the more conservative model, with higher exposures required for full effectiveness. Therefore, the exposure profiles of tecovirimat in plasma in nonhuman primates and humans were compared after the first dose (Panel E) and after the last dose at steady state (Panel F) to evaluate whether exposures in humans exceeded those in nonhuman primates, providing a reasonable expectation of efficacy in humans. Differences in Survival Rates with Tecovirimat as Compared with Placebo. Shown is a forest-plot summary comparing differences in survival rates between tecovirimat and placebo in each study. The exact 95% confidence intervals (horizontal bars in the forest plot) are based on the score statistic of the difference in survival rates. The P value is from a one-sided Fisher’s exact test for the comparison of tecovirimat with placebo. Data from the study of dose exploration and pharmacokinetics in rabbits are not shown on the forest plot, since the study did not include a placebo control.

A total of 452 persons underwent randomization and were assigned to receive tecovirimat at a dose of 600 mg twice daily (361 participants) or matching placebo (91 participants) for 14 consecutive days.

A total of 431 participants completed the trial. The overall rate of adherence was 94.4% in the placebo group and 93.6% in the tecovirimat group; the corresponding rates among participants in the pharmacokinetic portion of the trial were 100% and 96.9%. Because the risk of VARV infection persists, developing antiviral therapy to treat it is important. Because the smallpox vaccine is no longer used in the general population, herd immunity is minimal, and the vaccine is largely ineffective after the onset of clinical illness. These gaps could be mitigated by an effective smallpox antiviral drug to treat people who have clinically evident disease as well as those who have been exposed or potentially exposed to smallpox. A smallpox antiviral drug could be an important stopgap measure until the standard vaccine can be effectively deployed, while complementing the protective efficacy of the vaccine once it has been deployed. The eradication of smallpox and the limited usefulness and availability of animal models of VARV infection pose unique challenges in the development and validation of potential smallpox antiviral drugs. In contrast to other Animal Rule investigational scenarios, smallpox antiviral exploration requires the use of surrogate pathogens and hosts for human smallpox. Because of this unique complexity, the FDA convened an advisory panel on the subject of smallpox antiviral-drug development in December 2011. The panel concluded that lethal monkeypox virus infection in nonhuman primates and rabbitpox virus infection in rabbits allowed meaningful evaluation of potential smallpox antiviral drugs, although studies in human volunteers would be necessary to confirm that the doses in humans can safely provide similar exposure to that required for efficacy in animals. Cabozantinib in Patients with Advanced and Progressing Hepatocellular Carcinoma Cabozantinib inhibits tyrosine kinases, including vascular endothelial growth factor receptors 1, 2, and 3, MET, and AXL, which are implicated in the progression of hepatocellular carcinoma and the development of resistance to sorafenib, the standard initial treatment for advanced disease. This randomized, double-blind, phase 3 trial evaluated cabozantinib as compared with placebo in previously treated patients with advanced hepatocellular carcinoma. A total of 707 patients were randomly assigned in a 2:1 ratio to receive cabozantinib (60 mg once daily) or matching placebo. Eligible patients had received previous treatment with sorafenib, had disease progression after at least one systemic treatment for hepatocellular carcinoma, and may have received up to two previous systemic regimens for advanced hepatocellular carcinoma. The primary end point was overall survival. Secondary end points were progression-free survival and the objective response rate. Kaplan–Meier Analysis of Overall Survival and Progression-free Survival. Overall survival was defined as the time from randomization to death from any cause, and progression-free survival as the time from randomization to radiographic progression or death from any cause. Tick marks indicate censored data.

The most common grade 3 or 4 adverse events in the cabozantinib group were palmar–plantar erythrodysesthesia (17%, vs. 0% with placebo), hypertension (16% vs. 2%), increased aspartate aminotransferase level (12% vs. 7%), fatigue (10% vs. 4%), and diarrhea (10% vs. 2%). The most common adverse events of any grade leading to dose reductions in the cabozantinib group were palmar–plantar erythrodysesthesia (22%), diarrhea (10%), fatigue (7%), hypertension (7%), and increased aspartate aminotransferase level (6%). Serious adverse events were reported in 50% of the patients who received cabozantinib and in 37% of the patients who received placebo.

This randomized, phase 3 trial showed that cabozantinib treatment significantly prolonged survival in patients with previously treated advanced hepatocellular carcinoma. The median overall survival was 10.2 months with cabozantinib and 8.0 months with placebo, with a hazard ratio for death of 0.76. Corresponding to this survival benefit, a longer duration of progression-free survival was also observed: the median progression-free survival was 5.2 months with cabozantinib and 1.9 months with placebo, with a hazard ratio for disease progression or death of 0.44. Subgroup analyses of progression-free survival suggested that cabozantinib had clinical activity across subgroups of patients with various etiologic factors and across subgroups with other baseline characteristics. Subgroup analyses of overall survival were more variable, with broader confidence intervals. Chimeric Antigen Receptor Therapy

Genetically engineered T cells constitute a powerful new class of therapeutic agents that offer hope for curative responses in patients with cancer. Chimeric antigen-receptor T cells were recently approved by the Food and Drug Administration (FDA) and are poised to enter the practice of medicine for the treatment of and lymphoma. Synthetic biology approaches for cellular engineering provide a broadly expanded set of tools to program immune cells for enhanced function. Advances in T-cell engineering, genetic editing, the selection of the most functional lymphocytes, and cell manufacturing have the potential to broaden T-cell– based therapies and foster new applications beyond oncology in infectious diseases, organ transplantation, and autoimmunity. This review addresses the principles of T-cell engineering and synthetic immunity, with a focus on the efficacy and toxic effects of current CAR therapies. CARs are engineered receptors that graft a defined specificity onto an immune effector cell, typically a T cell, and augment T-cell function.9 Once infused, CAR T cells engraft and undergo extensive proliferation in the patient. Each CAR T cell can kill Chimeric Antigen Receptor (CAR) T Cells Engrafting, Trafficking many tumor cells, and CAR T cells may promote to Tumor, and Proliferating Extensively after Infusion. After immune surveillance to prevent tumor recurrence infusion, CAR T cells leave the blood and travel to sites of tumor, where they identify and kill tumor cells. This can trigger extensive through antigen release, by assisting tumor-infiltrating proliferation of CAR T cells and the release of tumor antigens, lymphocytes to attack tumors, or by their own which activates the immune system to recruit non–CAR T cells, persistence. thus eliciting further antitumor responses in a process known as cross priming. CARs are synthetic receptors that redirect the specificity, function, and metabolism of T cells. CARs consist of a T-cell activating domain (typically including the zeta chain of the CD3 complex) and extracellular immunoglobulin-derived heavy and light chains to direct specificity. These minimal structures, termed first- generation CARs,9 recognize antigen independently of HLA but do not direct sustained T-cell responses, owing to their limited signaling capability. Chimeric costimulatory receptors, which enhance proliferation and afford antiapoptotic functions in human primary T cells,21 paved the way for dual-signaling CARs that could effectively direct the expansion of functional T cells on repeated exposure to antigen. These receptors, termed second- generation CARs, enabled the generation of the persistent “living drugs” that are the foundation of current CAR T-cell therapy.

Structure of CARs and T-Cell Receptors. Panel A shows the structure of a T-cell receptor, which consists of heterodimeric and antigen-specific α and β chains that closely associate with the invariant ε, δ, γ, and ζ chains of the CD3 complex. The T-cell receptor binds to the HLA allele that has a bound peptide derived from a tumor antigen on the target cell. Panel B shows the CAR, which includes the single-chain variable fragment (scFv) that binds to tumor antigens, fused to a spacer and transmembrane domain. The intracellular domain contains costimulatory domains, such as CD28 and 4-1BB and the CD3ζ chain, which drive signal activation and amplification of CAR T cells. S–S denotes disulfide bond.

In some patients, CAR T cells induce a clinical syndrome of fevers, hypotension, hypoxia, and neurologic changes associated with marked elevations of serum cytokine levels.This spectrum of clinical and laboratory findings has been termed the cytokine release syndrome. The occurrence of the cytokine release syndrome is associated with both CD19 and B-cell maturation antigen (BCMA, also known as CD269) CARs, and in the case of CD19 CARs, the severity of the cytokine release syndrome is associated with tumor burden as measured by blasts in bone marrow at the time of treatment. The cytokine release syndrome manifests with a noninfectious flulike syndrome and can progress to life-threatening capillary leakage with hypoxia and hypotension. The onset of the cytokine release syndrome correlates with the pharmacokinetic characteristics of the CAR T cells, with a temporal association between the syndrome and peak levels of CAR T cells. The cytokine release syndrome is an on-target toxic effect and is not common in patients who do not have a clinical response after CAR therapy. This syndrome is associated with T-cell activation and high levels of cytokines, including interleukin-6 and interferon-γ. Tocilizumab (Actemra), an anti–interleukin-6-receptor antagonist, is usually effective in the management of severe cytokine release syndrome induced by CAR T cells. A Sickening Tale A 44-year-old man presented to the emergency department with presyncope after 3 days of profuse vomiting and nonbloody diarrhea. He was hypotensive. Venous blood gas measurements showed a pH of 7.29, bicarbonate level of 17 mmol per liter, sodium level of 127 mmol per liter, potassium level of 2.5 mmol per liter, chloride level of 102 mmol per liter, and glucose level of 286 mg per deciliter (15.9 mmol per liter). A 44-year-old man presented to the emergency department with presyncope after 3 days of profuse vomiting and nonbloody diarrhea. He was hypotensive. Venous blood gas measurements showed a pH of 7.29, bicarbonate level of 17 mmol per liter, sodium level of 127 mmol per liter, potassium level of 2.5 mmol per liter, chloride level of 102 mmol per liter, and glucose level of 286 mg per deciliter (15.9 mmol per liter). The blood pressure was 75/46 mm Hg, and the heart rate 106 beats per minute. The patient was afebrile, and pulmonary and abdominal examinations were unremarkable. The pupils were of normal size and reacted appropriately to light. There were no oral lesions or excessive secretions. Hyperkeratosis and hyperpigmentation with deep fissures were observed on the hands Photographs Obtained on Presentation. The patient had and feet, with no signs of infection (Figure 1). hyperkeratosis and hyperpigmentation with deep fissures on the hands (not shown) and feet. Bone Marrow–Biopsy Specimen. A bone marrow–biopsy specimen was examined through an oil-immersion lens. The specimen shows nonspecific erythroid dysplasia with karyorrhexis (nuclear fragmentation with chromatin in cytoplasm) (black arrow) and binucleated mature erythroid forms (red arrows).

A neurologic examination was normal; no fasciculations were noted. An electrocardiogram showed sinus tachycardia with a corrected QT (QTc) interval of 406 seconds and no ischemic changes. The hemoglobin level was 15.4 g per deciliter; the white-cell count was 8000 per cubic millimeter, with 80% neutrophils and 10% lymphocytes; and the platelet count was 281,000 per cubic millimeter. The sodium level was 128 mmol per liter, potassium 2.6 mmol per liter, creatinine 3.1 mg per deciliter (270 μmol per liter), chloride 104 mmol per liter, bicarbonate 17 mmol per liter, urea 72.5 mg per deciliter (25.9 mmol per liter), bilirubin 2.2 mg per deciliter (38 μmol per liter) (normal value, <1.2 mg per deciliter [<21 μmol per liter]), alanine aminotransferase 61 U per liter (normal range, 5 to 54), C-reactive protein 67.2 mg per liter (normal value, <10), and prothrombin time 19.8 seconds (normal range, 8.5 to 12.5). The ketone level by finger prick was 0.2 mmol per liter (normal value, <0.6). The glycated hemoglobin level was 6.1%. A urinalysis was unremarkable. Lumbar puncture revealed normal protein and glucose levels and no white or red cells; bacterial cultures were negative. Polymerase-chain-reaction assays for herpes simplex virus and enterovirus were negative. MRI of the head was normal. Acute kidney injury resolved with conservative management. Antibiotic agents were stopped after 7 days. However, the hepatitis progressed, with a peak alanine aminotransferase level of 253 U per liter and a γ-glutamyltransferase level of 1135 U per liter (normal value, <61). Progressive pancytopenia developed between 7 and 10 days after admission, with a nadir hemoglobin level of 81 g per liter, a white-cell count of 1600 per cubic millimeter (25% neutrophils and 48% lymphocytes), and a platelet count of 59,000 per cubic millimeter.

The patient had normal vitamin B12 and folate levels and a ferritin level of 1779 μg per liter (normal range, 30 to 500). A blood smear showed normochromic normocytic red cells and some atypical lymphocytes and neutrophils with . After confirmation that the patient had not recently eaten seafood, a screening test for heavy metals was ordered 5 days after admission. The results, which were received on day 17, showed markedly elevated total arsenic levels of 4812 μg per liter in urine and 323 μg per liter in the blood (reference range for both, <52). Further assessment of urinary arsenic confirmed inorganic arsenic poisoning with 61% trivalent arsenite, 4% pentavalent arsenate, 17% monomethylarsonic acid, and 16% dimethylarsenic acid. A test for arsenobetaine (organic arsenic) was negative. That day, chelation therapy was initiated with oral succimer (2,3-dimercaptosuccinic acid) at a dose of 10 mg per kilogram of body weight three times daily for 5 days, followed by twice Photograph of Vesicular Rash. Soon after commencement of daily for an additional 2 weeks. The patient was succimer therapy, a rash developed on the left C4 dermatome (shown) as well as the right flank and the forearm. reexamined for the characteristic nail changes of arsenic poisoning (i.e., Mees lines, or white bands across the width of the nail); however, these were not present.

On day 3 of chelation therapy, a vesicular rash developed on the upper arm, which became generalized over the next 48 hours. Swab specimens were positive for VZV, and the patient was treated with acyclovir. Despite chelation therapy, the peripheral neuropathy continued to progress. He had sensory change in a “glove-and-stocking” distribution to the level of the shoulders in the arms and to the perineal region in the legs. Owing to severely impaired proprioception and bilateral foot drop, he was unable to walk or stand. Nerve-conduction studies confirmed a generalized sensory and motor neuropathy. An additional course of chelation therapy with intravenous and then oral unithiol (sodium 2,3- dimercapto-1-propanesulfonic acid) was administered. Every 10 to 12 days, 24-hour urine specimens were tested for arsenic levels; the arsenic level decreased with each subsequent specimen. Chelation therapy was discontinued when the urinary arsenic level was 22 μg per liter. The patient had a prolonged stay at a rehabilitation facility but had substantial neurologic recovery. At discharge, almost 4 months after the initial presentation, he had mild residual impairment in proprioception in his feet and was able to ambulate with bilateral ankle–foot orthoses. An environmental health investigation was conducted at his property and revealed arsenic levels of up to 55 μg per liter in the freshwater dams from which he had drunk. Although this level of arsenic would not be expected to cause acute poisoning, there was a delay of 6 weeks between the time the patient drank the water and the time the water was tested. The arsenic level was probably higher at the time he consumed the water, owing to the heavy monsoonal flooding. In the Northern Territory, high levels of arsenic have been found around gold- exploration sites. The patient’s property was approximately 200 km north of an extensive area of past gold mining, and the aquifer extends through the entire region. There were no arsenic-containing herbicides or pesticides found on the property to suggest an alternative environmental exposure. No similar cases were reported in the area.

A dacrocyte (or dacryocyte) is a type of poikilocyte that Teardrop erythrocytes (syn. dakryocytes) is shaped like a teardrop (a "teardrop cell"). A marked play a key role in the evaluation of increase of dacrocytes is known as "dacrocytosis". peripheral blood smears in patients with These tear drop cells are found primarily in diseases anemia, especially as part of the with bone marrow fibrosis, such as: primary “leukoerythroblastic picture”. Teardrop- myelofibrosis, myelodysplastisc syndromes during the shaped red blood cells can be seen in a late course of the disease, rare form of acute wide range of diseases that lead to bone and myelophtisis caused by metastatic carcinoma. Rare marrow fibrosis, which is often causes are myelofibrosis associated with post- accompanied by extramedullary irradiation, toxins, autoimmune diseases, metabolic hematopoesis. The differential diagnoses conditions, inborn hemolytic anemias, iron-deficient encompass (PMF), anemia or β-thalassemia myelodysplastisc syndromes during the late course of the disease, rare forms of acute leucemias and myelophtisis caused by metastatic carcinoma. Rarely, MF associated with post-irradiation, toxins, autoimmune diseases, metabolic conditions, inborn hemolytic anemias, iron-deficient anemia or β-thalassaemia can lead to the formation of teardrops as visualized on peripheral blood smears. Sodium bicarbonate therapy for patients with severe metabolic acidaemia in the intensive care unit (BICAR-ICU): a multicentre, open-label RCT Acute acidaemia is frequently observed during critical illness. Sodium bicarbonate infusion for the treatment of severe metabolic acidaemia is a possible treatment option but remains controversial, as no studies to date have examined its effect on clinical outcomes. Therefore, we aimed to evaluate whether sodium bicarbonate infusion would improve these outcomes in critically ill patients. We included adult patients (aged ≥18 years) who were admitted within 48 h to the ICU with severe acidaemia (pH ≤7·20, PaCO2 ≤45 mm Hg, and sodium bicarbonate concentration ≤20 mmol/L) and with a total Sequential Organ Failure Assessment score of 4 or more or an arterial lactate concentration of 2 mmol/L or more. We randomly assigned patients (1:1), by stratified randomisation with minimisation via a restricted web platform, to receive either no sodium bicarbonate (control group) or 4·2% of intravenous sodium bicarbonate infusion (bicarbonate group) to maintain the arterial pH above 7·30. Our protocol recommended that the volume of each infusion should be within the range of 125–250 mL in 30 min, with a maximum of 1000 mL within 24 h after inclusion. The primary outcome was a composite of death from any cause by day 28 and the presence of at least one organ failure at day 7. 4.2% sodium bicarbonate iv. 125-250 ml/30 min, may 1000 mL/24 h goal of pH 7.3 or more.

Sodium bicarbonate 4.2 % (0.5 mEq/mL) 62 to 125 mmol/30 min up to 500 mmol/day.

Time to death in the overall population (A) and patients with prespecified acute kidney injury (B), and the 28-day mortality risk difference in the overall population and in the three prespecified strata (C) AKIN=Acute Kidney Injury Network. *A χ2 test was done to compare day 28 mortality proportion in each group. For multiple comparisons in each prespecified stratum, a Holm-Bonferroni method was done to compute an adjusted p value. 100 (52%) of 194 patients in the control group and 68 (35%) of 195 in the bicarbonate group underwent renal-replacement therapy during their ICU stay (absolute difference estimate −16·7 days, 95% CI −26·4 to −7·0; p=0·0009); and when indicated, renal-replacement therapy was started earlier in the control group than in the bicarbonate group. The number of days alive free from renal-replacement therapy was also significantly lower in the control group than in the bicarbonate group. Hyperkalaemia and acidaemia were the main reasons for initiation of renal- replacement therapy in the control group. Sodium bicarbonate treatment was associated with less hyperkalaemia and less persistent acidaemia than no sodium bicarbonate treatment at day 7. Serum creatinine and serum blood urea nitrogen were the main reasons to start renal-replacement therapy in the bicarbonate group There are, however, limitations in our study. No specific control solution was recommended in the control group because there is no fluid without an effect on the acid–base balance. The fluid therapy from enrolment to day 2 was, however, similar in the two groups. Additionally, the physicians caring for the patients in the ICU could not be masked because regular monitoring of arterial blood gases is part of the routine care in patients with severe metabolic acidaemia with a very high risk of mortality. Furthermore, sodium bicarbonate infusion was titrated to reach and maintain a targeted pH of 7·30. nother limitation is that the protocol suggested a range of 4·2% sodium bicarbonate volume (125–250 mL per infusion) in the bicarbonate group rather than using a formula to calculate the base deficit and provide a tailored sodium bicarbonate infusion; therefore, we cannot extrapolate whether different ways of administration would have resulted in other outcomes. We also chose not to stratify patients according to the acidaemia mechanism, because the trial was designed to be a pragmatic study.

Management of multimorbidity using a patient-centred care model: a pragmatic cluster-randomised trial of the 3D approach The management of people with multiple chronic conditions challenges health-care systems designed around single conditions. There is international consensus that care for multimorbidity should be patient-centred, focus on quality of life, and promote self-management towards agreed goals. However, there is little evidence about the effectiveness of this approach. Our hypothesis was that the patient-centred, so-called 3D approach (based on dimensions of health, depression, and drugs) for patients with multimorbidity would improve their health-related quality of life, which is the ultimate aim of the 3D intervention. Practices were randomly allocated to continue usual care (17 practices) or to provide 6-monthly comprehensive 3D reviews, incorporating patient-centred strategies that reflected international consensus on best care (16 practices). Randomisation was computer-generated, stratified by area, and minimised by practice deprivation and list size. Adults with three or more chronic conditions were recruited. The primary outcome was quality of life (assessed with EQ-5D-5L) after 15 months' follow-up. Participants were not masked to group assignment, but analysis of outcomes was blinded. We analysed the primary outcome in the intention-to-treat population, with missing data being multiply imputed. Baseline characteristics

Data are mean (SD), n (%), n/N (%), or median (IQR). IMD=Index of Multiple Deprivation. QOF=UK Quality and Outcomes Framework. *English and Scottish IMD scores are based on similar variables but calculated differently; data available as mean score for English practices, but proportion of patients living in 15% most deprived data zones for Scottish practices. †Conditions with similar clinical management were grouped and only counted once. ‡Including coronary heart disease, hypertension, heart failure, peripheral arterial disease, and chronic kidney disease stages 3 to 5. §Including schizophrenia, psychosis, and bipolar disease. Outcomes at 15 months Process of care outcomes at 15 months

Although the intervention was not associated with an improvement in quality of life or the secondary outcomes of perceived illness burden or treatment burden, and had mixed effects on the process of care, it was associated with significant improvements in measures of patient- centred care.

This trial has several strengths. It is the largest trial of an intervention to improve management of multimorbidity, and was rigorously done in line with recommended standards for cluster- randomised trials. We recruited a population of patients with major health needs: two-thirds of participants rated their health as fair or worse and many reported clear deficiencies in the care of their chronic conditions. The use of broad eligibility criteria in a range of practices in different settings enhances external validity. The findings are likely to be generalisable to other countries where patients have chronic disease reviews focused on management of individual diseases. The trial was highly pragmatic and reflects the effectiveness of the intervention in real-world implementation.

Personalised perioperative care by e-health after intermediate-grade abdominal surgery: a multicentre, single-blind, randomised, placebo-controlled trial Instructing and guiding patients after surgery is essential for successful The intervention care programme comprised three parts: a website, an app, and an activity tracker. The aim of the different recovery. However, the time that health- parts of the intervention was to prepare participants in the best care professionals can spend with their way for surgery and to support them during the postoperative patients postoperatively has been period. With the intervention programme, participants had the reduced because of efficiency-driven, option to develop a personalised convalescence plan, could shortened hospital stays. We evaluated access information about the perioperative period by text and the effect of a personalised e-health- video animations, could use a monitor providing personal feedback on the recovery process, and had use of an e-consult care programme on return to normal function. By using an activity tracker, participants assigned the activities after surgery. Participants in intervention programme were provided on a day-to-day basis the intervention group had access to a with their current recovery status, based on a baseline perioperative, personalised, e-health- measurement from the week before surgery. care programme, which managed recovery expectations and provided postoperative guidance tailored to the patient. The control group received usual care and access to a placebo website containing standard general recovery advice. Participants were unaware of the study hypothesis and were asked to complete questionnaires at five timepoints during the 6-month period after surgery. The primary outcome was time between surgery and return to normal activities, measured using personalised patient-reported outcome measures. Intention-to-treat and per- protocol analyses were done. Baseline characteristics

Data are number of patients (%), median (IQR), or mean (SD). PROMIS-PF=Dutch– Flemish Patient-Reported Outcomes Measurement Information System Physical Function. *Only applicable to employed participants; light or medium intensity level defined as sedentary work, no heavy lifting required; heavy intensity level defined as lifting and carrying loads required. †Number of days participants expect that they will return to work after surgery. ‡Number of days participants expect that they will return to normal activities after surgery. §T-score of physical function short form (a T-score of 50 represents the average score of the general US population). ¶Mean first threshold of the Item Response Theory item characteristic curve of the eight selected items on baseline. *Intention-to-treat analysis, adjusted for factors on which randomisation was stratified: hospital, surgical procedure, and sex. †Intention-to-treat analysis, adjusted for stratification factors and factors that could affect the length of the recovery period (score of the Recovery Index short versionPrimary form [RI5], which is focused on pain, fatigue, and physical functioning), recovery expectations on baseline (lengthoutcome in days), and work status. 5 ‡In the intervention group only, participants who made a convalescencemeasure plan were included; analysis adjusted for factors on which randomisation was stratified.

Idiopathic nephrotic syndrome in children

The incidence of idiopathic nephrotic syndrome (NS) is 1·15–16·9 per 100 000 children, varying by ethnicity and region. The cause remains unknown but the pathogenesis of idiopathic NS is thought to involve immune dysregulation, systemic circulating factors, or inherited structural abnormalities of the podocyte. Genetic risk is more commonly described among children with steroid-resistant disease. The mainstay of therapy is prednisone for the vast majority of patients who are steroid responsive; however, the disease can run a frequently relapsing course, necessitating the need for alternative immunosuppressive agents. Infection and venous thromboembolism are the main complications of NS with also increased risk of acute kidney injury. Prognosis in terms of long-term kidney outcome overall is excellent for steroid-responsive disease, and steroid resistance is an important determinant of future risk of chronic or end-stage kidney disease.

Incidence of childhood nephrotic syndrome per 100 000 persons by ethnicity, reported from 1946 to 2014 (A) and variability of steroid responsiveness by ethnicity among children with nephrotic syndrome in reported studies from 1986 to 2014 (B) Published with permission from Ethnic differences in childhood nephrotic syndrome, published in Frontiers in Pediatrics, 2016. n=total number of patients; SR%=proportion of steroid resistance. *New Zealand European, Maori, Pacific Island, Asian, Other. †Only those with steroid-sensitive nephrotic syndrome. ‡Estimated on the basis of data in published studies. The glomerular filtration barrier and pathogenesis of idiopathic nephrotic syndrome Within the kidney is the glomerulus, a capillary tuft that filters the blood. The podocyte, glomerular basement membrane and the fenestrated glomerular endothelium comprise the glomerular filtration barrier allowing the ultrafiltrate to enter the urinary space. The podocyte has extensive cellular extensions that interdigitate and these foot processes are connected by the slit diaphragm. In nephrotic syndrome, there is extensive effacement of the podocytes and loss of this barrier to protein, allowing excessive serum albumin to leak into the urine. The pathogenesis of idiopathic nephrotic syndrome is hypothesised to be either immune-mediated, owing to a systemic podocyte- derived circulating factor, or, in rarer or familial forms, a genetic variant. Numerous mutations are associated with steroid- resistant nephrotic syndrome that affect various parts of the podocyte itself, or the other constituents of the glomerular basement membrane. These include mutations affecting the podocyte nucleus, mitochondria or lysosomes, the slit diaphragm or actin cytoskeleton, and the glomerular basement membrane. Nephrin, podocin, and CD2AP, for example, are essential components of a zipper-like structure spanning the interdigitating foot processes of the podocyte, the slit diaphragm and link directly with the podocyte actin cytoskeleton. The actin cytoskeleton is further supported by microfilaments that maintain structural stability and facilitate the dynamic nature of the podocyte structure and function. The importance of these microfilaments is evident as mutations in both α-actinin 4 and INF2, which are involved in actin regulation and polymerisation lead to FSGS. It is suspected that dysfunction or dysregulation of T lymphocytes are involved in the pathogenesis of NS. Supportive evidence includes the efficacy of immunosuppressive agents in NS, spontaneous NS remission following infection with measles, and the resolution of NS following chemotherapy for Hodgkin's and other T-cell lymphomas, which can trigger or precede NS. Lastly, development of NS after allergic reactions to various stings and poisons suggests an immune-mediated role in disease pathogenesis. Principal treatments for nephrotic syndrome at diagnosis and follow-up After initial therapy with steroids, children are classified as having SSNS or SRNS after at least 8 weeks of therapy. Frequently relapsing SSNS can first be treated with low-dose alternate-day steroids prior to consideration of steroid-sparing agents. Typically, the steroid-sparing agents include cyclophosphamide, or levamisole, and if this fails and the child continues to relapse or is steroid dependent, then a calcineurin inhibitor is often the next agent, or mycophenolate mofetil. The scarcity of trial evidence has resulted in substantial variation in choice of steroid-sparing agents based on physicians' preference, drug availability by country, and cost. SSNS=steroid sensitive nephrotic syndrome. SRNS=steroid resistant nephrotic syndrome. FRNS=frequently relapsing nephrotic syndrome. SDNS=steroid dependent nephrotic syndrome. ACE=angiotensin converting enzyme inhibitor. ARB=angiotensin receptor blocker. Published protocols for steroid treatment (prednisone or prednisolone) for initial presentation of idiopathic nephrotic syndrome

Sepsis and septic shock is a common condition that is associated with unacceptably high mortality and, for many of those who survive, long-term morbidity. Increased awareness of the condition resulting from ongoing campaigns and the evidence arising from research in the past 10 years have increased understanding of this problem among clinicians and lay people, and have led to improved outcomes. The World Health Assembly and WHO made sepsis a global health priority in 2017 and have adopted a resolution to improve the prevention, diagnosis, and management of sepsis. In 2016, a new definition of sepsis (Sepsis-3) was developed. Sepsis is now defined as infection with organ dysfunction. This definition codifies organ dysfunction using the Sequential Organ Failure Assessment score. Ongoing research aims to improve definition of patient populations to allow for individualised management strategies matched to a patient's molecular and biochemical profile. The search continues for improved diagnostic techniques that can facilitate this aim, and for a pharmacological agent that can improve outcomes by modifying the disease process. While waiting for this goal to be achieved, improved basic care driven by education and quality-improvement programmes offers the best hope of increasing favourable outcomes.

Description of sequential organ failure assessment (SOFA) scoring system

PAMP-PRR pathways in sepsis PAMP=pathogen-associated molecular pattern. PRR=pattern recognition receptor.

A male newborn baby was delivered by caesarean section at 38 weeks' gestational age because of a prenatal ultrasound diagnosis of a congenital diaphragmatic hernia. Shortly after delivery he was in respiratory distress and cyanotic, and unable to move freely. He was rapidly intubated and treated with high-frequency oscillatory ventilation. When he was stable, an x-ray was carried out at the bedside. This showed herniated bowel loops in the left hemithorax, displacement of the mediastinum to the contralateral side, and severely reduced lung space and unclear lung fields bilaterally. The left hemi-diaphragm could not be seen separately.

Bochdalek hernia Chest x-ray showing herniated bowel loops in the left hemithorax, displacement of the mediastinum to the contralateral side, severely reduced lung space and unclear lung fields bilaterally (A). Upper gastrointestinal tract x-ray showing the stomach and bowel loops stained with contrast in the left hemithorax (B). A series of upper gastrointestinal x-rays, using water-soluble iodinated contrast media passed through a nasogastric catheter, were also taken to further assess the patient's condition. The stomach and loops of bowel stained with contrast were clearly visible in the left hemithorax. The patient underwent a patch repair of the left posterolateral diaphragmatic hernia and the herniated viscera were returned to the abdominal cavity. The contents of hernia were identified as colon, small bowel, stomach, and spleen. The patient had an uneventful post-operative period and was well at 6 months' follow-up. In this case the diagnosis was a Bochdalek hernia, also known as a posterolateral diaphragmatic hernia or pleuro-peritoneal hernia. The anatomical defect is in the postero-lateral part of the diaphragm allowing abdominal viscera to herniate through into the thorax. The condition was first described by the Czech anatomist and pathologist, Vincenz Alexaner Bochdalek (1801–1883) in 1848. Bochdalek hernia is a cause of respiratory distress in the newborn baby; symptoms include cyanosis, tachycardia, and one side of the chest cavity appearing larger than the other.