https://www.mdc-berlin.de/de/veroeffentlichungstypen/clinical- journal-club

Als gemeinsame Einrichtung von MDC und Charité fördert das Experimental and Clinical Research Center die Zusammenarbeit zwischen Grundlagenwissenschaftlern und klinischen Forschern. Hier werden neue Ansätze für Diagnose, Prävention und Therapie von Herz-Kreislauf- und Stoffwechselerkrankungen, Krebs sowie neurologischen Erkrankungen entwickelt und zeitnah am Patienten eingesetzt. Sie sind eingelanden, um uns beizutreten. Bewerben Sie sich! A 69-year-old man with type 2 mellitus presented to the clinic for a routine ocular examination. He had a history of cataract surgery 3 years ago for a retinal detachment in the right eye. Clinical examination of the right eye showed a white substance covering the upper third of the iris. Visual acuity was 20/400 in the right eye and 20/40 in the left eye. What is the diagnosis?

Loculated hypopyon

Ghost cell

Synchysis scintillans

Silicone oil hyperoleon

Iridodialysis

Slit-lamp examination of the right eye revealed a layer of emulsified silicone oil in the superior anterior chamber, known as a hyperoleon, that moved slightly with tilting of the head. The long-term use of silicone oil as an endotamponade in ocular surgery can result in complications associated with emulsification of silicone oil and prolapse through anatomically compromised areas. The density of silicone oil is lower than that of aqueous humor, and therefore, it settles at the top of the anterior chamber. The silicone oil was surgically removed, and the patient’s visual acuity improved to 20/80. Als Hypopyon bezeichnet man eine Ansammlung von Eiter in der Vorderkammer des Auges.

Ursächlich für Hypopyone sind in der Regel Entzündungen, die durch in das Auge eindringende Mikroorganismen entstehen, z.B.: Erreger, die nach einer perforierenden Verletzung des Auges eindringen können

Bakterien, die Geschwüre der Hornhaut (Ulcus serpens corneae) verursachen und mit ihren Toxinen eine eitrige Entzündungsreaktion hervorrufen virale Infektionen des Auges (Herpeskeratitis) bei Kontaklinsenträgern kommt es häufig zu einem Hypopyon im Rahmen einer eitrigen Konjunktivitis durch Pseudomonas

Ein Hypopyon tritt aber auch in Verbindung mit intraokulären Tumoren (Retinoblastom, Leu kämie) auf. Ghost cell glaucoma is a secondary open-angle glaucoma caused by degenerated red blood cells (ghost cells) blocking the .

Ghost cell glaucoma may occur after vitreous hemorrhage.

Causes of ghost cell glaucoma include ocular trauma, systemic diseases such as diabetes or /trait, iritis (Fuchs heterochromic iridocyclitis, herpes simplex, herpes zoster, etc.), intraocular tumors (retinoblastoma, malignant melanoma, etc.), glaucoma hyphema syndrome, rubeosis iridis, iris varices, papillary microhemangiomas, and ocular surgery including but not limited to cataract extraction, laser trabeculoplasty and iridotomy. One case report of ghost cell glaucoma after a snake bite has been reported. Ghost cell glaucoma has also been reported to occur spontaneously. Synchysis scintillans is a degenerative condition of the eye resulting in liquefied vitreous humor and the accumulation of cholesterol crystals within the vitreous. It is also known as cholesterolosis bulbi. The vitreous liquifies in a process known as syneresis. Synchysis scintillans appears as small white floaters that freely move in the posterior part of the eye, giving a snow globe effect. It is most commonly seen in eyes that have suffered from a degenerative disease and are end-stage. In humans as well, the condition is seen rarely. Associated with the advanced stages of diabetic retinopathy, but the exact pathogenesis is unknown. The condition is symptomless and untreatable. It appears as a beautiful shower of golden rain in ophthalmoscopic examination. Iridodialysis, is a localized separation or tearing away of the iris from its attachment to the ciliary body.

Iridodialyses are usually caused by blunt trauma to the eye, but may also be caused by penetrating eye injuries. An iridodialysis may be an iatrogenic of any intraocular surgery and at one time they were created intentionally as part of intracapsular cataract extraction. Iridodialyses have been reported to have occurred from boxing, airbag deployments, high- pressure water jets, elastic bungee cords, bottle caps opened under pressure, water balloons, fireworks, and various types of balls. Hyperoleon A 33-year-old woman presented with pain in the left eye. She had a history of wearing glasses of high minus power (–11D) in both eyes. She had undergone vitreoretinal surgery with silicone oil (SO) tamponade for retinal breaks as management of rhegmatogenous retinal detachment (RRD) in the left eye 2 years prior. There was aphakia, inferior peripheral iridectomy (PI), emulsified SO in the anterior chamber accumulating superiorly with a horizontal oil–aqueous level (hyperoleon), increased (IOP) and glaucomatous optic neuropathy.

Hyperoleon is seen superiorly in the anterior chamber as SO (specific gravity 0.97) is lighter than . On the contrary, hypopyon and hyphaema are manifestations of deposition of pus and haemorrhage, respectively, in the inferior part of the anterior chamber. Hypopyon denotes an inflammatory or infective process and should not be confused with a hyperoleon. Hyperoleon is a manifestation of emulsification of SO and is commonly associated with glaucoma. Inferior PI (Ando's PI) is performed in the SO-filled eye to prevent pupillary block glaucoma. Hyperoleon necessitates SO removal. Endovascular Thrombectomy with or without Intravenous Alteplase in Acute Stroke In acute ischemic stroke, there is uncertainty regarding the benefit and risk of administering intravenous alteplase before endovascular thrombectomy. We conducted a trial at 41 academic tertiary care centers in China to evaluate endovascular thrombectomy with or without intravenous alteplase in patients with acute ischemic stroke. Patients with acute ischemic stroke from large-vessel occlusion in the anterior circulation were randomly assigned in a 1:1 ratio to undergo endovascular thrombectomy alone (thrombectomy-alone group) or endovascular thrombectomy preceded by intravenous alteplase, at a dose of 0.9 mg per kilogram of body weight, administered within 4.5 hours after symptom onset (combination-therapy group). The primary analysis for noninferiority assessed the between-group difference in the distribution of the modified Rankin scale scores (range, 0 [no symptoms] to 6 [death]) at 90 days on the basis of a lower boundary of the 95% confidence interval of the adjusted common odds ratio equal to or larger than 0.8. We assessed various secondary outcomes, including death and reperfusion of the ischemic area.

Rivaroxaban in Peripheral Artery Disease after Revascularization

Patients with peripheral artery disease who have undergone lower-extremity revascularization are at high risk for major adverse limb and cardiovascular events. The efficacy and safety of rivaroxaban in this context are uncertain. In a double-blind trial, patients with peripheral artery disease who had undergone revascularization were randomly assigned to receive rivaroxaban (2.5 mg twice daily) plus aspirin or placebo plus aspirin. The primary efficacy outcome was a composite of acute limb ischemia, major amputation for vascular causes, myocardial infarction, ischemic stroke, or death from cardiovascular causes. The principal safety outcome was major bleeding, defined according to the Thrombolysis in Myocardial Infarction (TIMI) classification; major bleeding as defined by the International Society on Thrombosis and Haemostasis (ISTH) was a secondary safety outcome.

Kaplan–Meier Analysis of the Primary Composite Efficacy Outcome. The primary efficacy outcome was a composite of acute limb ischemia, major amputation for vascular causes, myocardial infarction, ischemic stroke, or cardiovascular death. The inset shows the same data on an expanded y axis.

Remdesivir for the Treatment of Covid-19 — Preliminary Report

Although several therapeutic agents have been evaluated for the treatment of coronavirus disease 2019 (Covid- 19), none have yet been shown to be efficacious. We conducted a double- blind, randomized, placebo- controlled trial of intravenous remdesivir in adults hospitalized with Covid-19 with evidence of lower respiratory tract involvement. Patients were randomly assigned to receive either remdesivir (200 mg loading dose on day 1, followed by 100 mg daily for up to 9 additional days) or placebo for up to 10 days. The primary outcome was the time to recovery, defined by either discharge from the hospital or hospitalization for infection-control purposes only.

Preliminary results of this trial suggest that a 10-day course of remdesivir was superior to placebo in the treatment of hospitalized patients with Covid-19. This benefit was seen in the number of days to recovery (median, 11 days, as compared with 15; rate ratio for recovery, 1.32 [95% CI, 1.12 to 1.55]) and in recovery according to the ordinal scale score at day 15 (odds ratio, 1.50; 95% CI, 1.18 to 1.91). Even though the trial was ongoing, the data and safety monitoring board made the recommendation to unblind the results to the trial team members from the NIAID, who subsequently decided to make the results public. Given the strength of the results about remdesivir, these findings were deemed to be of immediate importance for the care of patients still participating in the trial as well as for those outside the trial who might benefit from treatment with remdesivir. The benefit was most apparent in patients with a baseline ordinal score of 5 (requiring oxygen), a finding most likely due to the larger sample size in this category (since the interaction test of treatment by baseline score on the ordinal scale was not significant). Confidence intervals for baseline ordinal scores of 4 (not receiving oxygen), 6 (receiving high-flow oxygen), and 7 (receiving ECMO or mechanical ventilation) are wide. We note that the median recovery time for patients in category 7 could not be estimated, which suggests that the follow-up time may have been too short to evaluate this subgroup. Additional analyses of outcomes such as the time to a one- or two-point improvement on the ordinal scale score will be conducted after the full cohort has completed 28 days of follow- up and may provide additional insight into the treatment of this critical subgroup. Our findings highlight the need to identify Covid-19 cases and start antiviral treatment before the pulmonary disease progresses to require mechanical ventilation. The primary outcome of the current trial was changed with protocol version 3 on April 2, 2020, from a comparison of the eight-category ordinal scale scores on day 15 to a comparison of time to recovery up to day 29. Little was known about the natural clinical course of Covid-19 when the trial was designed in February 2020. Emerging data suggested that Covid-19 had a more protracted course than was previously known, which aroused concern that a difference in outcome after day 15 would have been missed by a single assessment at day 15. The amendment was proposed on March 22, 2020, by trial statisticians who were unaware of treatment assignment and had no knowledge of outcome data; when this change was proposed 72 patients had been enrolled. Although changes in the primary outcome are not common for diseases that are well understood, it is recognized that in some trials, such as those involving poorly understood diseases, circumstances may require a change in the way an outcome is assessed or may necessitate a different outcome. The original primary outcome became the key secondary end point. In the end, findings for both primary and key secondary end points were significantly different between the remdesivir and placebo groups. Children account for less than 2% of identified cases of coronavirus disease 2019 (COVID-19). It is hypothesized that the lower risk among children is due to differential expression of angiotensin-converting enzyme 2 (ACE2),3 the receptor that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) uses for host entry. We investigated ACE2 gene expression in the nasal epithelium of children and adults. We conducted a retrospective examination of nasal epithelium from individuals aged 4 to 60 years encountered within the Mount Sinai Health System, New York, New York, during 2015-2018. Samples were collected from individuals with and without asthma for research on nasal biomarkers of asthma. The study was approved by the Mount Sinai institutional review board. Written informed consent was obtained from participants (or their parents for minors). Nasal epithelium was collected using a cytology brush that was immediately placed in RNA stabilization fluid and stored at −80 °C. RNA was isolated within 6 months. RNA samples were checked for quality and sequenced as a single batch in 2018. Sequence data processing included sequence alignment and normalization of gene expression counts across genes and samples.

When referring to a group of cells inoculated with virus particles, the multiplicity of infection or MOI is the ratio of the number of virus particles to the number of target cells present in a defined space. To compare the transcriptional response of SARS-CoV-2 with other respiratory viruses, including MERS-CoV, SARS-CoV-1, human parainfluenza virus 3 (HPIV3), respiratory syncytial virus (RSV), and influenza virus (IAV), we first chose to focus on infection in a variety of respiratory cell lines GO = Gene ontology

Transmission of SARS-CoV-2 in Domestic Cats Reports of human-to-feline transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and of limited airborne transmission among cats prompted us to evaluate nasal shedding of SARS-CoV-2 from inoculated cats and the subsequent transmission of the virus by direct contact between virus-inoculated cats and cats with no previous infection with the virus. Three domestic cats were inoculated with SARS-CoV-2 on day 0. One day after inoculation, a cat with no previous SARS-CoV-2 infection was cohoused with each of the inoculated cats to assess whether transmission of the virus by direct contact would occur between the cats in each of the three pairs The cats with no previous infection were cohoused with the inoculated cats on day 1. Two days later (day 3), one of the cats with no previous infection had infectious virus detected in a nasal swab specimen, and 5 days later, virus was detected in all three cats that were cohoused with the inoculated cats. Virus titers in the cats that were cohoused with the inoculated cats peaked at 4.5 log10 plaque-forming units per milliliter, and virus shedding lasted 4 to 5 days. No virus was detected in any of the rectal swabs tested. Although there have been reports of symptomatic infected cats, none of the cats in our study showed any symptoms, including abnormal body temperature, substantial weight loss (Fig. S1), or conjunctivitis. All the animals had IgG antibody titers between 1:5120 and 1:20,480 on day 24 after the initial inoculation. With reports of transmission of SARS-CoV-2 from humans to domestic cats and to tigers and lions at the Bronx Zoo, coupled with our data showing the ease of transmission between domestic cats, there is a public health need to recognize and further investigate the potential chain of human–cat–human transmission. This is of particular importance given the potential for SARS-CoV-2 transmission between family members in households with cats while living under “shelter-in- place” orders. In 2016, an H7N2 influenza outbreak in New York City cat shelters highlighted the public health implications of cat-to-human transmission to workers in animal shelters. Moreover, cats may be a silent intermediate host of SARS-CoV-2, because B. infected cats may not show any appreciable symptoms that might be recognized by their owners. The Centers for Disease Control and Prevention has issued guidelines for pet owners regarding SARS-CoV-2. Given the need to stop the coronavirus disease 2019 pandemic through various mechanisms, including breaking transmission chains, a better understanding of the role cats may play in the transmission of SARS- CoV-2 to humans is needed. How to Discover Antiviral Drugs Quickly We urgently need effective drugs for coronavirus disease 2019 (Covid-19), but what is the quickest way to find them? One approach that sometimes seems akin to a “Hail Mary” pass in American football is to hope that drugs that have worked against a different virus (such as hepatitis C or Ebola) will also work against Covid-19. Alternatively, we can be rational and specifically target proteins of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) so as to interrupt its life cycle. The SARS-CoV-2 genome encodes approximately 25 proteins that are needed by the virus to infect humans and to replicate. Among these are the notorious spike (S) protein, which recognizes human angiotensin- converting enzyme 2 in the initial stage of infection; two proteases, which cleave viral and human proteins; the RNA polymerase, which synthesizes viral RNA; and the RNA-cleaving endoribonuclease. Finding drugs that can bind to the viral proteins and stop them from working is a logical way forward and the priority of many research laboratories.

The SARS-CoV-2 Virion and Its Proteins.Although all the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) proteins are potential drug targets, some are likely to be more easy to find a drug against, in part because they play principal roles in the viral lifecycle and also lack human protein homologues. Examples include the spike glycoprotein, the papain-like protease, the chymotrypsin-like main protease, and the RNA-dependent RNA polymerase. ACE2 denotes angiotensin-converting enzyme 2, NSP nonstructural protein, ORF open reading frame, and RdRP RNA-dependent RNA polymerase. One approach toward this goal involves mimicking nature with the use of computational structure-based drug discovery. In this process, computers “dock” trial compounds into binding sites in three-dimensional models of the protein targets. The binding affinities of the compounds are calculated with the use of physics- based equations that quantify the interactions between the drug and its target. The top-ranked compounds are then tested experimentally to see if they do indeed bind and have the required downstream effects (such as stopping viral infectivity) on cells and in animal models. Structure-based drug discovery has been important in finding antiviral drugs, an example being nelfinavir, discovered in the 1990s, to treat human immunodeficiency virus (HIV) infection. Unfortunately, though, at that time the process was relatively inefficient: calculations were inaccurate and computers so feeble that only about 100 compounds could be docked at a time. Moreover, both the target and the drug had to be held rigid in the docking process in a lock-and-key approach. Rigid docking does not often take place in real life, because proteins undergo thermally driven internal motions that lead to fluctuating binding-site shapes. Modern supercomputers such as the Summit supercomputer at Oak Ridge National Laboratory, which is currently the world’s most powerful, perform massively parallel processing in which many calculations are performed at the same time. This enables molecular-dynamics simulations of many replicas of the target to be run in parallel, each exploring a slightly different conformational space. Thus, a comprehensive simulation model of a SARS-CoV-2 protein drug target can be obtained with the use of Summit in a day, whereas it would take months with the use of a typical computer cluster. Supercomputers are also used in rapid parallel docking of large databases of compounds. The structure-based drug-discovery field is thus primed for quick results. So, what is happening now? The laborious, decade-long, classic pathway for the discovery and approval of new drugs could hardly be less well suited to the present pandemic. Repurposing existing drugs offers a potentially rapid mechanism to deployment, since the safety profiles are known. Therefore, a preliminary report of a supercomputer- driven ensemble docking study of a repurposing compound database to the viral S protein was published on a preprint server in mid-February, with 8000 compounds ranked according to the calculated binding affinity to the receptor- binding domain of the S protein. Top-ranked compounds from the original S-protein virtual screen are being tested for activity against the live virus. The results will inform future calculations in a speedy, iterative process. Emerging and Reemerging Sexually Transmitted Infections

The 21st century has seen a global resurgence of sexually transmitted infections (STIs). From a nadir in the 1990s, the rates of gonorrhea, syphilis, and chlamydia infections have increased substantially in high-income countries, with particular increases among men who have sex with men (MSM). Concurrent with the increase in these established STIs are emerging epidemics and outbreaks of “nonclassical” sexually transmissible pathogens that cause a wide range of clinical syndromes. These pathogens include enteric pathogens (e.g., shigella and hepatitis A virus), those spread by close contact (e.g., Neisseria meningitidis), and recently characterized pathogens that can spread through sexual contact (e.g., Zika virus) Sexually Transmissible Enteric Pathogens Shigella Sexual transmission of shigella species was reported in the 1970s, with regular outbreaks of Shigella sonnei and S. flexneri in urban centers among MSM. Shigellosis ranges from self- limiting gastroenteritis to severe, bloody dysentery. Behavioral factors associated with sexually transmissible shigellosis include direct oral–anal contact, “chemsex” (use of drugs to enhance sexual experiences), condomless sex, multiple sexual partners, use of social networking (apps) to meet sexual partners, and attendance at sex parties. Hepatitis A Virus Hepatitis A virus (HAV) causes an acute, self-limiting hepatitis that is fulminant in less than 0.5% of infections. HAV is transmitted by the fecal–oral route through ingestion of contaminated food or water or by direct contact with an infectious person. In countries where the prevalence of HAV infection is low, such as the United States, the low incidence of childhood infection has resulted in a large proportion of nonimmune adults, increasing the potential for large-scale outbreaks, including outbreaks spread by sexual contact among MSM. Other Enteric Pathogens Sexual transmission of enteric pathogens other than shigella and HAV has also been described. Campylobacter species have been associated with gastrointestinal outbreaks in MSM, including a sustained outbreak, lasting for approximately 10 years, of erythromycin- and ciprofloxacin-resistant Campylobacter jejuni in Quebec, Canada. Patients with Sexually Transmissible Enteric Infections Sexual transmission of enteric pathogens is well recognized and can be direct (e.g., through oral–anal contact) or indirect (e.g., through contact with fecally contaminated fingers or objects). Outbreaks of sexually transmissible enteric infections among MSM can be driven by a combination of pathogen, host, and environmental factors

Neisseria meningitidis N. meningitidis colonizes the nasopharynx in approximately 10% of healthy persons and, less frequently, also colonizes other mucosal sites, such as the cervix, urethra, and rectum. The pathogen has increasingly been recognized as sexually transmissible, with two distinct clinical contexts emerging: N. meningitidis–associated urethritis in heterosexual men and invasive meningococcal disease in MSM. Lymphogranuloma venereum Lymphogranuloma venereum (LGV) is caused by Chlamydia trachomatis serovar L1, L2, or L3. Unlike infections caused by the more common chlamydial serovars D through K, LGV infections generally spread through the lymphatics to regional lymph nodes, resulting in inguinal lymphadenopathy. Rectal LGV infection can cause proctitis with rectal pain and discharge and in some cases may be clinically severe, with proctocolitis mimicking inflammatory bowel disease. Mycoplasma genitalium M. genitalium was first described as an STI in 1981, when it was isolated from two men with nongonococcal urethritis. Because M. genitalium does not grow in routine laboratory culture, molecular testing is used for diagnosis, with the first Food and Drug Administration–approved nucleic acid amplification test available in the United States as of 2019 for use on urogenital samples from both symptomatic and asymptomatic persons. Zika Virus Zika virus (ZIKV) is a flavivirus transmitted by aedes mosquitoes, which causes a self-limiting denguelike illness, with symptoms including fever, rash, , and arthralgia. Of particular concern is the effect of ZIKV infection during pregnancy, which can result in microcephaly and other fetal brain anomalies. Ebola Virus Cases of sexual transmission of Ebola virus have been reported since the large outbreak of Ebola that occurred in West Africa between 2014 and 2016. Ebola virus can be found in the semen of male survivors of Ebola virus disease, providing a biologic basis for sexual transmission months after recovery. New Issues with Established STIs Syphilis Syphilis remains a major public health problem globally, with the WHO estimating that there were 6 million new infections worldwide in 2016. Syphilis can result in serious morbidity, including ocular syphilis, neurosyphilis, and congenital infection. Over the past decade, the incidence of syphilis among MSM has increased markedly in many countries. For example, in the United States, the rate of primary or secondary syphilis among MSM increased from 11.7 cases per 100,000 population in 2014 to 18.7 per 100,000 in 2018. The incidence of syphilis has been particularly high among MSM who are receiving preexposure prophylaxis against HIV infection, underscoring the importance of regular syphilis screening together with HIV testing in MSM who are using preexposure prophylaxis against HIV infection. Since primary syphilis can resemble other STIs that cause anogenital ulceration, multiplex PCR testing for the simultaneous detection of pathogens such as Treponema pallidum and herpes simplex virus has been used to improve diagnostic accuracy. Gonorrhea Another key emerging issue is increasing antimicrobial resistance in N. gonorrhoeae, which the CDC has identified as an urgent threat to public health in the United States. It is estimated that there are approximately 550,000 drug-resistant N. gonorrhoeae infections per year in the United States. Of particular concern is reduced susceptibility to ceftriaxone, azithromycin, or both — the two major drugs recommended for first-line treatment in most high-income countries. Conclusions Rates of established STIs in many countries are approaching levels not seen since the 1970s, with concerns about public health priorities such as increasing antimicrobial resistance in N. gonorrhoeae and the rising incidence of congenital syphilis. New or reemerging sexually transmissible pathogens with potentially serious morbidity present additional challenges to public health control, health services, and community responses. The incidence of these STIs will probably continue to increase as a result of enhanced human interconnectedness due to growth in international travel, in online social networking, and in numbers of people taking preexposure prophylaxis. Timely testing and treatment have been critical for the control of STIs, and this applies equally to newer sexually transmissible pathogens. A 37-year-old man with hemophilia type A presented to the orthopedic clinic with progressive difficulty walking. He had a history of inadequate factor VIII replacement therapy and had had malunion of a traumatic fracture of the left femoral shaft that had been managed without surgery 10 years earlier. Since then, the patient had repeated episodes of swelling of the left thigh and progressive shortening of the leg. He could not bear weight on the left leg and walked with crutches. Physical examination showed swelling but no pain in the left thigh and restricted active and passive movements of the left hip. The distance from the greater trochanter to the lateral malleolus was 10 cm shorter on the left than on the right. The patient’s factor VIII level was less than 1 IU per deciliter (reference range, 50 to 150). Anteroposterior radiographs of the legs (Panel A) and left femur (Panel B) showed a deformity of the left femur with a “soap bubble” appearance consistent with a hemophilic pseudotumor. Hemophilic pseudotumor is a complication of hemophilia arising from repeated bleeding into and subsequent destruction of the bone, often in patients who are receiving inadequate factor replacement. The patient was evaluated for surgery and was scheduled to undergo total femur replacement. An 8-year-old boy presented with subcutaneous nodules associated with a 1-week history of fever 2 months after starting treatment for relapsing B-cell leukemia. He had had pancytopenia for 57 days, and laboratory studies showed a hemoglobin level of 7.5 g per deciliter (reference range, 11.5 to 14.5), a white-cell count of 200 per cubic millimeter (reference range, 5000 to 11,000), and a platelet count of 12,000 per cubic millimeter (reference range, 150,000 to 400,000). Fevers persisted despite the initiation of broad-spectrum intravenous antibiotic and antifungal treatment, and 1 week later, the subcutaneous nodules developed. Physical examination revealed nodules ranging from 5 to 18 mm in diameter on the chest, back, arms, and legs (Panel A). A biopsy specimen of a nodule was obtained. Microscopic examination of a dry smear stained with lactophenol cotton blue revealed septated hyphae and spores (Panel B), and Fusarium dimerum was grown in culture. Gram’s staining of a blood culture revealed hyphae and spores (Panel C), and cultures also revealed F. d i m e ru m . The patient completed a prolonged course of treatment with antifungal therapy. His fever resolved within 11 days, and the skin lesions resolved within 20 days. A 47-Year-Old Woman with Recurrent Melanoma and Pulmonary Nodules A 47-year-old woman with malignant melanoma was seen in the pulmonary clinic of this hospital because of new abnormal findings on chest imaging. The patient had observed routine quarterly surveillance imaging after resection of right axillary melanoma, radiation therapy, and initiation of pembrolizumab therapy 3 years earlier. The most recent imaging was performed 6 days before this evaluation.

Six days before evaluation at this hospital, CT of the chest was performed after the administration of intravenous contrast material; the scan shows new bilateral hilar and subcarinal lymphadenopathy (Panel A), a new peripheral patchy consolidation in the left upper lobe (Panel B), and new bilateral pulmonary nodules (Panels C and D, arrows). Positron-emission tomography and CT had been performed 3 years before the current evaluation; the scan shows a 3.5-cm right axillary soft-tissue nodal mass (Panel E, arrow) with foci of intense 18F-fluorodeoxyglucose uptake (Panel F) and no other sites of avidity.

The patient was referred by her oncologist for urgent evaluation in the pulmonary clinic of this hospital. On evaluation, the patient reported no symptoms, specifically no fever, weight loss, night sweats, fatigue, malaise, headache, chest pain, cough, hemoptysis, new or changed skin lesions (except a mild traumatic abrasion on the right arm), pruritus, or new masses. Three years before the current evaluation, locally advanced melanoma in the right axilla was diagnosed on the basis of a positron-emission tomographic and CT image that showed a 3.5-cm right axillary nodal conglomerate mass with multiple foci of intense 18F-fluorodeoxyglucose (FDG) uptake; no other sites of FDG avidity were seen (Fig. E and F). Multiple pulmonary nodules, measuring 2 to 4 mm in greatest dimension, in the right lobe and hypodense hepatic lesions, measuring 9 mm in the right lobe and 10 mm in the left lobe, were noted. MRI of the abdomen suggested that the hepatic lesion in the right lobe corresponded to a hemangioma and the hepatic lesion in the left lobe a cyst. MRI of the head, performed before and after the administration of intravenous contrast material, was normal. At that time, dissection of the right axillary lymph nodes was performed, and examination of the specimens revealed metastatic melanoma in 25 of 39 lymph nodes, with a high degree of extracapsular extension. Molecular profiling identified the BRAF V600E mutation. The patient received radiation therapy to the right axilla and supraclavicular fossa (total dose of 4800 cGy over a period of 5 weeks), followed by pembrolizumab every 3 weeks for the next 12 months. The patient was born on the northern coast of South America and had immigrated to the United States as a child. She lived in New England with her husband, two children, and two cats. She worked in the health care industry. She drank one or two glasses of wine per day and did not smoke tobacco or use illicit drugs. One month before this evaluation, she and her family had traveled to the northern coast of South America for 1 week. On the trip, the patient spent most her time outdoors, including taking trips to the jungle and swimming in fresh water, and ate local cuisine, such as water chestnuts. When she returned home with her family, her husband and one of her children had generalized myalgias and malaise that resolved spontaneously. On examination, the temperature was 37.0°C, the blood pressure 123/68 mm Hg, the pulse 56 beats per minute, the respiratory rate 18 breaths per minute, and the oxygen saturation 100% while the patient was breathing ambient air. The body-mass index (the weight in kilograms divided by the square of the height in meters) was 20.8. She appeared well, and the lungs were clear on auscultation. Examination showed fair skin, multiple nevi without suspicious features, and healed scars at the sites of previous surgical procedures. There were lichenoid nodules on the fingers of both hands. The remainder of the physical examination was normal. The levels of electrolytes, glucose, and lactate dehydrogenase were normal, as were results of renal- and liver-function tests. The complete blood count and differential count were also normal. Blood samples were obtained for culture. An interferon-γ release assay for Mycobacterium tuberculosis was negative, and the level of 1,3-β-d-glucan was less than 31 pg per milliliter (reference value, <60). Diagnostic tests were performed. Problem Representation Following this paradigm, the problem representation in this case includes key facts about the patient (i.e., she is in her 40s, she received immunotherapy for metastatic melanoma, and she recently traveled to South America) and key (i.e., finding of bilateral pulmonary nodules, hilar and mediastinal lymphadenopathy, and left upper lobe infiltrate without associated symptoms). Timing is also important, with key dates showing that the patient had completed pembrolizumab treatment 2 years before the current presentation and had not had lung disease or evidence of melanoma since that time. Assessing Probabilities of Diagnoses Ideally, once we have defined the problem representation, we should be able to translate the representation into probabilities of various diagnoses. Finding that information can be surprisingly challenging. Most clinical studies describe patients with a given diagnosis, thereby enabling the assessment of the probability that, for example, patients with sarcoidosis have hilar lymphadenopathy, but not the probability that patients with hilar lymphadenopathy have sarcoidosis. Useful information can sometimes be found in studies evaluating new diagnostic tests. Two studies that evaluated the use of endobronchial ultrasound-guided transbronchial needle aspiration in determining the underlying causes of hilar or mediastinal lymphadenopathy provide information about the final diagnoses of the patients. If this patient’s presentation is unlikely to represent an autoimmune complication of PD-1 inhibitor therapy, then a granulomatous infection becomes a more likely diagnosis. The most common pulmonary infections that are manifested by hilar and mediastinal lymphadenopathy are tuberculosis and fungal infections, primarily coccidioidomycosis and histoplasmosis and, less commonly, blastomycosis and cryptococcal disease. Pulmonary infiltrates with lymphadenopathy are commonly seen with primary tuberculosis but not with reactivation of the disease. However, primary tuberculosis is uncommon in immunocompetent adults and generally manifests with cough, fever, and fatigue. Furthermore, given the patient’s negative interferon-γ release assay for tuberculosis, the probability of this diagnosis is low. Both coccidioidomycosis and histoplasmosis can be manifested by pulmonary infiltrates, nodules, and lymphadenopathy in immunocompetent hosts. With both infections, pulmonary nodules can have ground-glass halos on CT — a finding associated with an adjacent area of hemorrhage or tissue injury. However, a halo sign occurs with other conditions, and information about its predictive ability is hard to find. Patients who have either coccidioidomycosis or histoplasmosis are usually asymptomatic, but 40% of patients with coccidioidomycosis have an influenza-like illness with fever, cough, and fatigue. Distinguishing between these infections often depends on a patient’s history of exposure. Exposure to the fungi that cause either infection is unlikely in the northeastern region of the United States, making this patient’s trip to South America her most likely source of exposure — a hypothesis that is supported by the presence of the concomitant mild febrile illnesses of her family members. Histoplasmosis is far more common than coccidioidomycosis in that region. A negative 1,3-β-d-glucan test lowers the probability of both diagnoses but does not rule out either one. Thus, histoplasmosis becomes the most likely diagnosis in this case. Clinical Impression Given the aggressive nature of this patient’s melanoma and her high nodal burden of disease before surgery, as well as extranodal extension, I was most concerned about recurrence of metastatic disease. Alternatively, late immune-related adverse effects from immunotherapy were a consideration, but this patient’s clinical course did not reflect the typical pattern of immune-related pneumonitis. She underwent an extensive workup for infectious causes because of her recent travel to South America, and while waiting for those results, she underwent a bronchoscopy. We performed a flexible bronchoscopy with endobronchial ultrasound-guided transbronchial needle aspiration of the lymph nodes in the mediastinum and hila (stations 11R, 7, and 11L). The rapid on-site evaluation of the specimens revealed no cancer cells, so we proceeded with obtaining parenchymal lung-biopsy specimens through the esophagus. We used endoscopic ultrasonography with a bronchoscope to obtain a biopsy specimen of the pulmonary nodule that had been noted in the right lower lobe near the esophagus. Histologic examination of the lung-biopsy specimen revealed a granulomatous cellular infiltrate. This finding could suggest metastatic melanoma, given the patient’s history and the diverse histologic appearances of this disease. However, on immunohistochemical analysis, the lung-biopsy specimen did not show the melanoma markers HMB45 and S100. A microbiologic evaluation performed in parallel revealed growth of a tan-white mold after 12 days of incubation at 30°C. Microscopic Interventional Diagnostic Strategies. examination with lactophenol cotton-blue stain showed slender Mediastinal and hilar lymph nodes can be accessed by means of a variety of procedures, septate hyphae, microconidia, and conidia with characteristic including endobronchial ultrasonography protrusions called tubercles that lend a flower-like appearance. (EBUS), endoscopic ultrasonography (EUS), Notably, this mold grew from a tissue specimen containing yeast, and mediastinoscopy. In this case, lymph indicating that it was a dimorphic fungus. Dimorphic fungi include H. nodes at stations 11R, 7, and 11L were capsulatum, Blastomyces dermatitidis, Sporothrix schenckii, accessed by means of EBUS, and a pulmonary coccidioides species, Paracoccidioides brasiliensis, and Penicillium nodule in the right lower lobe near the pulmonary ligament (9R) was accessed marneffei, with H. capsulatum being the most likely in this case, through the esophagus by means of given its 2-to-4-μm size. Additional molecular testing with a endoscopic ultrasonography with a chemiluminescent DNA probe that targets H. capsulatum ribosomal bronchoscope (EUS-B). The insets show the RNA was positive. In isolation, this finding could indicate either of manner in which EBUS, EUS, or EUS-B can be two variants — H. capsulatum var. capsulatum or H. capsulatum used to sample structures that are in proximity var. duboisii — but H. capsulatum var. duboisii is found only in to the wall of the trachea, bronchi, or esophagus with real-time ultrasound guidance. Africa and those cells typically measure 6 to 12 μm in diameter. Biopsy Specimens of the Lung and Lymph Node and Microbiologic Studies. Hematoxylin and eosin staining of biopsy specimens of the lung (Panel A) and the lymph node (Panel B) shows granulomas (outlined by dashed lines). Gomori methenamine silver staining of the lymph-node specimen (Panel C) highlights yeast cells, measuring 2 to 4 μm in diameter, with narrow-based budding (arrow; micrometer ruler units). Lactophenol cotton-blue staining of the cultured mold (Panel D) shows slender septate hyphae (arrowhead), microconidia (black arrow), and conidia (red arrow); the inset shows a magnified view of conidia with characteristic tubercles (protrusions).

Pathological Diagnosis Histoplasma capsulatum var. capsulatum infection.

Standard radiation therapy delivers a dose of 2 Gy to the tumour at each fraction, 5 times a week during several weeks. This traditional fractionation regimen is aimed at maximising the local control of the tumour while minimising the toxicity to other healthy tissues based on radiobiology models. However, such fractionation regimen might not be beneficial for all tumours, in which case the dose per fraction can be increased without lowering the quality of the treatment. Hypofractionated radiotherapy is increasingly being used to treat cancer. For this radiation treatment, the total dose of radiation is divided into large doses and treatments are given once a day or less often. Hypofractionated radiotherapy is given over a shorter period of time than standard radiation therapy. This makes it more convenient for the patient as there are fewer appointments to attend. Also, there is less demand on staff and equipment time, making it a very resource efficient treatment while providing the same outcome for the patient. However, there are different levels of hypofractionation depending on the type of cancer. For prostate cancer for example, standard radiotherapy is given daily for 37 fractions. However, a recent trial on Conventional or Hypofractionated High dose intensity modulated radiotherapy for Prostate cancer (CHHiP), demonstrated that this could be reduced to 20 daily fractions. This is moderate hypofractionation

SDI actually captures three different but important aspects of development: income, education, and fertility.

The SDI variables are convincing. Is any political (and religious) system willing to address these problems?

Eine Enthesiopathie ist eine Gruppe von krankhaften Störungen meist gelenknaher Sehnenansatzpunkte. Eine bekannte Enthesiopathie ist der sogenannte Tennisarm. Sie ist in der Regel schmerzhaft und geht mit einer nichtbakteriellen (aseptischen) Entzündung einher. Als Frühzeichen der Spondylitis ankylosans und des vergleichsweise harmlosen Morbus Forestier lässt sich die Enthesopathie auf einfachen Röntgenbildern erkennen. Our patient had these results:

Crude estimate: FEPhos = 27%; Tubular Phos reabsorption = 73% Tubular reabsorption of phosphate= Urine phosphate should be zero FEPhos should be 0%; reabsorption 100% Phosphate-regulating neutral endopeptidase, X-linked also known as phosphate-regulating gene with homologies to endopeptidases on the X chromosome or metalloendopeptidase homolog PEX is an enzyme that in humans is encoded by the PHEX gene. The protein encoded by this gene is a transmembrane endopeptidase that belongs to the type II integral membrane zinc-dependent endopeptidase family. The protein is thought to be involved in bone and dentin mineralization and renal phosphate reabsorption. The bone and dentin protein osteopontin (OPN) which inhibits mineralization in the skeleton and in teeth is a substrate for PHEX. In the absence of functional PHEX in the mouse model (Hyp) of X-linked hypophosphatemia (XLH), and in human XLH where PHEX activity is decreased or absent, in addition to renal phosphate wasting, osteopontin and osteopontin fragments accumulate in bone and teeth and may contribute locally to the osteomalacia characteristic of XLH/HYP. XLH patients have soft and deformed skeletons and soft teeth that easily become infected.

Dann los zur Demo!

Second amendment: "A well regulated Militia, being necessary to the security of a free State, the right of the people to keep and bear Arms, shall not be infringed."