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A 19-year-old man presented with a 3-day history of worsening vision in his right eye. He had previously presented at 5 years of age with reduced visual acuity and macular cystic degeneration in both eyes. Examination of the right fundus is shown. Optical coherence tomography revealed a full-thickness retinal detachment. What is the underlying condition?

X-linked retinoschisis

Goldmann-Favre syndrome

Eale‘s disease

Wagner syndrome

Familial exudative vitreoretinopathy

X-linked retinoschisis is an inherited retinal disease that occurs primarily in males.

Die X-chromosomale Retinoschisis (XLRS) ist einegenetische Augenkrankheit männlicher Patienten mitVerlust der Sehkraft durch juvenileMakuladegeneration.

Schätzungen der weltweiten Prävalenz der männlichenBetroffenen liegen zwischen 1:5,000-1:25,000.Klinische BeschreibungDie XLRS ist eine symmetrisch beidseitige Störung derMakula mit Beginn im ersten Lebensjahrzehnt. Sie wirdmit Sehschwäche und Leseschwierigkeiten manifest. Inschweren Fällen kann auch ein Nystagmushinzukommen. Am Augenhintergrund bestehenmikrozystische Veränderungen der Netzhaut in derMakula-Region und Aufspaltungen in derNervenfaserschicht, oder Schisis (Radspeichen-Muster)und Schleier im Glaskörper. In schweren Fällen kommtes zu vollständiger Ablösung der Netzhaut mit starkverminderter Sehkraft oder Erblindung. In weiterfortgeschrittenen Stadien der Krankheit könnenGlaskörperblutungen, Netzhautablösung undneovaskuläres Glaukom auftreten und einen schwerenVisusverlust auslösen. Weibliche Überträgerinnenhaben nur selten Sehstörungen.ÄtiologieUrsache der Krankheit sind Mutationen im RS1-Gen(Xp22; Missense, Nonsense, Splice site, Deletionenund Insertionen). Das Gen kodiert für Retinoschisin, einAdhäsionsprotein, das wahrscheinlich an derstrukturellen und funktionellen Integrität der Retinabeteiligt ist.

Enhanced-S-Cone SyndromDie Begriffe Enhanced-S-Cone Syndrom (ESCS) und Goldmann-Favre Syndrom bezeichnen wahrscheinlich verschieden schwere Manifestationen derselben Erkrankung. Beide Varianten sind in einer Familie beobachtet worden. Das Goldmann-Favre Syndrom wird oft den Vitreoretinopathien zugerechnet, die neueren elektrophysiologischen Befunde sprechen für eine retinale Erkrankung.•Synonym: Goldmann-Favre Syndrom•Englisch: Enhanced S cone syndrome, Goldmann-Favre syndrome•Häufigkeit: selten

•Genetik:• Autosomal rezessiv: Mutationen im

NR2E3-Gen•Symptomatik:

• Kongenitale Nachtblindheit• Im Verlauf Visusminderung und

Gesichtsfeldeinschränkung bis hin zur Erblindung

• Bei ESCS stationärer Verlauf oder geringe Progredienz

Die Eales-Krankheit (ED) ist eine idiopathische, entzündliche retinale venöse Verschlusskrankheit, die durch 3 Stadien gekennzeichnet ist: Vaskulitis, Okklusion und Neovaskularisierung der Netzhaut, was zu wiederkehrenden Glaskörperblutungen und Sehverlust führt.Das Alter des Auftretens von ED beträgt 20-30 Jahre (bei Asiaten frühzeitiger). ED ist gekennzeichnet durch 3 aufeinanderfolgende Gefäßreaktionen, die den Verlauf der Erkrankung bestimmen: Entzündung (periphere retinale Perivaskulitis), Okklusion (periphere retinale kapillare Nicht-Perfusion) und Neovaskularisierung der Netzhaut, was oft zu Glaskörperblutungen führt. Die ersten beiden Stadien sind im Allgemeinen asymptomatisch, während Glaskörperblutungen (oft plötzlich und einseitig) durch kleine Flecken, Floater, 'Spinnweben' und eine Abnahme der Sehschärfe (oft Remission) gekennzeichnet sind. Das zweite Auge ist in 50-90% der Fälle nach einem Abstand von 3-10 Jahren betroffen. Wiederholungen sind häufig. Wiederkehrende Blutungen führen zu traktionellen Netzhautablösungen, Netzhautrissen und epimakulären Membranen. Andere können eine leichte Sehbehinderung im Zusammenhang mit einer retinalen Vaskulitis (ohne Glaskörperblutungen) aufweisen. Darüber hinaus wurden Kopfschmerzen, Schwankungen der peripheren Durchblutung, Dyspepsie, chronische Verstopfung und Epistaxis ebenfalls mit ED in Verbindung gebracht. ED führt selten zu Blindheit, auch nicht bei Patienten mit Glaskörperblutungen.

Die Wagner-Krankheit ist eine seltene vitreo-retinale Degeneration. Sie wird autosomal-dominant mit kompletter Penetranz, aber variabler Expressivität vererbt. Das diagnostische Merkmal ist eine Degeneration des Glaskörpers mit Filamenten oder schnur-ähnlichen Strukturen oder avaskulären Bändern und eine periphere Verdichtung des Glaskörpers in der Zirkumferenz, am Äquator oder retroäquatorial. Das Zentrum des Glaskörpers erscheint optisch leer. In der peripheren Retina entwickeln sich zunehmend Pigmentveränderungen und eine chorioretinale Degeneration. In 30% der Fälle besteht ein chronisches Weitwinkel-Glaukom, in 14% eine Netzhautablösung. Die Krankheit beginnt in der Jugend mit moderater Myopie und schreitet bis zur Entstehung einer Katarakt schon vor dem 40. Lebensjahr fort. Bei der Wagner-Krankheit sind nur die Augen betroffen. Einige Familien mit Kopplung an Marker der Chromosomenregion 5q13-q14 haben eine Dysgenesie des vorderen Augensegments. Eine Familie mit Symptomen ähnlich der Wagner-Krankheit aber mit größerer Häufigkeit von Netzhautablösungen (sog. erosive Vitreoretinopathie) zeigte ebenfalls Kopplung zu der 5q-Region. Patienten mit Stickler-Syndrom (z.T. auch Wagner-Stickler-Syndrom oder Hereditäre Arthro-Ophthalmopathie genannt; 3 Gene) haben ebenfalls eine frühe Katarakt und Glaskörperdegeneration. Es besteht aber eine hohe Rate (50%) von Netzhautablösungen und die Patienten haben zusätzlich ein flaches Mittelgesicht, Gaumenspalte, Arthritis und Hörverlust. Andererseits fehlen ihnen eine Reihe von Symptomen der Wagner-Krankheit (chorio-retinale Atrophie, Nachtblindheit, Dyysgenesie der vorderen Augensegmentes, periphere Netzhautablösung durch Glaskörperzug).

Familial Exudative Vitreoretinopathy (FEVR) defines a group of inherited diseases with abnormal retinal angiogenesis leading to incomplete vascularization of the peripheral retina. It can be inherited in an autosomal dominant, autosomal recessive, or X-linked recessive fashion. Genes linked to the disease discovered so far are NDP, FZD4, LRP5, TSPAN12, KIF11 and ZN408. Classically, the severity of avascular peripheral retina tends to be asymmetric and with varied penetrance within the same family. Similar to retinopathy of prematurity, this retinal ischemia may lead to secondary neovascularization causing traction, exudation, retinal folds, retinal detachment, foveal displacement, and retinal dysplasia. Criswick and Schepens initially postulated the cause of FEVR was caused by the “proliferation of fetal-type retinal vessels, much like those seen in retrolental fibroplasia.” Fluorescein angiography then showed the pathogenesis to be from incomplete peripheral vascularization.

History suggests that we are actually at much greater risk of exaggerated fears and misplaced priorities. There are many historical examples of panic about epidemics that never materialized (e.g., H1N1 influenza in 1976, 2006, and 2009). There are countless other examples of societies worrying about a small threat (e.g., the risk of Ebola spreading in the United States in 2014) while ignoring much larger ones hidden in plain sight. SARS-CoV-2 had killed roughly 5000 people by March 12. That is a fraction of influenza’s annual toll. While the Covid-19 epidemic has unfolded, China has probably lost 5000 people each day to ischemic heart disease. So why do so many Americans refuse influenza vaccines? Why did China shut down its economy to contain Covid-19 while doing little to curb cigarette use? Societies and their citizens misunderstand the relative importance of the health risks they face. The future course of Covid-19 remains unclear (and I may rue these words by year’s end). Nonetheless, citizens and their leaders need to think carefully, weigh risks in context, and pursue policies commensurate with the magnitude of the threat.Which raises one last question of history and political leadership. A “swine flu” scare struck the United States in 1976 in the midst of a presidential campaign. Gerald Ford reacted aggressively and endorsed mass immunization. When people fell ill or died after receiving the vaccine, and when the feared pandemic never materialized, Ford’s plan backfired and may have contributed to his defeat that November. When AIDS struck in 1981, Ronald Reagan ignored the epidemic throughout his entire first term. Yet he won reelection in a landslide. The current administration, thankfully, has not followed Reagan’s lead. Will it succeed where Ford went awry? Initial assessments of the U.S. government’s response have been mixed. The history of epidemics offers considerable advice, but only if people know the history and respond with wisdom.

An Emergency Hospital in Brookline, Massachusetts, Where Patients Were Cared for during the 1918 Influenza Epidemic

Verschobene Hb-O2 Kurve nach links, weil Hb klebriger ist,Verschobene Hb-O2 Kurve nach rechts, weil Hb weniger klebrig ist; links ist in der Lunge gut, rechts ist am Gewebe gut

Aufgelöstes O2 3 %100

Christian Bohr und der Bohr Effekt

Konformation der Ketten und dieses geniale Molekül

Conservative Oxygen Therapy during Mechanical Ventilation in the ICU

Patients who are undergoing mechanical ventilation in the intensive care unit (ICU) often receive a high fraction of inspired oxygen (Fio2) and have a high arterial oxygen tension. The conservative use of oxygen may reduce oxygen exposure, diminish lung and systemic oxidative injury, and thereby increase the number of ventilator-free days (days alive and free from mechanical ventilation). We randomly assigned 1000 adult patients who were anticipated to require mechanical ventilation beyond the day after recruitment in the ICU to receive conservative or usual oxygen therapy. In the two groups, the default lower limit for oxygen saturation as measured by pulse oximetry (Spo2) was 90%. In the conservative-oxygen group, the upper limit of the Spo2 alarm was set to sound when the level reached 97%, and the Fio2 was decreased to 0.21 if the Spo2 was above the acceptable lower limit. In the usual-oxygen group, there were no specific measures limiting the Fio2 or the Spo2. The primary outcome was the number of ventilator-free days from randomization until day 28.

Liberal or Conservative Oxygen Therapy for Acute Respiratory Distress Syndrome

In patients with acute respiratory distress syndrome (ARDS), the National Heart, Lung, and Blood Institute ARDS Clinical Trials Network recommends a target partial pressure of arterial oxygen (Pao2) between 55 and 80 mm Hg. Prospective validation of this range in patients with ARDS is lacking. We hypothesized that targeting the lower limit of this range would improve outcomes in patients with ARDS. In this multicenter, randomized trial, we assigned patients with ARDS to receive either conservative oxygen therapy (target Pao2, 55 to 70 mm Hg; oxygen saturation as measured by pulse oximetry [Spo2], 88 to 92%) or liberal oxygen therapy (target Pao2, 90 to 105 mm Hg; Spo2, ≥96%) for 7 days. The same mechanical-ventilation strategies were used in both groups. The primary outcome was death from any cause at 28 days.

Oxygen Exposure. Differences in the mean fraction of inspired oxygen (Fio2) (Panel A), partial pressure of arterial oxygen (Pao2) (Panel B), and arterial oxygen saturation (Sao2) (Panel C) over the first 7 days of mechanical ventilation are shown. Between-group differences were significant for the three variables. Blood gas analysis was performed every 6 hours. bars represent confidence intervals.

Masern sind eine hoch ansteckende Infektionskrankheit, die vor allem Kinder betrifft. Neben den typischen roten Hautflecken (Masern-Exanthem) ruft die Erkrankung Fieber und einen erheblich geschwächten Allgemeinzustand hervor. Diese sogenannte Kinderkrankheit wird durch das Masernvirus hervorgerufen und kann in manchen Fällen lebensbedrohlich sein durch schwere Verläufe (Komplikationen) mit Lungen-und Hirnentzündungen. In den meisten

Ländern ist die Erkrankung meldepflichtig. Die Diagnose erfolgt durch das klinische Bild und einen Antikörpernachweis im Blut. Eine spezifische Therapie existiert nicht, der Erkrankung und somit auch den Komplikationen kann jedoch durch Impfung ab dem zwölften Lebensmonat vorgebeugt werden. Das Masernvirus ist ein ausschließlich im Menschen vorkommendes (humanpathogenes), etwa 120–140 Nanometer großes einzelsträngiges RNA-Virus aus der Familie der Paramyxoviren (Genus Morbillivirus). Es ist eng mit dem Hundestaupevirus und am engsten mit dem mittlerweile ausgerottetem Erreger der Rinderpest verwandt.

Consequences of Undervaccination — Measles Outbreak, New York City, 2018–2019

Measles was declared eliminated in the United States in 2000, but the risk of outbreaks owing to international importations remains. An outbreak of measles in New York City began when one unvaccinated child returned home from Israel with measles; onset of rash occurred on September 30, 2018, 9 days after the child returned home. We investigated suspected cases of measles by conducting interviews, reviewing medical and immunization records, identifying exposed persons, and performing diagnostic testing. Measles–mumps–rubella (MMR) vaccine (given as either MMR or measles–mumps–rubella–varicella vaccine and collectively referred to as MMR vaccine) uptake was monitored with the use of the Citywide Immunization Registry. The total direct cost to the New York City Department of Health and Mental Hygiene was calculated.

A majority of the patients (93.4%) were part of the Orthodox Jewish community and resided in the Williamsburg (473 patients [72.9%]) or Borough Park (121 patients [18.6%]) neighborhood of Brooklyn. Most of the patients in both neighborhoods were children, but in Borough Park, the median age shifted from 1 year (during the period from October 2018 through January 2019) to 13.5 years (during the period from February 2019 through July 2019). The median age of the patients in Williamsburg was 3 years. In April 2019, the outbreak spread from Borough Park to neighboring Sunset Park, Brooklyn, where limited measles transmission occurred. Limited transmission also occurred in Crown Heights, Brooklyn (8 patients [1.2%]), where half the cases were in persons 18 years of age or older. Additional affected patients resided in other New York City neighborhoods but generally were associated with exposure that linked back to Williamsburg, Borough Park, or other areas outside New York City where measles was present. Among the 43 patients (6.6%) who were not part of the Orthodox Jewish community, a majority (38 patients) were Latino.

Among 49 patients (7.6%) who were hospitalized, 20 (40.8%) were admitted to an intensive unit care, 10 (20.4%) underwent noninvasive mechanical ventilation, and 40 (81.6%) had more than one complication, available with the full text of this article at NEJM.org). Among 37 children who were hospitalized with measles, 35 (94.6%) were confirmed to be unvaccinated; of the remaining children, neither of whom had an underlying medical condition, 1 child had received one dose of MMRV vaccine and the other child had an unknown vaccination status. The vaccination status was unknown for all 12 hospitalized adults. Measles was reported in 3 pregnant persons at 14 weeks, 33 weeks, and 34 weeks of gestation; no complications associated with measles occurred, and all the infants were born healthy and tested negative for measles.

Transmission commonly occurred in settings including the home (through contact with immediate and extended family members, friends, and neighbors), schools, and childcare programs. Measles was acquired from outside New York City in 11 patients; these locations included Israel (4 patients), the United Kingdom (2 patients), Ukraine (1 patient), New York outside New York City (3 patients), and New Jersey (1 patient). A total of 40.8% of the patients were thought to have acquired the disease through community-wide transmission, with no single point source reported; the transmission setting could not be identified for 4.8% of the patients.

Numbers of Doses of MMR Vaccine Administered to Children 12 to 59 Months of Age in Williamsburg, Brooklyn. School and childcare exclusion letters were issued on December 6, 2018, on December 21, 2018, and on January 9, 2019. Updated exclusion guidance was issued on February 13, 2019, to allow some students in kindergarten through 12th grade to attend school. Schools and childcare facilities were notified of updated exclusion requirements on April 2, 2019. Adapted from the New York City Department of Health and Mental Hygiene Citywide Immunization Registry; data are as of September 1, 2019. The measles–mumps–rubella (MMR) vaccine was given as either MMR or measles–mumps–rubella–varicella vaccine and collectively referred to as MMR vaccine.

Interrupting measles transmission was challenging because of the complexity of the outbreak, including numerous chains of transmission fueled by importation, nonadherence to the school and childcare center exclusions mandated by the Department of Health and Mental Hygiene, and transmission in schools and childcare centers with high numbers of religious exemptions to vaccination. Anecdotal reports suggested that parents were holding “measles parties” to deliberately expose their unimmunized children to measles. In addition, in some cases, the diagnosis of measles was made several weeks to months after illness had begun, when the children’s parents brought them to a medical provider for serologic testing so they could return to school. Delayed identification of measles in these situations hindered the ability of the Department of Health and Mental Hygiene to implement real-time control measures.

Association of Aspirin with Hepatocellular Carcinoma and Liver-Related Mortality

More information is needed about the long-term effects of low-dose aspirin (≤160 mg) on incident hepatocellular carcinoma, liver-related mortality, and gastrointestinal bleeding in persons with chronic hepatitis B or hepatitis C virus infection. Using nationwide Swedish registries, we identified all adults who received a diagnosis of chronic hepatitis B or hepatitis C from 2005 through 2015 and who did not have a history of aspirin use (50,275 patients). Patients who were starting to take low-dose aspirin (14,205 patients) were identified by their first filled prescriptions for 90 or more consecutive doses of aspirin. We constructed a propensity score and applied inverse probability of treatment weighting to balance baseline characteristics between groups. Using Cox proportional-hazards regression modeling, we estimated the risk of hepatocellular carcinoma and liver-related mortality, accounting for competing events.

Cumulative Incidence of Hepatocellular Carcinoma among Aspirin Users and Nonusers. Aspirin use was defined as a filled prescription for 90 or more consecutive cumulative defined daily doses of low-dose aspirin after the index date (the date on which a patient filled the first aspirin prescription after the 180-day entry period); nonuse was defined as fewer than 90 consecutive cumulative defined daily doses — or no use —during the same 90-day interval after the 180-day entry period. We calculated the P value using Gray’s test for equality of the cumulative incidence functions between each exposure group after inverse probability of treatment weighting, accounting for competing risks of death, emigration, and liver transplantation. The inset shows the same data on an expanded y axis.

BleedingAspirin users did not have a significantly higher 10-year cumulative incidence of gastrointestinal bleeding than nonusers (7.8% and 6.9%, respectively; risk difference, 0.9 percentage points [95% CI, −0.6 to 2.4]) or of major gastrointestinal bleeding than nonusers (1.8% and 1.3%, respectively; risk difference, 0.5 percentage points [95% CI, −1.6 to 2.6]) (Table S7). Among aspirin users, the risks of any gastrointestinal bleeding were similar among those with compensated cirrhosis and those without cirrhosis (8.3% and 7.5%, respectively; risk difference, 0.8 percentage points [95% CI, −1.0 to 2.6]), as were the risks of major gastrointestinal bleeding (3.6% and 2.4%, respectively; risk difference, 1.2 percentage points [95% CI, −0.5 to 2.9]). These findings were similar across subgroup strata (Table S8); however, given the small size of certain subgroups, the findings should be interpreted with caution.

Liver-Related Mortality among Aspirin Users and Nonusers. Aspirin use was defined as a filled prescription for 90 or more consecutive cumulative defined daily doses of low-dose aspirin after the index date (the date on which a patient filled the first aspirin prescription after the 180-day entry period); nonuse was defined as fewer than 90 consecutive cumulative defined daily doses — or no use — during the same 90-day interval after the 180-day entry period. We calculated the P value using Gray’s test for equality of the cumulative incidence functions between each exposure group after inverse probability of treatment weighting,accounting for competing risks of nonliver-related death, emigration, and liver transplantation. The inset shows the same data on an expanded y axis.

DiscussionIn a nationwide population with chronic viral hepatitis, use of low-dose aspirin (75 mg or 160 mg) was associated with a substantially lower risk of incident hepatocellular carcinoma and lower liver-related mortality than no use of aspirin. The apparent benefits of aspirin were duration-dependent, with a significantly lower risk of hepatocellular carcinoma after 3 to 5 years of use than with short-term use. In addition, the benefits were not accompanied by a substantially higher incidence of gastrointestinal bleeding. Our results were consistent regardless of sex, cause of hepatitis, or underlying compensated cirrhosis, which suggests that the benefits of aspirin may apply to a broad at-risk population.In conclusion, in a nationwide population of persons with chronic viral hepatitis, low-dose aspirin use was associated with a duration-dependent significantly lower risk of incident hepatocellular carcinoma and liver-related death than no use of aspirin, without a significantly higher risk of gastrointestinal bleeding. Our findings support the need for randomized clinical trials designed to test the benefits of aspirin for primary prevention of hepatocellular carcinoma.

Complications of Unsafe and Self-Managed Abortion

When abortion is legally restricted or otherwise inaccessible, girls, women, and those who care about them look outside formal medical care to end pregnancies. Worldwide, people increasingly choose misoprostol or a combination of mifepristone and misoprostol to end pregnancies on their own (referred to as self-managed abortion). These medications are safer and more effective than older, invasive techniques of self-managed abortion, and patients who have used these medications may be clinically indistinguishable from those who have had uncomplicated spontaneous pregnancy loss. Similarly, patients with complications of self-managed medication-induced abortion and those with complications of miscarriage may have identical clinical presentations.As U.S. abortion laws become increasingly restrictive, people will decide to end pregnancies without clinical supervision. Health care providers must become familiar with the normal course of self-managed abortion with medications and its rare complications, as well as complications of unsafe methods.

Ultrasound Findings after Successful Medication-Induced Abortion. Echogenic material in the uterus, called a thickened endometrial stripe, is a normal finding and is consistent with successful medication-induced abortion. Intervention is not needed on the basis of this ultrasound finding alone.

Sites of Uterine Injury. The figure is adapted from Borgatta and Stubblefield.34 Four types of injury are shown. The first is a lateral low cervical perforation with laceration of descending branches of the uterine artery, which generally results in vaginal bleeding through the cervical canal, without intraabdominal bleeding. The second is a lateral perforation at the junction of the cervix and lower uterine segment, with laceration of the ascending branch of the uterine artery, which can result in broad-ligament bleeding or hematoma and intraabdominal bleeding. With both types of vascular injury, vessels may initially constrict, with temporary cessation of bleeding, but recurrence is possible minutes, hours, or days later, resulting in clinically significant blood loss over time. The third type of injury is a fundal perforation, which is associated with a lower risk of hemorrhage than the first two types. However, injury to the bowel or omentum may accompany a fundal injury. The fourth type of injury is a perforation in the lower uterine segment (anterior [not shown] or posterior); anterior perforations may involve the bladder, including the trigone. With all perforations, the risk of complications and need for treatment depend on the instrument that caused the injury and whether the injury was recognized at the time of the procedure. Small fundal or lower-uterine-segment perforations caused by improper placement of uterine sounds or dilators may not require intervention, and it may be possible to complete the procedure under ultrasound guidance. Larger perforations, or those involving the use of suction, forceps, or sharp instruments outside the uterine cavity, require laparoscopy or laparotomy for assessment of the extent of damage.

ConclusionsAs U.S. abortion restrictions increase, self-managed abortion will undoubtedly also increase. Health care providers must prepare for this clinical reality. This involves becoming comfortable with the ambiguity of providing care without knowing whether it is for spontaneous or induced abortion. It also involves preparing to manage life-threatening complications of abortion, which are most likely to be caused by unsafe means. Given the safety of the combination of mifepristone and misoprostol for self-managed abortion, the biggest danger to patients may be legal prosecution. Both the American Medical Association and the American College of Obstetricians and Gynecologists take strong positions against criminalization of self-managed abortion, because it deters patients with complications from seeking care. Furthermore, since medication-induced abortion and spontaneous abortion are clinically indistinguishable, criminalization of the former would inevitably lead to policing of all reproductive-age women with bleeding or pregnancy loss. Doctors and health care institutions must develop strategies that favor effective, compassionate clinical care over legal investigation of patients.

A 29-year-old man with perinatally acquired human immunodeficiency virus (HIV) infection presented to the hospital with abdominal pain and drenching night sweats. He had a history of intermittent adherence to antiretroviral therapy; on presentation, the CD4 count was 18 cells per cubic millimeter (reference range, 500 to 1500), and the HIV viral load was undetectable. Severe abdominal distention, splenomegaly, and diffuse abdominal tenderness to palpation were noted on physical examination. Computed tomography of the abdomen confirmed massive splenomegaly with multifocal infarction of the splenic parenchyma (Panel A). The patient underwent embolization of the splenic artery followed by splenectomy. Histopathological examination revealed near-total replacement of the splenic parenchyma by extensive necrosis and nodular aggregates of histiocytes with a spindle-shaped appearance (Panel B). Acid-fast staining revealed aggregates of mycobacteria that had undergone phagocytosis by histiocytes, a finding consistent with a phenomenon known as mycobacterial spindle-cell pseudotumor (Panel C, showing histiocytes with abundant intracellular mycobacteria; the inset, at higher magnification, shows a single intracellular mycobacterium [arrowhead]). Previously obtained blood cultures showed growth of Mycobacterium avium–intracellulare complex. Treatment with ethambutol, rifabutin, and clarithromycin was initiated, and the patient was discharged with a plan to continue long-term antimycobacterial therapy.

A 48-year-old man who had recently immigrated to France and had not yet established routine medical care presented to the emergency department with shortness of breath. He had a history of end-stage renal disease for which hemodialysis had been initiated 10 years earlier. A physical examination showed mandibular prominence, thoracic kyphosis, and crackles in both lungs. Laboratory studies showed a calcium level of 1.9 mmol per liter (7.6 mg per deciliter) (normal range, 2.2 to 2.6 mmol per liter [8.8 to 10.4 mg per deciliter]), a phosphate level of 0.96 mmol per liter (2.97 mg per deciliter) (normal range, 0.81 to 1.58 mmol per liter [2.51 to 4.89 mg per deciliter]), a 25-hydroxyvitamin D level of 13 nmol per liter (5.2 ng per milliliter) (normal range, 75 to 175 nmol per liter [30 to 70 ng per milliliter]), and a parathyroid hormone level of 4081 ng per liter (normal range, 11.5 to 78.4). Computed tomography (Panel A) and three-dimensional reconstruction (Panel B) of the face revealed mandibular hypertrophy and a heterogeneous appearance of the bone, with both cystic lesions and patches of osteolysis. Similar bony lesions were found in the spine, iliac bone, and femur. Osteitis fibrosa cystica is a skeletal disorder that is caused by sustained hyperparathyroidism, often due to chronic renal failure, resulting in the formation of cystlike tumors in the bone. Treatment with cinacalcet and vitamin D supplementation were started. His shortness of breath resolved after hemodialysis was reinitiated. At a follow-up visit 6 months after treatment was initiated, the parathyroid hormone level had decreased to 1743 ng per liter and the 25-hydroxyvitamin D level had returned to a normal level, but the bone lesions had not regressed.

An 89-Year-Old Man with Recurrent Abdominal Pain and Bloody Stools

Two years before the current evaluation, the patient underwent repair of a right inguinal hernia. After he recovered from that procedure, he had intermittent pain in the right lower quadrant. Four months before the current evaluation, he was admitted to this hospital for diffuse abdominal pain followed by presyncope during an attempt to defecate. Examination was notable for bilateral lower abdominal tenderness and a crescendo–decrescendo systolic murmur (grade 2/6) at the left sternal border. Laboratory test results are shown.

CT Scans of the Abdomen and Pelvis from the First and Second Admissions. Coronal images obtained 4 months before the current evaluation (first admission) (Panels A and B), after the administration of oral but not intravenous contrast material, show segmental wall thickening and mesenteric inflammatory changes involving a short segment of the distal descending colon, which contains multiple diverticula (arrows). An axial image obtained 2 months before the current evaluation (second admission) (Panel C), after the administration of intravenous and oral contrast material, shows segmental wall thickening, mucosal enhancement and edema, and mesenteric vascular engorgement involving the sigmoid colon and rectum, without associated diverticula (arrow). The wall thickening of the distal descending colon that was seen during the first admission has resolved (arrowhead).

Endoscopic Images and Biopsy Specimens from the Third Admission. Images obtained during flexible sigmoidoscopy (Panels A and B) show diffusely erythematous, congested, eroded (Panel A, arrow), friable mucosa in the sigmoid colon, with spontaneous bleeding (Panel B, arrow). Hematoxylin and eosin staining of the biopsy specimens (Panel C) shows evidence of active chronic colitis, including replacement of the lamina propria with lymphocytes and plasma cells (single arrow) and surface erosion (double arrow). Immunostaining (Panel D) shows cytomegalovirus inclusion bodies (in brown; arrows), a finding indicative of cytomegalovirus infection.

CT Scan, Endoscopic Images, and Biopsy Specimens from the Current Admission. Axial and coronal CT images (Panels A and B, respectively), obtained after the administration of intravenous and oral contrast material, show contiguous wall thickening and mucosal enhancement and edema (arrows) involving the entire colon; the rectum was also involved. Also shown is mural thrombus in an abdominal aortic aneurysm (Panel A, arrowhead). Images obtained during flexible sigmoidoscopy (Panels C and D) show diffuse severe colonic inflammation, erythema, edema, friability, and deep ulcerations (Panel C, arrow) in the rectum and sigmoid colon. Hematoxylin and eosin staining of the biopsy specimens (Panels E and F) shows severely active chronic colitis characterized by replacement of the lamina propria with lymphocytes and plasma cells (Panel E), as well as a cleft-shaped embolus in a small vessel (Panel F, arrow).

InfectionInfectious colitis due to a bacterial pathogen, which is normally a major consideration in a patient with acute bloody diarrhea, is unlikely to account for the months of symptoms seen in this case. Could recurrence of C. difficile infection, which had been diagnosed during this patient’s second admission, explain his entire clinical course? Pseudomembranes are not classically seen in patients with recurrent C. difficile disease or inflammatory bowel disease, so the absence of pseudomembranes on endoscopic examination does not rule out recurrent infection. CancerGastrointestinal cancer should be considered in patients with chronic lower gastrointestinal blood loss. In this patient, the features of the clinical presentation and the endoscopic findings make colorectal carcinoma and colonic lymphoma unlikely. However, plasma-cell dyscrasia and gastrointestinal amyloidosis can lead to chronic bloody diarrhea.Colonic IschemiaCould this patient’s abdominal pain and bloody diarrhea be due to ischemia? Colonic ischemia is manifested by acute, self-limited bloody diarrhea and is thus unlikely in this case. Given the findings on examination of the biopsy specimens of the rectum and sigmoid colon, cholesterol crystal embolization should also be considered. This patient had a history of vascular disease and a known abdominal aortic aneurysm, and although his aortic mural thrombus was probably chronic and of little clinical relevance, showering of the colonic circulation with cholesterol emboli from an aortic plaque is possible. Patients with cholesterol embolization most commonly present with abdominal pain and bleeding,6 with eosinophilia classically developing during the early stages.InflammationAn inflammatory process is the most likely explanation for this patient’s illness. His history of diverticulosis suggests the possibility of segmental colitis associated with diverticulosis, which could account for many of the features seen in this case, including the persistent bloody diarrhea, abdominal pain, relatively normal laboratory test results, and erythematous, friable mucosa seen on endoscopic examination. Segmental colitis associated with diverticulosis involves only segments of inflamed colon that are close to the diverticula, with areas of healthy mucosa interspersed between the inflamed areas.Ulcerative ColitisC. difficile infection is the infection that is most commonly associated with inflammatory bowel disease,9 and it frequently exacerbates the severity of the disease.

Ulcerative ColitisC. difficile infection is the infection that is most commonly associated with inflammatory bowel disease,and it frequently exacerbates the severity of the disease.Follow-upOnce the diagnosis of ulcerative colitis was established in this case, intravenous glucocorticoid therapy was started. Vancomycin and ganciclovir were discontinued. Inflammatory markers decreased. However, the patient continued to have bowel movements every 2 to 3 hours, accompanied by intermittent bloody stools. He had limited mobility, and anorexia worsened. He was thought to be too frail to undergo surgery. Infliximab therapy was considered, but unfortunately, aspiration pneumonia developed and the patient’s clinical condition deteriorated. Because he had active infection, infliximab infusion was withheld. Given the patient’s frailty, severity of illness, and limited therapeutic options, his care was transitioned to comfort measures only. He died on hospital day 22 while sleeping.

SARS-CoV-2 Infection among Travelers Returning from Wuhan, ChinaWe followed up on 94 persons who boarded an evacuation flight from Wuhan to Singapore on January 30, 2020. Screening for body temperature was conducted at check-in and before boarding, and 3 febrile persons were prevented from boarding (Figure 1); no additional information regarding the status of these 3 febrile persons was available. Surgical masks were provided to passengers on board the plane. On arrival in Singapore, the passengers underwent repeat screening for body temperature (fever was defined as a body temperature ≥38°C), and 2 persons (a woman 48 years of age [Patient 1] and a woman 47 years of age [Patient 2]) had a fever. The 2 febrile women were transferred immediately to a hospital, and they tested positive for SARS-CoV-2 (their clinical course is described in the Supplementary Appendix, available with the full text of this letter at NEJM.org).

The remaining 92 afebrile passengers (age range, 2 to 82 years) were quarantined for 14 days at a government quarantine facility, where they were checked for symptoms and fever three times daily. Six persons reported symptoms (4 on quarantine day 2 and 2 on quarantine day 3) and were placed in isolation in a hospital and underwent polymerase-chain-reaction (PCR) testing; all 6 persons tested negative for SARS-CoV-2. On quarantine day 3, samples from 76 of the 86 asymptomatic persons (75 nasopharyngeal swab samples and 1 nasal swab sample) were obtained and tested by means of PCR assay. A 17-year-old boy (the son of Patient 1) tested positive for Covid-19 and continued to have PCR-positive status for 2 weeks, and a 41-year-old man had an inconclusive result (positive for N gene and negative for ORF1ab gene). On quarantine day 6, samples from all 87 quarantined asymptomatic persons (85 nasopharyngeal swab samples and 2 nasal swab samples [3 of the 6 persons who had been transferred to the hospital before February 2 had returned to the government quarantine facility]) were obtained and tested; all tested negative. All persons who were not isolated in the hospital were released from quarantine on day 14, and all remained uninfected with Covid-19. Understanding the implications of transmission of SARS-CoV-2 infection from persons with asymptomatic or very mild symptomatic cases of Covid-19 is vital for the formulation of containment strategies.

Nerinetide is in clinical development for the treatment of acute ischaemic stroke. Ischaemic stroke is the most common type of stroke. It happens when a blood vessel is blocked by a blood clot, cutting off blood flow to part of the brain (ischaemia). Without blood supply, brain cells can be damaged or destroyed because they may not receive enough oxygen. Symptoms may include numbness or weakness on one side of the body and problems with balance, speech and swallowing. Symptoms may range from mild and resolve, through severe strokes that can lead to long-term disability, coma and death. Early treatment is critical to improve outcomes and aims to restore blood flow to the brain, prevent and possibly repair the damage. Current therapies address only the restoration of blood flow, but not protection of the brain by enhancing its resilience to ischaemia.Nerinetide is an innovative new drug that protects the brain during an acute ischaemic stroke. As a neuroprotectant, nerinetide does not dissolve blood clots, but effectively pauses the toxic chemical reactions triggered by stroke. Treatment with nerinetide is being positioned to be initiated as soon as possible after the onset of symptoms. If licensed, nerinetide would provide critical time to patients with a stroke by stopping the loss of brain cells until further treatment can be administered.