A 58-year-old man presented to the outpatient pulmonary clinic with a productive cough and a history of weight loss of 10 kg during the preceding 3 months. He was an active smoker and for the preceding 4 years had worked in a factory processing cotton. Computed tomography of the chest and abdomen revealed multiple pulmonary nodules (Panel A) associated with pericardial effusion, pleural effusions in both lungs, and multiple liver lesions. On biopsy of the lung, multiple lesions containing sulfur granules were observed along the bronchial vascular bundle (Panels B and C, with Panel C providing a closeup view of the circled area in Panel B; staining with hematoxylin and eosin). What is the most likely diagnosis?

Nocardiosis

Actinomycosis

Aspergillosis

Histoplasmosis

Blastomycosis The patient received a diagnosis of disseminated actinomycosis, an uncommon, slowly progressive bacterial infection caused by actinomyces species that can be manifested in the formation of multiple abscesses and sulfur granules in infected tissue. The patient received a 4-week course of high-dose penicillin intravenously, which was followed by an extended course of oral amoxicillin. Actinomycosis is a rare infectious bacterial disease caused by Actinomyces species. About 70% of infections are due to either Actinomyces israelii or A. gerencseriae. Infection can also be caused by other Actinomyces species, as well as Propionibacterium propionicus, which presents similar symptoms. The condition is likely to be polymicrobial aerobic anaerobic infection. The disease is characterised by the formation of painful abscesses in the mouth, lungs, breast, or gastrointestinal tract. Actinomycosis abscesses grow larger as the disease progresses, often over months. In severe cases, they may penetrate the surrounding bone and muscle to the skin, where they break open and leak large amounts of pus, which often contains characteristic granules (sulfur granules) filled with progeny bacteria. These granules are named due to their appearance, but are not actually composed of sulfur. Actinomycosis is primarily caused by any of several members of the bacterial genus Actinomyces. These bacteria are generally anaerobes. In animals, they normally live in the small spaces between the teeth and gums, causing infection only when they can multiply freely in anoxicenvironments. An affected human often has recently had dental work, poor oral hygiene, periodontal disease, radiation therapy, or trauma (broken jaw) causing local tissue damage to the oral mucosa, all of which predispose the person to developing actinomycosis. We care for an 84-year-old lady with Wegener's granulomatosis. Ten months ago, she presented with acute renal failure and lung haemorrhage. She had bilateral patchy pulmonary infiltrates. A renal biopsy revealed rapidly progressive glomerulonephritis with >50% crescent formation. The immunofluorescence showed a pauci-immune pattern. She required haemodialysis for 3 weeks before responding to cyclophosphamide and prednisone. Aside from polymyalgia rheumatica, temporal arteritis, macular degeneration, atrial fibrillation and mitral insufficiency, she enjoyed reasonably good health. Her response to cyclophosphamide and prednisone was gratifying and her serum creatinine concentration decreased to 170 µmol/l. This admission was routine for her tenth intravenous cylcophosphamide treatment.

Question What do you think the lump might be? Silver stain (upper panel) and H&E stain (lower panel) showing a typical Actinomyces drusen surrounded by granulocytes. These ‘sulfur granules’ consist of branched, Gram-positive filaments of ∼1 µm width that are best seen with silver staining. An additional compound is the so-called Splendore–Hoeppli material consisting of amorphous material staining intensely eosinophilic in an H&E stain. Die Spanische Grippe war eine Pandemie, die durch einen ungewöhnlich virulenten Abkömmling des Influenzavirus (Subtyp A/H1N1) verursacht wurde und zwischen 1918 und 1920 mindestens 25 Millionen, nach einer Bilanz der Fachzeitschrift Bulletin of the History of Medicine vom Frühjahr 2002 sogar knapp 50 Millionen Todesopfer forderte. Die Auswirkung der Pandemie ist damit in absoluten Zahlen mit dem Ausbruch der Pest von 1348 vergleichbar, der damals mehr als ein Drittel der europäischen Bevölkerung zum Opfer fiel. Eine Besonderheit der Spanischen Grippe war, dass ihr vor allem 20- bis 40-jährige Menschen erlagen, während Influenzaviren sonst besonders Kleinkinder und alte Menschen gefährden. Varianten des Subtyps A H1N1 verursachten 1977/1978 den Ausbruch der Russischen Grippe und 2009 der „Schweinegrippe“-Pandemie. Die Spanische Grippe trat in drei Wellen auf, im Frühjahr 1918, im Herbst 1918 und in vielen Teilen der Welt noch einmal 1919. Die erste Ausbreitungswelle im Frühjahr 1918 wies keine merklich erhöhte Todesrate auf. Erst die Herbstwelle 1918 und die spätere, dritte Welle im Frühjahr 1919 waren mit einer außergewöhnlich hohen Letalität verbunden. Zum Höhepunkt der „Herbstwelle“ schätzten die preußischenund die Schweizer Gesundheitsbehörden, dass zwei von drei Bürgern erkrankt waren. Baloxavir Marboxil for Uncomplicated Influenza in Adults and Adolescents Baloxavir marboxil is a selective inhibitor of influenza cap-dependent endonuclease. It has shown therapeutic activity in preclinical models of influenza A and B virus infections, including strains resistant to current antiviral agents. We conducted two randomized, double-blind, controlled trials involving otherwise healthy outpatients with acute uncomplicated influenza. After a dose-ranging (10 to 40 mg) placebo-controlled trial, we undertook a placebo- and oseltamivir-controlled trial of single-dose, weight-based doses of baloxavir (40 or 80 mg) in patients 12 to 64 years of age during the 2016–2017 season. The dose of oseltamivir was 75 mg twice daily for 5 days. The primary efficacy end point was the time to alleviation of influenza symptoms in the intention-to-treat infected population. Kaplan–Meier Curves of the Time to Alleviation of Influenza Symptoms with Baloxavir versus Placebo in the Phase 3 Trial. Shown are data for 455 patients assigned to baloxavir and 230 assigned to placebo (intention-to- treat infected population; 1 patient in each group did not have data that could be evaluated). The median time to alleviation of symptoms was 26.5 hours shorter in the baloxavir group (53.7 hours; 95% CI, 49.5 to 58.5) than in the placebo group (80.2 hours; 95% CI, 72.6 to 87.1) (P<0.001). Data from patients who did not have alleviation of symptoms were censored (tick marks) at the last observation time point. Change from Baseline in Influenza Infectious Viral Load over Time in the Phase 3 Trial. Panel A shows the change from baseline (dashed line) in influenza infectious viral load over time in the baloxavir group (427 patients) and placebo group (210 patients). The mean (±SD) viral loads on day 1 (before the initiation of the trial regimen) were 5.79±1.87 and 5.56±1.89 log10 50% tissue- culture infective dose (TCID50) per milliliter in the baloxavir and placebo groups, respectively. Asterisks indicate a P value of less than 0.05 for the comparison with placebo. Panel B shows the change from baseline in influenza infectious viral load in adults 20 to 64 years of age in the baloxavir group (352 patients) and oseltamivir group (359 patients). The mean (±SD) viral loads on day 1 were 5.76±1.90 and 5.94±1.69 log10 TCID50 per milliliter in the baloxavir and oseltamivir groups, respectively. Asterisks indicate a P value of less than 0.05 for the comparison with oseltamivir. In both panels, � bars indicate standard deviations. Adverse events were reported in 20.7% of baloxavir recipients, 24.6% of placebo recipients, and 24.8% of oseltamivir recipients. Adverse events that were associated with cessation of the trial regimen occurred in 0.3 to 0.4% of patients across groups. Two serious adverse events were noted in baloxavir recipients (incarcerated inguinal hernia and aseptic meningitis), but neither was considered to be related to the trial regimen by investigators who were unaware of the trial-group assignments. Adverse events that were considered to be related to the trial regimen were more common in oseltamivir recipients (8.4%) than in baloxavir recipients (4.4%, P=0.009) or placebo recipients (3.9%). Coronary CT angiography (CTA) is the use of computed tomography (CT) angiography to assess the coronary arteries of the heart. The subject receives an intravenous injection of radiocontrast and then the heart is scanned using a high speed CT scanner, allowing physicians to assess the extent of occlusion in the coronary arteries, usually in order to diagnose coronary artery disease. CTA is superior to coronary CT calcium scan in determining the risk of Major Adverse Cardiac Events (MACE). Faster CT machines, due to multidetector capabilities, have made imaging of the heart and circulatory system very practical in a number of clinical settings.[2] The faster capability has allowed the imaging of the heart with minimal involuntary motion, which creates motion blur on the image, and has a number of practical applications. At present, it appears that the greatest utility of cardiac CT lies in ruling out coronary artery disease rather than ruling it in. This is because the test is highly sensitive (over 90% detection rate), so a negative test result largely rules out coronary artery disease (i.e. the test has a high negative predictive value). The test is somewhat less specific, however, so a positive result is less conclusive and may need to be confirmed by subsequent invasive angiography. The positive predictive value of cardiac CTA is approximately 82% and the negative predictive value is around 93%. Coronary CT Angiography and 5-Year Risk of Myocardial Infarction

Although coronary computed tomographic angiography (CTA) improves diagnostic certainty in the assessment of patients with stable chest pain, its effect on 5-year clinical outcomes is unknown. In an open-label, multicenter, parallel-group trial, we randomly assigned 4146 patients with stable chest pain who had been referred to a cardiology clinic for evaluation to standard care plus CTA (2073 patients) or to standard care alone (2073 patients). Investigations, treatments, and clinical outcomes were assessed over 3 to 7 years of follow-up. The primary end point was death from coronary heart disease or nonfatal myocardial infarction at 5 years. Percentage of Patients Who Underwent Invasive Coronary Angiography and Coronary Revascularization, According to Year of Follow-up. Patients with stable chest pain were randomly assigned to undergo coronary computed tomographic angiography (CTA) in addition to receiving standard care or to receive standard care alone. Shown are cumulative event curves for the percentage of patients who underwent invasive coronary angiography (Panel A) and coronary revascularization (Panel B) over the course of the 5-year follow-up.

Cumulative Incidence of Death from Coronary Heart Disease or Nonfatal Myocardial Infarction. Panel A shows cumulative event curves for the primary end point of death from coronary heart disease or nonfatal myocardial infarction among patients assigned to CTA in addition to standard care and those assigned to standard care alone. Panel B shows the cumulative risk of nonfatal myocardial infarction in each group. The inset in each panel shows the same data on an enlarged y axis. Subgroup Analyses for the Primary End Point of Death from Coronary Heart Disease or Nonfatal Myocardial Infarction at 5 Years. P values are for the interaction between the randomized groups and the potential risk factor of interest and were calculated in a Cox proportional-hazards analysis that was adjusted for center and minimization variables. P values are reported without adjustment for multiplicity of testing. The sizes of the squares are proportional to the sizes of the subgroups. Ten-year cardiovascular risk was assessed according to the ASSIGN score, which ranges from 1 to 99, with higher scores indicating a higher risk of cardiovascular disease14; shown are the number of patients with scores above and below the median score of 15. The National Institute for Health and Care Excellence (NICE) classification is a symptom-based approach that classifies patients with recent onset of chest pain into one of two categories: those with nonanginal chest pain and those with possible angina. CHD denotes coronary heart disease. We report the 5-year clinical outcomes. We found that the use of CTA, with consequent changes in treatment, resulted in a significantly lower rate of death from coronary heart disease or nonfatal myocardial infarction than standard care alone. Although the rates of invasive coronary angiography and coronary revascularization were higher in the CTA group than in the standard-care group in the first few months of follow-up, we did not find any differences in the overall use of invasive coronary angiography and coronary revascularization at 5 years. Our findings suggest that the use of CTA resulted in more correct diagnoses of coronary heart disease than standard care alone, which, in turn, led to the use of appropriate therapies, and this change in management resulted in fewer clinical events in the CTA group than in the standard-care group. In the SCOT-HEART trial, we found that the use of CTA in patients who had been referred to a cardiology clinic for assessment of stable chest pain resulted in a lower subsequent risk of death from coronary heart disease or nonfatal myocardial infarction than standard care alone. This benefit was achieved without greater long-term use of invasive coronary angiography or coronary revascularization in the CTA group. Das follikuläre Lymphom ist das häufigste indolente Lymphom. Die WHO unterscheidet verschiedene Grade. Follikuläre Lymphome Grad 1-3A gehören zu den indolenten, Grad 3B zu den aggressiven Lymphomen. Häufigste, klonale, genetische Aberration ist eine balancierte Translokation t(14;18) mit Überexpression des BCL2-Proteins. Diese Translokation ist charakteristisch für das follikuläre Lymphom, aber nicht spezifisch. Das klinische Bild ist geprägt von einer langsam progredienten Lymphadenopathie. Sie kann über längere Zeit ohne weitere klinische Symptomatik bestehen. Die große Mehrzahl der Patienten mit follikulärem Lymphom wird erst im fortgeschrittenen Krankheitsstadium diagnostiziert. Der Follicular Lymphoma International Prognostic Index (FLIPI) ermöglicht die Differenzierung von drei Gruppen mit unterschiedlicher Prognose. Die Therapie erfolgt stadienabhängig. In den frühen Stadien hat die Bestrahlung der betroffenen Lymphknotenregionen einen kurativen Anspruch. In den fortgeschrittenen Stadien ist der Therapieanspruch palliativ. Eine medikamentöse Therapie wird erst bei klinischer Symptomatik eingeleitet. Mit der Kombination aus Chemotherapie und dem Anti-CD20-Antikörper Rituximab werden Remissionsraten von ≥90% erreicht. Der klinische Verlauf follikulärer Lymphome ist sehr variabel. Überlebenszeiten reichen von einigen Jahren bis über 2 Jahrzehnte. Rituximab plus Lenalidomide in Advanced Untreated Follicular Lymphoma

Rituximab plus chemotherapy has been shown to be effective in patients with advanced-stage, previously untreated follicular lymphoma; nevertheless, most patients will have a relapse. Combination immunotherapy with lenalidomide and rituximab is an immunomodulatory regimen that has shown promising activity in patients with indolent B-cell non-Hodgkin’s lymphoma. We conducted this multicenter, international, phase 3 superiority trial to evaluate rituximab plus lenalidomide, as compared with rituximab plus chemotherapy, in patients with previously untreated follicular lymphoma. Patients were randomly assigned to receive one of the two regimens, followed by maintenance monotherapy with rituximab. Treatment with rituximab plus lenalidomide consisted of 18 cycles of the two drugs, followed by rituximab maintenance therapy every 8 weeks for 12 cycles (six additional doses). Treatment with rituximab plus chemotherapy consisted of the investigator’s choice of one of three rituximab-based regimens, followed by maintenance monotherapy with rituximab every 8 weeks for 12 cycles. The primary end points were complete response (confirmed or unconfirmed) at 120 weeks and progression-free survival.

Progression-free Survival and Overall Survival in the Intention-to- Treat Population. Panel A shows estimates of progression-free survival as assessed by an independent review committee, and Panel B shows estimates of overall survival. Subgroup Analyses of Progression-free Survival and Confirmed or Unconfirmed Complete Response at 120 Weeks. Panel A shows the results of the prespecified subgroup analysis of progression-free survival. The dashed vertical line indicates a hazard ratio of 1.10, normalized to the overall population. No interaction between treatment group and any of the subgroups was found.

Panel B shows the results of the prespecified subgroup analysis of confirmed or unconfirmed complete response at 120 weeks. The vertical line normalizes the plot to the overall difference in the rate of confirmed or unconfirmed complete response at 120 weeks between the rituximab–chemotherapy group and the rituximab– lenalidomide group (4.85%). A Follicular Lymphoma International Prognostic Index (FLIPI) score indicates low (0 or 1), intermediate (2), or high (3 to 5) risk on the basis of a scoring system that assigns one point for each of the following risk factors: a hemoglobin level of less than 12 g per deciliter, more than four nodal areas (with the exception of spleen), age older than 60 years, a lactate dehydrogenase level above the upper limit of the normal range, and Ann Arbor stage III or IV disease. A significant interaction between treatment group and subgroup was found in the subgroup defined according to disease stage (I or II vs. III or IV). The interaction was determined to be quantitative instead of qualitative according to the Gail and Simon (1985) test Anemia (in 66% vs. 89% of the patients), fatigue (23% vs. 29%), nausea (20% vs. 42%), vomiting (7% vs. 19%), peripheral neuropathy (7% vs. 16%), leukopenia (4% vs. 10%), febrile neutropenia (2% vs. 7%), and alopecia (1% vs. 9%). Conversely, adverse events of any grade that were more common with rituximab plus lenalidomide than with rituximab plus chemotherapy included cutaneous reactions (in 43% vs. 24% of the patients), diarrhea (37% vs. 19%), rash (29% vs. 8%), abdominal pain (15% vs. 9%), myalgia (14% vs. 6%), muscle spasms (13% vs. 4%), and tumor flare reaction (6% vs. <1%). RELEVANCE was a randomized, phase 3 trial that compared an immunomodulatory regimen, rituximab plus lenalidomide, with the current standard of care, rituximab plus chemotherapy, in previously untreated patients with advanced follicular lymphoma who were in need of treatment according to GELF criteria. Overall, both treatment groups showed good outcomes, and a median has not yet been reached for either progression-free survival or overall survival. Superiority was not shown for either regimen. The RELEVANCE trial was designed as a superiority trial on the basis of results of early phase 2 trials that showed high rates of best confirmed or unconfirmed complete response with rituximab plus lenalidomide in previously untreated patients with indolent lymphoma who did not have to meet GELF criteria before the initiation of treatment. At the time that the RELEVANCE trial was designed, the phase 2 trials had short follow-up periods for assessment of confirmed or unconfirmed complete response and immature time-to-event data. However, the efficacy of rituximab plus lenalidomide appeared to be similar to that of rituximab plus chemotherapy, although the safety profile appeared to differ between the two regimens.

The efficacy of rituximab plus lenalidomide was similar to that of rituximab plus chemotherapy; however, differences between the two groups were noted in safety profiles, with a higher incidence of grade 3 or 4 neutropenia and febrile neutropenia of any grade with rituximab plus chemotherapy and a higher incidence of grade 3 or 4 cutaneous reactions with rituximab plus lenalidomide. Theory and practice in the design of physician payment incentives.

Combining the economic literature on principal-agent relationships with examples of marketplace innovations allows analysis of the evolution of methods for paying physicians. Agency theory and the economic principles of performance-based compensation are applied in the context of imperfect information, risk aversion, multiple interrelated tasks, and team production efficiencies. Fee-for-service and capitation are flawed methods of motivating physicians to achieve specific goals. Payment innovations that blend elements of fee-for- service, capitation, and case rates can preserve the advantages and attenuate the disadvantages of each. These innovations include capitation with fee-for-service carve- outs, department budgets with individual fee- for-service or "contact" capitation, and case rates for defined episodes of illness. The context within which payment incentives are embedded, includes such non-price mechanisms as screening and monitoring and such organizational relationships as employment and ownership. The analysis has implications for health services research and public policy with respect to physician payment incentives. Quality of Care in the United Kingdom after Removal of Financial Incentives

The benefits of pay-for-performance schemes in improving the quality of care remain uncertain. There is little information on the effect of removing incentives from existing pay-for-performance schemes. We conducted interrupted time-series analyses of electronic medical record (EMR) data from 2010 to 2017 for 12 quality-of-care indicators in the United Kingdom’s Quality and Outcomes Framework for which financial incentives were removed in 2014 and 6 indicators for which incentives were maintained. We estimated the effects of removing incentives on changes in performance on quality-of-care measures. Removal of financial incentives was associated with an immediate decline in performance on quality measures. In part, the decline probably reflected changes in EMR documentation, but declines on measures involving laboratory testing suggest that incentive removal also changed the care delivered. As compared with expected values on the basis of previous trends, there were significant, moderate-to-large reductions in documented quality for all 12 indicators in the year after incentives were removed, with small, mainly negative changes in trend in subsequent years.

Documented Quality of Care for Indicators with Financial Incentives That Were Either Removed or Maintained at the End of 2013– 2014. Shown are the percentages of patients in whom quality-of-care indicators were documented during the period from 2010–2011 to 2016–2017. Indicators for which incentives were removed are shown in Panels A, C, and E; the vertical red lines indicate the year of removal. Indicators for which incentives were maintained are shown in Panels B, D, and F. Panels A and B show clinical-process indicators, Panels C and D show intermediate-outcome indicators, and Panels E and F show health-advice indicators. CHD denotes coronary heart disease, and TIA transient ischemic attack.

Our analysis of information documented in EMRs showed that there were immediate reductions in quality-of-care measures for all 12 indicators in the first year after the removal of financial incentives, with only small additional changes in the following 2 years.

Our analysis of information documented in EMRs showed that there were immediate reductions in quality-of-care measures for all 12 indicators in the first year after the removal of financial incentives, with only small additional changes in the following 2 years. Reductions were generally largest for indicators related to documented provision of health advice, with absolute reductions ranging from 46.1 to 71.6 percentage points 3 years after removal of financial incentives, and for the indicator related to documentation of seizure-free status in patients with epilepsy, with an absolute reduction of 53.6 percentage points. These were indicators for which the physician was required to check boxes in the EMR to indicate that care had been delivered, and the large reductions observed could indicate either that care was no longer given or that it was no longer documented. Changes were smaller, although still substantial, for performance on clinical-process and intermediate-outcome indicators, for which data such as blood pressure and smoking status are routinely recorded in coded form and laboratory test values are automatically entered into the EMR. The smallest change in performance at 3 years was a reduction of 9.2 percentage points in thyroid-function testing in patients with hypothyroidism. There were no large changes in documented quality on indicators for which incentives were not removed. Removal of incentives was usually associated with increased variation in documented quality among practices, but socioeconomic disparities narrowed rather than widened after incentive removal.

Financial incentives that simply pay providers to deliver specified levels of quality therefore seem unlikely to deliver sustainable improvement unless they are aligned with more comprehensive interventions that change the organization of care and future clinical practice. Browse Clinical Problem-Solving

A 55-year-old man was evaluated in the clinic after returning from a 5-month visit to Pakistan. He reported a 3-month history of intermittent fevers and fatigue without night sweats, weight loss, headache, cough, diarrhea, rash, dysuria, or arthralgias. His vital signs and physical examination were normal. The differential diagnosis for fever and fatigue is broad. The new onset of fever after international travel prioritizes the possibility of an infectious process. Infections that are endemic in Pakistan and that may cause a prolonged, undifferentiated fever include tuberculosis, visceral leishmania infection, brucellosis, and relapsing fever. In addition to infections, the differential diagnosis includes autoimmune and autoinflammatory disorders, cancer, and drug-induced reactions. The patient had been born and raised in Pakistan and had immigrated to the mid-Atlantic region of the United States in his 30s. His medical history included coronary artery disease, stroke, hypertension, hyperlipidemia, and gastroesophageal reflux disease. His medications were losartan, aspirin, clopidogrel, metoprolol, pravastatin, and as-needed sublingual nitroglycerin. He had no family history of cancer or autoimmune disease. He was a retired restaurant owner, and he had a smoking history of 60 pack-years but had quit smoking 12 years earlier. He was in a monogamous relationship with his wife. He reported no heavy alcohol intake or illicit drug use. CT Images of the Abdomen and Pelvis Showing Splenomegaly. Panel A shows the axial view, and Panel B the coronal view. L denotes left, and R right. Five months later, the patient returned to the clinic and Serum electrolyte levels, renal function, and reported having daily fevers, continued fatigue, new urinalysis were normal. The aspartate drenching night sweats, nonproductive cough, and aminotransferase level was 119 U per liter (normal myalgias. His temperature was 38.4°C. His pulse was range, 0 to 37), and the alanine aminotransferase level 48 U per liter (normal range, 0 to 40); the 116 beats per minute, blood pressure 124/88 mm Hg, alkaline phosphatase and bilirubin levels were and respiratory rate 16 breaths per minute with oxygen normal. The white-cell count was 3410 per cubic saturation of 97% while he was breathing ambient air. millimeter (56% neutrophils, 18% lymphocytes, The patient was referred to the emergency department. 25% monocytes, <1% eosinophils). The He appeared to be uncomfortable. Cardiac, respiratory, hemoglobin level was 13.1 g per deciliter, the abdominal, neurologic, skin, and musculoskeletal mean corpuscular volume was 86.0 fl, and the platelet count was 127,000 per cubic millimeter. examinations were normal. The erythrocyte sedimentation rate was 37 mm per Serum electrolyte levels, renal function, and urinalysis hour (normal range, 1 to 20), and the C-reactive were normal. The aspartate aminotransferase level was protein level was 2.9 mg per deciliter (normal 119 U per liter (normal range, 0 to 37), and the alanine value, <0.5). A radiograph of the chest was normal. aminotransferase level 48 U per liter (normal range, 0 The serum creatine kinase level was 92 U per liter to 40); the alkaline phosphatase and bilirubin levels (normal range, 24 to 195), and the lactate dehydrogenase (LDH) level was 1942 U per liter were normal. The white-cell count was 3410 per cubic (normal range, 118 to 273). Blood, sputum, and millimeter (56% neutrophils, 18% lymphocytes, 25% stool bacterial cultures were sterile. Polymerase- monocytes, <1% eosinophils). The hemoglobin level chain-reaction (PCR) testing for influenza type A was 13.1 g per deciliter, the mean corpuscular volume and B was negative. HIV, hepatitis C antibody, and was 86.0 fl, and the platelet count was 127,000 per hepatitis B surface antigen and core antibody tests cubic millimeter. The erythrocyte sedimentation rate were negative. Staining for acid-fast bacilli and PCR testing for Mycobacterium tuberculosis in was 37 mm per hour (normal range, 1 to 20), and the sputum samples were negative, as was an C-reactive protein level was 2.9 mg per deciliter (normal interferon-γ release assay. A peripheral-blood value, <0.5). A radiograph of the chest was normal. smear showed occasional atypical, reactive- Although the findings are nonspecific, an elevated LDH appearing lymphocytes and thrombocytopenia. level with fever and cytopenias may indicate a Serum protein electrophoresis and free light chains lymphoma. Imaging would be helpful in looking for were normal. lymphadenopathy or a source of infection. Solid tumors cause fever less commonly. Three skin-biopsy samples were obtained at random on the left upper arm, abdomen, and left thigh. Pathological examination revealed intravascular B-cell lymphoma in all the specimens. The patient was transferred to the oncology center and started receiving rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). He completed six cycles of therapy and had a complete remission. His energy and appetite returned to normal. Repeat skin- biopsy samples obtained after the completion of therapy were negative for intravascular lymphoma. One year after diagnosis, he remained afebrile and had no fatigue, cough, confusion, forgetfulness, or abdominal symptoms. Intravascular lymphoma is a rare, extranodal subtype of diffuse large B-cell lymphoma. The incidence in the United States is less than 1 case per every 10 million persons but has been increasing, possibly owing to heightened awareness since this cancer was categorized as a distinct entity in 2007. Diagnosis requires a tissue biopsy of an involved organ and may involve repeat biopsies. Histopathological testing reveals malignant lymphoid cells within the lumina of small vessels, capillaries, and sinusoids of affected organs. The use of hematoxylin and eosin staining alone may be insufficient for diagnosis. The neoplastic cells are typically B cells with high CD20 expression, occasional CD5 expression, and rare CD10 expression. Therefore, CD20 immunohistochemical staining is typically required for diagnosis. It is hypothesized that abnormal expression of adhesion and homing receptors Malignant Cells in Skin-Biopsy Samples. Panel A accounts for the localization within these small vessels. There shows hematoxylin and eosin staining of a skin- are rare cases of intravascular lymphoma with T-cell and biopsy sample showing malignant large B cells natural killer cell markers. However, these are classified within small-vessel lumen. Panel B shows CD20 separately and represent different disease entities. staining (brown) of a skin-biopsy sample showing malignant cells that are CD20-positive. Random (also known as “blind”) skin biopsy, with samples of normal-appearing skin obtained from the thighs, arms, or abdomen, has emerged as a valuable, relatively noninvasive diagnostic tool. In one study involving 11 patients who had received a diagnosis on the basis of bone marrow examination, 10 patients (91%) had positive results on random skin biopsy. Other small case series (involving 24 and 32 patients) also suggest that random skin biopsy aids in the diagnosis of patients with fever of unknown origin and an elevated LDH level when intravascular lymphoma is suspected. The rarity of the disease, its frequently rapidly progressive course, and the nonspecific nature of the presenting symptoms often result in diagnostic delays, and in some cases the disease is identified only at autopsy. It is essential to recognize the potential value of random skin biopsy for prompt diagnosis. The present case highlights intravascular lymphoma as a cause of fever of unknown origin. This patient underwent an exhaustive search over a period of many months to investigate his persistent fever and pancytopenia. Ultimately, it was the addition of a relatively simple skin biopsy that identified the disorder that was lurking just beneath the surface. Intravascular lymphoma is treatable. A retrospective study involving 106 patients showed a progression-free survival rate of 56% and an overall survival rate of 66% at 2 years among patients who had been treated with rituximab-containing chemotherapy regimens (e.g., R-CHOP). There have been no randomized, controlled trials of therapy for this condition. Left undiagnosed, it is fatal. Circulating Extracellular Vesicles in Human Disease

It is well known that cells release fluid-filled sacs (vesicles) to the extracellular environment during cell death, or apoptosis, but it has been increasingly recognized that healthy cells may also release vesicles in the process of normal functions. Vesicles that are released by healthy cells have a wide variety of names (e.g., ectosomes, microparticles, microvesicles, exosomes, and oncosomes), with the term “extracellular vesicles” typically used as a generic reference to secreted vesicles. Extracellular vesicles are found in circulation and contain cell-derived biomolecules (e.g., RNA, protein, and metabolites). Extracellular vesicles are implicated in trafficking of molecules between cells and as such have an effect on physiologic function and serve as biomarkers for disease. Nevertheless, important limitations — including practical difficulties in assaying low concentrations of extracellular vesicles in circulation, identifying their tissue of origin, and specifying which molecular cargo is most relevant — have restrained enthusiasm for research into the role of extracellular vesicles in vivo. The goal of this article is to provide a brief introduction to extracellular vesicles, with a specific focus on translational and clinical studies to highlight emerging evidence that suggests a potential role in human disease. Given the explosion of work in this field, it is difficult to cover the breadth of diseases in which extracellular vesicles may be functionally relevant. As such, the reader is referred to the expanding literature in this field for more details. Size and Contents of Extracellular Vesicles. Classic descriptions of extracellular vesicles have relied on size, with exosomes defined as having a diameter of less than 150 nm and larger vesicles (microvesicles, including ectosomes, microparticles, and oncosomes) measuring up to 1000 nm in diameter. Microvesicles may contain endocytic markers that distinguish them from other organelles with internal membranes, such as autophagic bodies or multilamellar lysosomes, although overlap in these markers is known to occur. Exosomes may contain protein markers associated with the endosomal pathway that is specific to their mode of formation. Extracellular vesicles that are formed by shedding from the plasma membrane may contain markers such as integrins and P- selectin. Extracellular vesicles may contain a variety of proteins, lipids, and nucleic acids that may be specific for, and thereby reflect, the cell of origin. They may also contain a wide variety of small noncoding RNAs, such as microRNAs, piwi-interacting RNA, and small nucleolar RNAs. However, there is substantial overlap in content among extracellular vesicles of various sizes and origins. MHC denotes major histocompatibility complex, and piwi P-element–induced wimpy testis; the RNA designations are circular (circ), long noncoding (lnc), messenger (m), and micro (mi). Possible Role of Extracellular Vesicles in the Diagnosis and Prognosis of Various Diseases. Extracellular vesicles contain partially overlapping contents and shared mechanisms for communication and function. Investigations into a broad variety of diseases — oncologic, cardiometabolic, neurologic, and infectious — support a functional and potentially therapeutic role for extracellular vesicles. The results of these studies suggest that extracellular vesicles may be useful as biomarkers of disease progression or therapeutic response. Cancer The role of extracellular vesicles and their contents as potential contributors to oncogenesis, metastatic disease, and resistance to chemotherapy is a rapidly expanding area of research in cancer biology. Extracellular vesicles can funnel chemotherapeutic agents out of a cancer cell through bulk transport within vesicles or active efflux mechanisms and may also express molecules that divert biologic agents away from malignant cells (e.g., human epidermal growth factor receptor 2 [HER2] in breast cancer). Cardiometabolic Disease The function of extracellular vesicles in cardiovascular and metabolic diseases shares features with its role in cancer, with emerging evidence of cross-talk between different cell types in the heart that is mediated by extracellular vesicles. For example, angiotensin II elicits the release of extracellular vesicles from cardiac fibroblasts, which can potentiate cardiac hypertrophy through altering of gene expression in cardiomyocytes. In addition, microRNA 155 that is contained within macrophage-derived extracellular vesicles decreases fibroblast proliferation and increases inflammation in mice,3which suggests that extracellular vesicle–mediated cross-talk between noncardiomyocyte-cell types may affect cardiac structure. Neurologic Disease With the emergence of similar themes in cancer, cardiovascular disease, and neurologic disease, researchers have intense interest in exploring the potential role of extracellular vesicles in neurodegeneration, trauma, and stroke. In models of traumatic brain injury, the presence of increased amounts of microRNA 124 in extracellular vesicles from microglia has been associated with decreased inflammation and improved regrowth after injury. Infectious Disease Viruses can harness the cellular machinery of extracellular vesicles for multiple purposes, including increasing infectivity and evading the immune system. Extracellular vesicles that are derived from hepatoma cells infected with hepatitis C in vitro contain genetic information and proteins that promote infection in the absence of active interaction between viruses and target cells. Major Challenges Enthusiasm about basic, clinical, and translational studies of extracellular vesicles has spurred the formation of various international professional societies (e.g., the American Society for Exosomes and Microvesicles and the International Society for Extracellular Vesicles) to guide and standardize protocols for the study of extracellular vesicles and biomarker development. Current and Emerging Methods of Detection of Extracellular Vesicles. Current methods of isolating extracellular vesicles (e.g., density gradient centrifugation) are both time and labor intensive. Emerging technologies that may overcome some of these challenges include those that enable the characterization of single extracellular vesicles and those that allow for ultrasensitive detection of associated proteins or RNAs without the need for isolating extracellular vesicles. Even after isolation, analysis of the contents of extracellular vesicles is not currently standardized, with different methods for analyzing morphologic features and contents (e.g., RNA sequencing and proteomics). ELISA denotes enzyme-linked immunosorbent assay, FACS fluorescence-activated cell sorting, and RT-qPCR quantitative reverse transcriptase–polymerase chain reaction. Treatment correlates of successful outcomes in pulmonary multidrug-resistant tuberculosis: an individual patient data meta-analysis Treatment outcomes for multidrug-resistant tuberculosis remain poor. We aimed to estimate the association of treatment success and death with the use of individual drugs, and the optimal number and duration of treatment with those drugs in patients with multidrug-resistant tuberculosis. In this individual patient data meta-analysis, we searched MEDLINE, Embase, and the Cochrane Library to identify potentially eligible observational and experimental studies published between Jan 1, 2009, and April 30, 2016. We also searched reference lists from all systematic reviews of treatment of multidrug-resistant tuberculosis published since 2009. To be eligible, studies had to report original results, with end of treatment outcomes (treatment completion [success], failure, or relapse) in cohorts of at least 25 adults (aged >18 years). We used anonymised individual patient data from eligible studies, provided by study investigators, regarding clinical characteristics, treatment, and outcomes. Using propensity score-matched generalised mixed effects logistic, or linear regression, we calculated adjusted odds ratios and adjusted risk differences for success or death during treatment, for specific drugs currently used to treat multidrug-resistant tuberculosis, as well as the number of drugs used and treatment duration.

Association of each drug with treatment success and death during treatment We assessed 50 datasets from 25 countries, with 12 030 patients treated for multidrug-resistant tuberculosis. Of the drugs analysed, levofloxacin, moxifloxacin, linezolid, and bedaquiline were associated with greater treatment success and reduced death. Clofazimine and the carbapenems were associated with significantly improved treatment success but not reduced death. Pyrazinamide, streptomycin, amikacin, and cycloserine and terizidone were associated with modest benefits, but only in patients with susceptible isolates, whereas the use of kanamycin, capreomycin, ethionamide and protionamide, para-aminosalicylic acid, the macrolides, and amoxicillin-clavulanic acid (when used without carbapenems), were associated with no significant benefit or significantly worse outcomes.

Radial versus femoral access and bivalirudin versus unfractionated heparin in invasively managed patients with acute coronary syndrome (MATRIX)

The Minimizing Adverse Haemorrhagic Events by Transradial Access Site and Systemic Implementation of Angiox (MATRIX) programme was designed to assess the comparative safety and effectiveness of radial versus femoral access and of bivalirudin versus unfractionated heparin with optional glycoprotein IIb/IIIa inhibitors in patients with the whole spectrum of acute coronary syndrome undergoing invasive management. Here we describe the prespecified final 1-year outcomes of the entire programme. MATRIX was a programme of three nested, randomised, multicentre, open-label, superiority trials in patients with acute coronary syndrome in 78 hospitals in Italy, the Netherlands, Spain, and Sweden. Patients with ST-elevation myocardial infarction were simultaneously randomly assigned (1:1) before coronary angiography to radial or femoral access and to bivalirudin, with or without post-percutaneous coronary intervention infusion or unfractionated heparin (one-step inclusion). Patients with non-ST-elevation acute coronary syndrome were randomly assigned (1:1) before coronary angiography to radial or femoral access and, only if deemed eligible to percutaneous coronary intervention after angiography (two-step inclusion), entered the antithrombin type and treatment duration programmes. Randomisation sequences were computer generated, blocked, and stratified by intended new or current use of P2Y12 inhibitor (clopidogrel vs ticagrelor or prasugrel), and acute coronary syndrome type (ST- elevation myocardial infarction, troponin-positive, or troponin-negative non-ST-elevation acute coronary syndrome). Bivalirudin was given as a bolus of 0·75 mg/kg, followed immediately by an infusion of 1·75 mg/kg per h until completion of percutaneous coronary intervention. Heparin was given at 70–100 units per kg in patients not receiving glycoprotein IIb/IIIa inhibitors, and at 50–70 units per kg in patients receiving glycoprotein IIb/IIIa inhibitors. Clinical follow-up was done at 30 days and 1 year. Co-primary outcomes for MATRIX access and MATRIX antithrombin type were major adverse cardiovascular events, defined as the composite of all- cause mortality, myocardial infarction, or stroke up to 30 days; and net adverse clinical events, defined as the composite of non-coronary artery bypass graft-related major bleeding, or major adverse cardiovascular events up to 30 days. The primary outcome for MATRIX treatment duration was the composite of urgent target vessel revascularisation, definite stent thrombosis, or net adverse clinical events up to 30 days.

(A) All-cause mortality, myocardial infarction, or stroke. (B) All- cause mortality, myocardial infarction, stroke, or Bleeding Academic Research Consortium type 3 or 5 bleeding. RR=rate ratio. The first co-primary outcome of major adverse cardiovascular events occurred in 595 (14·2%) of 4197 patients with radial access and 659 (15·7%) of 4207 patients with femoral access, with an RR of 0·89 (95% CI 0·80–1·00) and two- sided p=0·0526. The second co-primary outcome of net adverse clinical events occurred in 639 (15·2%) of 4197 patients with radial access and 724 (17·2%) of 4207 patients with femoral access, with an RR of 0·87 (0·78–0·97; p=0·0128. Co-primary composite outcomes at 1 year in patients randomised to bivalirudin, with or without post-percutaneous coronary intervention and in patients randomised to unfractionated heparin

(A) All-cause mortality, myocardial infarction, or stroke. (B) All-cause mortality, myocardial infarction, stroke, or BARC type 3 or 5 bleeding. (C) All-cause mortality, myocardial infarction, stroke, definite stent thrombosis, urgent target vessel revascularisation or BARC type 2, 3, or 5 bleeding. BARC=Bleeding Academic Research Consortium. RR=rate ratio. Among patients with acute coronary syndrome undergoing invasive management, with or without ST-segment elevation, we found that use of radial access for coronary angiography, followed by percutaneous coronary intervention if indicated, was associated with reduced net adverse clinical events at 1 year. Major adverse cardiovascular events were not significantly reduced with radial access compared with femoral access. Differences between groups were driven by reductions in non-coronary artery bypass graft BARC major bleeding and cardiovascular, but not all-cause mortality with radial access. Major adverse cardiovascular and net adverse clinical events at 1 year were not lower with bivalirudin compared with unfractionated heparin with optional glycoprotein IIb/IIIa inhibitors. At secondary endpoints analysis, bleeding risk was markedly reduced and stent thrombosis rate was increased with bivalirudin compared with heparin. Post- percutaneous coronary intervention bivalirudin infusion after intervention was not associated with lower combined 1-year ischaemic risk and bleeding risk. Small coronary disease (<3 mm in diameter) Drug-coated balloons for small coronary artery disease (BASKET-SMALL 2): an open- label randomised non-inferiority trial Drug-coated balloons (DCB) are a novel therapeutic strategy for small native coronary artery disease. However, their safety and efficacy is poorly defined in comparison with drug-eluting stents (DES). BASKET- SMALL 2 was a multicentre, open-label, randomised non-inferiority trial. 758 patients with de-novo lesions (<3 mm in diameter) in coronary vessels and an indication for percutaneous coronary intervention were randomly allocated (1:1) to receive angioplasty with DCB versus implantation of a second-generation DES after successful predilatation via an interactive internet- based response system. Dual antiplatelet therapy was given according to current guidelines. The primary objective was to show non-inferiority of DCB versus DES regarding major adverse cardiac events (MACE; ie, cardiac death, non-fatal myocardial infarction, and target-vessel revascularisation) after 12 months. The non-inferiority margin was an absolute difference of 4% in MACE. Second-generation drug-eluting stents (DES) are the preferred treatment for percutaneous coronary intervention (PCI) in coronary artery disease. TIMI=thrombolysis in myocardial However, the efficacy of stents is restricted in small infarction. DCB=drug-coated balloons. coronary arteries. DES=drug-eluting stents. This limitation applies to bare metal stents (BMS) and first-generation and second-generation DES.

Cumulative incidence rates for MACE

According to the actual treatment that patients received. MACE=major adverse cardiac events. DCB=drug- coated balloons. DES=drug-eluting stents. The BASKET-SMALL 2 trial showed the non-inferiority of DCB versus DES regarding clinical events in a large all-comer population undergoing PCI in native small-vessel coronary artery disease. After 12 months, MACE rates were low and similar between the groups. The DCB technique is based on the interaction of a highly lipophilic drug with a coating matrix and allows for fast and homogenous drug delivery into the vessel wall. Although many devices exist on the market, balloons coated with paclitaxel and iopromide have shown favourable clinical results and are the most widely used to date. DCB is an established treatment option for the treatment of in-stent restenosis, but, in native small- vessel coronary artery disease, the technique has been tested in smaller studies only.

Armed conflict and child mortality in Africa: a geospatial analysis

A substantial portion of child deaths in Africa take place in countries with recent history of armed conflict and political instability. However, the extent to which armed conflict is an important cause of child mortality, especially in Africa, remains unknown. We matched child survival with proximity to armed conflict using information in the Uppsala Conflict Data Program Georeferenced Events Dataset on the location and intensity of armed conflict from 1995 to 2015 together with the location, timing, and survival of infants younger than 1 year (primary outcome) in 35 African countries. We measured the increase in mortality risk for infants exposed to armed conflicts within 50 km in the year of birth and, to study conflicts' extended health risks, up to 250 km away and 10 years before birth. We also examined the effects of conflicts of varying intensity and chronicity (conflicts lasting several years), and effect heterogeneity by residence and sex of the child. We then estimated the number and portion of deaths of infants younger than 1 year related to conflict. The distribution of armed conflict events in Africa, 1995–2015

The map shows the Uppsala Conflict Data Program conflict location data in the continent, with changing location over time. The study countries are grey with thick borders. The regional changes in high-density conflicts, and the absence of any obvious decline in the frequency of conflict in more recent years, are shown. Effect of armed conflict in first year of life on mortality of infants younger than 1 year

The effect of any conflict within 50 km of the infant's cluster (red bar), and the rising risk from conflicts of increasing intensity (blue bars) is shown in (A). The increasing risk from conflicts of increasing duration is shown in (B). We estimated the exposure based on the number of consecutive years of conflict near the infant's cluster. Effect of conflict on mortality of infants younger than 1 year, over time

(A) The coefficients from a regression with conflict exposure indicators for each year up to 10 years before birth. Each coefficient represents the independent lingering risk of mortality in the first year of life from historical conflict taking place up to 10 years before birth. Conflicts up to 8 years before birth show an independent relationship with increased mortality of infants younger than 1 year. (B) The cumulative mortality risk over time for conflicts within 0–50 km, 51–100 km, and 101–250 km from a child's birth, estimated in one regression, showing an attenuated effect at greater distances. Blue shading represents 95% CIs. Number of deaths of children younger than 5 years due to conflict in Africa

We used 0·1 degree × 0·1 degree gridded estimates of the number of births, infant mortality, and conflict timing and location, to estimate the number of observed deaths in each grid cell, and then the number of deaths expected in the absence of conflict. We aggregated the grid cell-level estimates for 1995 to 2015. We used national infant mortality for countries without gridded infant mortality. The scale indicates the number of deaths in each grid cell (roughly 10 km × 10 km). The biggest clusters of child deaths are apparent in Nigeria, east- central Africa (Uganda, Democratic Republic of the Congo, Burundi, and Kenya), Ethiopia, Libya, Egypt, and west Africa (centered around Sierra Leone). Thick borders and grey background represent study countries.

Als Bronchiektasen bezeichnet man in der Medizin irreversible sackförmige oder zylindrische Ausweitungen der mittelgroßen Atemwege (Bronchien). Dieser Zustand wird auch Bronchiektasie genannt. Begleitet werden diese Ausweitungen von einer chronischen nekrös eiternden bakteriellen Infektion der Bronchialwand. Es gibt eine angeborene und eine erworbene Form der Bronchiektasen. Angeborene Bronchiektasen können in nur einem Lungensegment oder einem Lungenlappen auftreten. Auch unbegrenztes Vorkommen wird beobachtet, meist in Zusammenhang mit anderen Defekten (beispielsweise beim Kartagener-Syndrom, der zystischen Fibrose oder nekrotisierenden und eiternden Pneumonien). Erworben werden Bronchiektasen durch frühkindliche Schädigungen, Infektionskrankheiten (Masern, Keuchhusten), allergische bronchopulmonale Aspergillose, Immunglobulinmangel, α-1-Antitrypsin-Mangel, Ziliendysfunktion, Mukoviszidose, tracheoösophagale Fisteln, Fremdkörperaspiration oder chronische Entzündungsvorgänge (beispielsweise chronische Bronchitis). Leitsymptome sind Husten und großvolumiger Auswurf („maulvolle Expektoration“ genannt), der süßlich-fade oder faulig riecht und sich im Glas typischerweise in drei Schichten („Drei-Schichten-Sputum“) absetzt: schaumige Oberschicht, schleimige Mittelschicht und zäher Bodensatz mit Eiter. Typisch sind Trommelschlegelfinger. Bronchiectasis in children: diagnosis and treatment

Bronchiectasis is conventionally defined as irreversible dilatation of the bronchial tree. Bronchiectasis unrelated to cystic fibrosis is an increasingly appreciated cause of chronic respiratory-related morbidity worldwide. Few randomised controlled trials provide high-level evidence for management strategies to treat the children affected by bronchiectasis. However, both decades-old and more recent studies using technological advances support the notion that prompt diagnosis and optimal management of paediatric bronchiectasis is particularly important in early childhood. Although considered to be of a non-reversible nature, mild bronchiectasis determined by radiography might be reversible at any age if treated early, and the lung function decline associated with disease progression could then be halted. Although some management strategies are extrapolated from cystic fibrosis or adult-based studies, or both, non-cystic fibrosis paediatric-specific data to help diagnose and manage these children still need to be generated. We present current knowledge and an updated definition of bronchiectasis, and review controversies relating to the management of children with bronchiectasis, including applying the concept of so-called treatable traits. Features of bronchiectasis seen in chest high resolution CT scans reconstructed from multidetector CT scans ranging from mild (cylindrical) to severe (cystic)

See Radiological diagnosis section for description of features. (A) Cylindrical bronchiectasis. Early bronchiectasis that is likely to be reversible if diagnosed early and treated aggressively. This CT scan of a 4 year old child shows in the left and right lower lobes and feature 3 in the right middle lobe. (B) Cylindrical bronchiectasis. A repeat CT scan 2 years later shows resolution of the bronchiectasis, but with linear fibrosis within the inferomedial aspect of the right middle lobe. Clinically the child was asymptomatic. (C) Varicose or fusiform and cystic bronchiectasis. A CT slice from a 22 month old child with previous pulmonary tuberculosis who migrated to Australia. This CT scan shows varicose bronchiectasis in the right upper lobe and the more severe cystic bronchiectasis in the left. In the left upper lobe, increased broncho-arterial ratio, bronchial wall thickening, lack of bronchial tapering, and presence of bronchial structures in the lung periphery are present with centrilobular densities with tree-in-bud appearances also visible. (D) Varicose or fusiform and cystic bronchiectasis. Following aggressive treatment, the repeat CT scan undertaken 3 years later shows improvement in the cystic bronchiectasis where some cystic areas have become varicose. Asymmetry is shown in the lung volumes with the right lung appearing hyperinflated relative to the left, suggesting impaired growth of the left lung. Framework for the development of paediatric bronchiectasis This adapted framework is based on a combination of Cole's vicious cycle theory, and both old and recent studies on protracted bacterial bronchitis, chronic suppurative lung disease, and bronchiectasis. The diagnostic criteria and features of protracted bacterial bronchitis are described in recent reviews from the past 3 years. The framework emphasises the importance of early detection and treatment of endobronchial suppuration (reflected by chronic wet cough), which halts the vicious cycle of infection-inflammation. Treatable traits in children with bronchiectasis A suggested approach based on asthma or chronic obstructive pulmonary disease data. These traits overlap—ie, children can have more than one trait and examples are listed for each trait. Pseudomonas aeruginosa eradication treatment pathway

Suggested eradication therapy for newly infected children. *The antibiotic choice is established by availability, susceptibility profile, tolerance, and patient adherence factors. For intravenous antibiotics, a two-drug regimen is suggested.

A myriad of heterogeneous risk or causative factors, or both, can lead to bronchiectasis in children. These factors and the various clinical symptoms vary among settings and countries, but share the common thread of cycles of chronic cough, recurrent respiratory infections, and endobronchial suppuration with persistent infection and inflammation. Interrupting these processes as early as possible is necessary to reverse or halt disease progression, and prevent further tissue damage. This interruption requires early diagnosis, which is dependent on clinical awareness and use of paediatric specific rather than adult derived definitions and data. We have proposed a paediatric specific diagnosis of bronchiectasis and suggest adopting the concept of treatable traits when managing these children, consistent with existing strategies to optimise the management of people with other chronic airway diseases. However, a greater evidence base is required to fully realise how these concepts would improve short-term clinical outcomes and long-term prognosis of children with bronchiectasis. Advances in bronchiectasis: endotyping, genetics, microbiome, and disease heterogeneity

Bronchiectasis is characterised by pathological dilation of the airways. More specifically, the radiographic demonstration of airway enlargement is the common feature of a heterogeneous set of conditions and clinical presentations. No approved therapies exist for the condition other than for bronchiectasis caused by cystic fibrosis. The heterogeneity of bronchiectasis is a major challenge in clinical practice and the main reason for difficulty in achieving endpoints in clinical trials. Recent observations of the past 2 years have improved the understanding of physicians regarding bronchiectasis, and have indicated that it might be more effective to classify patients in a different way. Patients could be categorised according to a heterogeneous group of endotypes (defined by a distinct functional or pathobiological mechanism) or by clinical phenotypes (defined by relevant and common features of the disease). In doing so, more specific therapies needed to effectively treat patients might finally be developed. Here, we describe some of the recent advances in endotyping, genetics, and disease heterogeneity of A cycle of events that promote a persistent and progressive bronchiectasis including observations related to the process over time. Impaired mucociliary clearance and retention microbiome. of airway phlegm disrupts normal host defences, rendering the airways susceptible to infection, which can become persistent. This process, in turn, incites an inflammatory response causing injury and abnormal remodelling of the airways, leading to bronchiectasis. CFTR mutation classification

CFTR mutation classification based on molecular defect. These molecular defects correspond to therapeutic approaches to restore the quantity of protein or its function, or both resulting in genotype specific CFTR modulator drugs used alone (ivacaftor) or in combination (lumacaftor–ivacaftor, tezacaftor–ivacaftor). CFTR=cystic fibrosis transmembrane conductance regulators. Cl=chloride ion. Ciliary dyskinesia gene classifications

Defects in cilia genes can be classified on the basis of ultrastructural effects seen on cross- sectional examination of cilia with electron microscopy. Note that some genes can be mutated without obvious structural abnormalities. Genes associated with the outer dynein arm include DNAH5, DNAI1, DNAI2, TXNDC3, DNAL1, ARMC4, CCDC114, and CCDC151. Genes associated with the inner and outer dynein arm include LLRC6, DNAAF1, DNAAF2, DNAAF3, CCDC103, ZMYND10, HEATR2, DYX1C1, SPAG1, and C21orf59. Genes associated with the inner dynein arm and axonemal disorganisation include CCDC39 and CCDC40. Genes associated with the central apparatus are HYDIN (RSPH4A and RSPH with disorganisation). Genes associated with normal ultrastructure are DNAH11, CCDC164, CCDC65, and RSPH1 (CCNO and MCIDAS with rare cilia). Potential endotypes for patients with idiopathic bronchiectasis with pulmonary non-tuberculous mycobacteria infections

Characterisation with biomarker measurements of sweat chloride, nasal nitric oxide, ciliary beat frequency, and body morphometrics coupled with the presence of relevant genetic variants could allow therapeutic targeting on the basis of the predominant endotype. CFTR=cystic fibrosis transmembrane conductance regulators. GMCSF=granulocyte-macrophage colony-stimulating factor. TGF-β=transforming growth factor-β. The understanding of chronic infection in bronchiectasis is evolving with the advent of sequencing technologies that allow a more comprehensive profiling of the bacterial communities in the lung, termed the microbiome. A microbiome analysis of healthy airways reveals a rich, diverse community of bacteria that are present in low abundance. It is premature to define the flora of the airways as healthy, as some, or all, of these microorganisms could represent transient populations introduced through microaspiration. Across many respiratory diseases it has been shown that disease is associated with a loss of bacterial diversity, (ie, through the loss of important bacterial taxa), or by the dominance of a single taxon or small group of taxa. The dominance of a single taxon or small group of taxa is referred to as a loss of evenness of the microbiota, whereas the loss of diversity is referred to as a loss of richness. Measures of richness and evenness, or composite diversity measures such as the Shannon-Wiener diversity index have a positive linear correlation with lung function in bronchiectasis, although it cannot be stated whether this result is causal or due to frequent antibiotic exposure as studies to date have been mostly cross-sectional. The proteobacteria, which include Pseudomonas and Haemophilus, come to dominate the diseased dysbiotic airway in bronchiectasis and have been associated with more neutrophil-mediated inflammation and exacerbations. However, there is a subgroup of patients with microbiota dominated with firmicutes (eg, the anaerobe Veillonella) that have frequent exacerbations despite lower amounts of neutrophilic inflammation. Ultimately, clinical variables can only provide modest predictive accuracy for bronchiectasis outcomes and provide little information about the underlying biology of the disease. Recent progress in understanding genotypes and endotypes, the process of defining groups of patients by pathobiology often with use of biomarkers, is at an early stage in bronchiectasis but offers promising approaches to develop therapeutic interventions for some patients with bronchiectasis. Hopefully, in the near future a standardised approach to the evaluation of patients with bronchiectasis will exist, and will use genetic analyses and local and systemic biomarkers to stratify patients in terms of prognosis and therapy. 15-year-old male presented with constipation, abdominal pain, and passage of foul-smelling stool mixed with multiple gravel stones. He did not have oliguria, fever, rectal bleeding, or any feature suggestive of peritonitis. The patient was not on any regular medication, and had a history of pica. On examination, he had diffuse abdominal tenderness. A digital rectal exam revealed a so-called colonic crunch sign. Complete haemogram and blood biochemistry were within normal limits. Straight abdominal radiograph revealed multiple opaque shadows of different sizes scattered throughout the colon. What is the most likely diagnosis?

Lanthanum Lithobezoars Phlebosclerotic colitis Schistosomiasis We report an unusual case of a giant lithobezoar that was extending from the caecum to the anal canal, and the patient had no features of absolute constipation or peritonitis. It is believed to be the first such giant colonic lithobezoar in the literature. A 9-year-old male child was admitted with a 3-year history of pica, recurrent constipation, abdominal pain, failure to thrive and painful defecation. Abdominal examination revealed moderate distention with multiple palpable intraluminal masses along the rectosigmoid, descending colon and the ascending colon up to the illeocaecal region, with no features of peritonitis. Anal inspection revealed stone pellets protruding through the anus. The rectal examination revealed hard, prickly masses filling the dilated rectum. It was impossible to negotiate and pass around the masses occluding the rectum. Under general anesthesia, following anal dilatation, 1,025 pieces of stones were completely recovered manually, with a diameter ranging between 5 mm to 2.5 cm. After evacuation, the patient was given laxatives as well as proctoclysis enema and he used to pass 40–60 pieces of stones a day for 7 days. On the 8th day, another radiograph of the abdomen revealed no residual stones. Mental health assessment by the pediatric psychiatrist did not reveal any gross abnormality. The patient was subsequently discharged on day 9 and was followed-up for a period of 6 months and was put under strict parental supervision. He had increased appetite and gained weight. Stones being manually removed under anesthesia