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Background: A new syndrome of vaccine-induced immune thrombotic thrombocytopenia (VITT) has emerged as a rare side-effect of vaccination against COVID-19. Cerebral venous thrombosis is the most common manifestation of this syndrome but, to our knowledge, has not previously been described in detail. We aimed to document the features of post-vaccination cerebral venous thrombosis with and without VITT and to assess whether VITT is associated with poorer outcomes. Methods: For this multicentre cohort study, clinicians were asked to submit all cases in which COVID-19 vaccination preceded the onset of cerebral venous thrombosis, regardless of the type of vaccine, interval between vaccine and onset of cerebral venous thrombosis symptoms, or blood test results. We collected clinical characteristics, laboratory results (including the results of tests for anti-platelet factor 4 antibodies where available), and radiological features at hospital admission of patients with cerebral venous thrombosis after vaccination against COVID-19, with no exclusion criteria. We defined cerebral venous thrombosis cases as VITT-associated if the lowest platelet count recorded during admission was below 150 × 109 per L and, if the D-dimer was measured, the highest value recorded was greater than 2000 μg/L. We compared the VITT and non-VITT groups for the proportion of patients who had died or were dependent on others to help them with their activities of daily living (modified Rankin score 3–6) at the end of hospital admission (the primary outcome of the study). The VITT group were also compared with a large cohort of patients with cerebral venous thrombosis described in the International Study on Cerebral Vein and Dural Sinus Thrombosis. Findings: Between April 1 and May 20, 2021, we received data on 99 patients from collaborators in 43 hospitals across the UK. Four patients were excluded because they did not have definitive evidence of cerebral venous thrombosis on imaging. Of the remaining 95 patients, 70 had VITT and 25 did not. The median age of the VITT group (47 years, IQR 32–55) was lower than in the non-VITT group (57 years; 41–62; p=0·0045). Patients with VITT-associated cerebral venous thrombosis had more intracranial veins thrombosed (median three, IQR 2–4) than non-VITT patients (two, 2–3; p=0·041) and more frequently had extracranial thrombosis (31 [44%] of 70 patients) compared with non-VITT patients (one [4%] of 25 patients; p=0·0003). The primary outcome of death or dependency occurred more frequently in patients with VITT-associated cerebral venous thrombosis (33 [47%] of 70 patients) compared with the non-VITT control group (four [16%] of 25 patients; p=0·0061). This adverse outcome was less frequent in patients with VITT who received non-heparin anticoagulants (18 [36%] of 50 patients) compared with those who did not (15 [75%] of 20 patients; p=0·0031), and in those who received intravenous immunoglobulin (22 [40%] of 55 patients) compared with those who did not (11 [73%] of 15 patients; p=0·022). Interpretation: Cerebral venous thrombosis is more severe in the context of VITT. Non-heparin anticoagulants and immunoglobulin treatment might improve outcomes of VITT-associated cerebral venous thrombosis. Since existing criteria excluded some patients with otherwise typical VITT-associated cerebral venous thrombosis, we propose new diagnostic criteria that are more appropriate.

The scientific community rapidly responded to the COVID-19 pandemic by developing novel SARS-CoV-2 vaccines (table 1). As of early June 2021, an estimated 2 billion doses have been administered worldwide.1 Neurological adverse events following immunisation (AEFI), such as cerebral venous sinus thrombosis and demyelinating episodes, have been reported. In some countries, these have led to the temporary halting of both vaccine trials and roll-out programmes. In the absence of clear evidence of causal associations between the vaccine and adverse events, or the rarity of the AEFIs themselves, programmes have thus far been restarted, although sometimes with modifications to recommendations.2 View this table: Table 1 SARS-CoV-2 vaccines approved for use by at least one regulatory body at the time of submission (early June 2021)71 Transient influenza-like symptoms such as headache, myalgia and fatigue have been reported in up to 5% of SARS-CoV-2 vaccine recipients in clinical trials,3 4 although these symptoms often indicate an appropriate immune response to vaccination.5 More severe potential adverse effects in the open-label phase of vaccine roll-outs are being collected through national surveillance systems. In the USA, roughly 372 adverse events have been reported per million doses, which is a lower rate than expected based on the clinical trials.6 In the UK, adverse events are reported via the Coronavirus Yellow Card reporting website. As of early June 2021, approximately 250 000 Yellow Cards have been submitted, equating to around three to seven Yellow Cards per 1000 doses.7 For comparison, the 2010 Pandemrix vaccination had a rate of around 0.6 Yellow Card submissions per 1000 doses.8 Increased pharmacovigilance surrounding SARS-CoV-2 vaccinations may lead to surveillance bias,9 safety alerts may lead to notoriety bias10 and recall bias may also occur. Nevertheless, with large numbers of people being vaccinated, often with a two-dose schedule, rare complications …

Purpose of review Traveller's diarrhea, though not life-threatening. is often a vexing problem, which impacts overall function of the traveller while on holiday. Increasing data is available regarding molecular diagnostic techniques, which may help obtain an early etiologic diagnosis. Use of antibiotics for traveller's diarrhea is controversial in this era of multidrug resistance and microbiome disruption. Recent findings Travel to the tropics promotes gut colonization with drug-resistant bacteria and this risk increases after treatment with antibiotics, leading to potential ecological impacts in the country of residence. Summary Traveller's diarrhea is common and can impact a traveller's itinerary leading to significant inconvenience, and occasional longer term sequelae. Though bacterial causes predominate, recommended treatment is conservative in mild-to-moderate cases. Molecular techniques for early diagnosis of traveller's diarrhea may help with appropriate management. Treatment with antibiotics is sometimes required but is associated with gut colonization by multidrug-resistant bacteria.

Background The coronavirus disease 2019 (COVID‐19) pandemic has resulted in substantial mortality. Some specialists proposed chloroquine (CQ) and hydroxychloroquine (HCQ) for treating or preventing the disease. The efficacy and safety of these drugs have been assessed in randomized controlled trials. Objectives To evaluate the effects of chloroquine (CQ) or hydroxychloroquine (HCQ) for 1) treating people with COVID‐19 on death and time to clearance of the virus; 2) preventing infection in people at risk of SARS‐CoV‐2 exposure; 3) preventing infection in people exposed to SARS‐CoV‐2. Search methods We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, Current Controlled Trials (www.controlled‐trials.com), and the COVID‐19‐specific resources www.covid‐nma.com and covid‐19.cochrane.org, for studies of any publication status and in any language. We performed all searches up to 15 September 2020. We contacted researchers to identify unpublished and ongoing studies. Selection criteria We included randomized controlled trials (RCTs) testing chloroquine or hydroxychloroquine in people with COVID‐19, people at risk of COVID‐19 exposure, and people exposed to COVID‐19. Adverse events (any, serious, and QT‐interval prolongation on electrocardiogram) were also extracted. Data collection and analysis Two review authors independently assessed eligibility of search results, extracted data from the included studies, and assessed risk of bias using the Cochrane ‘Risk of bias’ tool. We contacted study authors for clarification and additional data for some studies. We used risk ratios (RR) for dichotomous outcomes and mean differences (MD) for continuous outcomes, with 95% confidence intervals (CIs). We performed meta‐analysis using a random‐effects model for outcomes where pooling of effect estimates was appropriate. Main results 1. Treatment of COVID‐19 disease We included 12 trials involving 8569 participants, all of whom were adults. Studies were from China (4); Brazil, Egypt, Iran, Spain, Taiwan, the UK, and North America (each 1 study); and a global study in 30 countries (1 study). Nine were in hospitalized patients, and three from ambulatory care. Disease severity, prevalence of comorbidities, and use of co‐interventions varied substantially between trials. We found potential risks of bias across all domains for several trials. Nine trials compared HCQ with standard care (7779 participants), and one compared HCQ with placebo (491 participants); dosing schedules varied. HCQ makes little or no difference to death due to any cause (RR 1.09, 95% CI 0.99 to 1.19; 8208 participants; 9 trials; high‐certainty evidence). A sensitivity analysis using modified intention‐to‐treat results from three trials did not influence the pooled effect estimate. HCQ may make little or no difference to the proportion of people having negative PCR for SARS‐CoV‐2 on respiratory samples at day 14 from enrolment (RR 1.00, 95% CI 0.91 to 1.10; 213 participants; 3 trials; low‐certainty evidence). HCQ probably results in little to no difference in progression to mechanical ventilation (RR 1.11, 95% CI 0.91 to 1.37; 4521 participants; 3 trials; moderate‐certainty evidence). HCQ probably results in an almost three‐fold increased risk of adverse events (RR 2.90, 95% CI 1.49 to 5.64; 1394 participants; 6 trials; moderate‐certainty evidence), but may make little or no difference to the risk of serious adverse events (RR 0.82, 95% CI 0.37 to 1.79; 1004 participants; 6 trials; low‐certainty evidence). We are very uncertain about the effect of HCQ on time to clinical improvement or risk of prolongation of QT‐interval on electrocardiogram (very low‐certainty evidence). One trial (22 participants) randomized patients to CQ versus lopinavir/ritonavir, a drug with unknown efficacy against SARS‐CoV‐2, and did not report any difference for clinical recovery or adverse events. One trial compared HCQ combined with azithromycin against standard care (444 participants). This trial did not detect a difference in death, requirement for mechanical ventilation, length of hospital admission, or serious adverse events. A higher risk of adverse events was reported in the HCQ‐and‐azithromycin arm; this included QT‐interval prolongation, when measured. One trial compared HCQ with febuxostat, another drug with unknown efficacy against SARS‐CoV‐2 (60 participants). There was no difference detected in risk of hospitalization or change in computed tomography (CT) scan appearance of the lungs; no deaths were reported. 2. Preventing COVID‐19 disease in people at risk of exposure to SARS‐CoV‐2 Ongoing trials are yet to report results for this objective. 3. Preventing COVID‐19 disease in people who have been exposed to SARS‐CoV‐2 One trial (821 participants) compared HCQ with placebo as a prophylactic agent in the USA (around 90% of participants) and Canada. Asymptomatic adults (66% healthcare workers; mean age 40 years; 73% without comorbidity) with a history of exposure to people with confirmed COVID‐19 were recruited. We are very uncertain about the effect of HCQ on the primary outcomes, for which few events were reported: 20/821 (2.4%) developed confirmed COVID‐19 at 14 days from enrolment, and 2/821 (0.2%) were hospitalized due to COVID‐19 (very low‐certainty evidence). HCQ probably increases the risk of adverse events compared with placebo (RR 2.39, 95% CI 1.83 to 3.11; 700 participants; 1 trial; moderate‐certainty evidence). HCQ may result in little or no difference in serious adverse events (no RR: no participants experienced serious adverse events; low‐certainty evidence). One cluster‐randomized trial (2525 participants) compared HCQ with standard care for the prevention of COVID‐19 in people with a history of exposure to SARS‐CoV‐2 in Spain. Most participants were working or residing in nursing homes; mean age was 49 years. There was no difference in the risk of symptomatic confirmed COVID‐19 or production of antibodies to SARS‐CoV‐2 between the two study arms. Authors' conclusions HCQ for people infected with COVID‐19 has little or no effect on the risk of death and probably no effect on progression to mechanical ventilation. Adverse events are tripled compared to placebo, but very few serious adverse events were found. No further trials of hydroxychloroquine or chloroquine for treatment should be carried out. These results make it less likely that the drug is effective in protecting people from infection, although this is not excluded entirely. It is probably sensible to complete trials examining prevention of infection, and ensure these are carried out to a high standard to provide unambiguous results., Plain language summary Is chloroquine or hydroxychloroquine useful in treating people with COVID‐19, or in preventing infection in people who have been exposed to the virus? What is the aim of this review? COVID‐19 is an infectious respiratory disease caused by a coronavirus called SARS‐CoV‐2. If the infection becomes severe, people may need intensive care and support in hospital, including mechanical ventilation. Drugs used for other diseases were tried out in COVID‐19, and this included chloroquine, used for malaria; and hydroxychloroquine used for rheumatic diseases, such as rheumatoid arthritis or systemic lupus erythematosus. We sought evidence of the effects of these drugs in treating people ill with the disease; in preventing the disease in people at risk of getting the disease, such as health workers; and people exposed to the virus developing the disease. Key messages Hydroxychloroquine does not reduce deaths from COVID‐19, and probably does not reduce the number of people needing mechanical ventilation. Hydroxychloroquine caused more unwanted effects than a placebo treatment, though it did not appear to increase the number of serious unwanted effects. We do not think new studies of hydroxychloroquine should be started for treatment of COVID‐19. What was studied in the review? We searched for studies that looked at giving chloroquine and hydroxychloroquine to people with COVID‐19; people at risk of being exposed to the virus; and people who have been exposed to the virus. We found 14 relevant studies: 12 studies of chloroquine or hydroxychloroquine used to treat COVID‐19 in 8569 adults; two studies of hydroxychloroquine to stop COVID‐19 in 3346 adults who had been exposed to the virus but had no symptoms of infection. We did not find any completed studies of these medicines to stop COVID‐19 in people who were at risk of exposure to the virus; studies are still under way. The studies took place in China, Brazil, Egypt, Iran, Taiwan, North America, and Europe; one study was worldwide. Some studies were partly funded by pharmaceutical companies that manufacture hydroxychloroquine. What are the main results of our review? Treating COVID‐19 Compared with usual care or placebo, hydroxychloroquine: · clearly did not affect how many people died (of any cause; 9 studies in 8208 people); · probably did not affect how many people needed mechanical ventilation (3 studies; 4521 people); · may not affect how many people still tested positive for the virus after 14 days (3 studies; 213 people). We are uncertain whether hydroxychloroquine affected the number of people whose symptoms improved after 28 days. Compared with other antiviral treatment (lopinavir plus ritonavir), chloroquine made little or no difference to the time taken for symptoms to improve (1 study; 22 people). Compared with usual care in one study in 444 people, hydroxychloroquine given with azithromycin (an antibiotic) made no difference to: · how many people died; · how many needed mechanical ventilation; or · time spent in hospital. Compared with febuxostat (a medicine to treat gout), hydroxychloroquine made no difference to how many people were admitted to hospital or to changes seen on scans of people's lungs; no deaths were reported (1 study; 60 people). Preventing COVID‐19 in people exposed to it We are uncertain whether hydroxychloroquine affected how many people developed COVID‐19, or how many people were admitted to hospital with COVID‐19, compared with those receiving a placebo treatment (1 study; 821 people). Compared with usual care, hydroxychloroquine made no difference to the risk of developing COVID‐19, or antibodies to the virus, in people exposed to it (1 study; 2525 people). Unwanted effects When used for treating COVID‐19, compared with usual care or placebo, hydroxychloroquine: · probably increases the risk of mild unwanted effects (6 studies; 1394 people); · may not increase the risk of serious harmful effects (6 studies; 1004 people). When given along with azithromycin, hydroxychloroquine increased the risk of any unwanted effects, but made no difference to the risk of serious unwanted effects (1 study; 444 people). Compared with lopinavir plus ritonavir, chloroquine made little or no difference to the risk of unwanted effects (1 study; 22 people). When used for preventing COVID‐19, hydroxychloroquine probably causes more unwanted effects than placebo, but may not increase the risk of serious, harmful unwanted effects (1 study; 700 people). How confident are we in our results? We are confident about our results for how many people died and moderately confident about how many needed mechanical ventilation. We are moderately confident about the unwanted effects of hydroxychloroquine treatment, but less confident about our results for serious unwanted effects; these results might change with further evidence. How up‐to‐date is this review? We included evidence published up to 15 September 2020.

Background: Neurological COVID-19 disease has been reported widely, but often without using standard case definitions or detailed diagnostic work up. Several meta-analyses, based on such reports, describe the neurological diagnoses but give little information on outcomes and risk factors. Methods: We conducted an individual patient data meta-analysis of hospitalised patients with neurological COVID-19 disease, using standard case definitions. We invited authors of studies from the first pandemic wave, plus clinicians in the Global COVID-Neuro Network with unpublished data, to contribute, and extracted aggregate data from published reports. We analysed features associated with poor outcome (moderate to severe sequelae or death, 3-6, on the modified Rankin scale) using multivariable models. Findings: We identified 381 studies (31 unpublished) describing 4443 patients with COVID-19 and neurological disease: 83 of these provided IPD for 1979 (45%) patients. Encephalopathy (978 [49%]) and cerebrovascular events (506 [26%]), were the most common diagnoses in the IPD database and aggregate data. Respiratory and systemic symptoms preceded neurological features in 93% of patients; one third developed neurological disease after hospital admission. A poor outcome was more common in patients with cerebrovascular events (76% [95% CI 67-82]), than encephalopathy (54% [42-65]). Intensive care use was high (38% [35-41] overall), and also greater in the cerebrovascular patients. In the cerebrovascular, but not encephalopathic patients, risk factors for poor outcome included breathlessness on admission and elevated D-Dimer. Overall, 30-day mortality was 30% (27-32). The hazard of death was reduced for patients in the WHO European region, but increased in low- and lower-middle-income countries. Interpretation: Neurological COVID-19 disease poses a considerable burden in terms of disease outcomes and use of hospital resources. The different risk factors for encephalopathy and stroke suggest different disease mechanisms which may be amenable to intervention, especially in those who develop neurological symptoms after hospital admission. Funding This study was funded by the UK Medical Research Council’s Global Effort on COVID-19 Programme (MR/V033441/1); UK National Institute for Health Research (NIHR)-funded Global Health Research Group on Acute Brain Infections (17/63/110); and the NIHR Health Protection Research Unit in Emerging and Zoonotic Infections (NIHR200907), at University of Liverpool in partnership with Public Health England (PHE), in collaboration with Liverpool School of Tropical Medicine and the University of Oxford (Grant Nos. IS-HPU-1112-10117 and NIHR200907). Declaration of Interests: BS reports a grant from UKRI/DHSC Global Effort on COVID-19 Research (Medical Research Council) and non-financial support from UK National Institute for Health Research Global Health Research Group on Brain Infections. SL and TS are supported by a grant from the EU Zika Preparedness Latin American Network consortium (ZikaPLAN). ZikaPLAN has received funding from the EU's Horizon 2020 research and innovation programme under grant agreement number 734584. LCG reports non-financial support from Pfizer, non-financial support from Gilead. LB reports grants from GlaxoSmithKline, Research England and Wellcome Trust. AMBM reports grants from Conselho Nacional de Desenvolvimento Cientifico e Tecnologico CNPq/Brazil, and Sao Paulo Research Foundation FAPESP/Brazil. AP reports personal fees from ZAMBON, UCB , BIOMARIN, and ABBvie pharma. TS was an adviser to the GlaxoSmithKline Ebola Vaccine programme, chaired a Siemens Diagnostics clinical advisory board, and advises the WHO Brain Health Unit Forum on Neurology and COVID-19; TS has also previously filed a patent for a test for bacterial meningitis based on a blood test (GB 1606537.7, April 14, 2016), and has grants from the UK Medical Research Council and National Institute for Health Research. All other authors declare no conflict of interest

Encephalopathy is a common complication of COVID-19 that can both be a challenge to manage and also negatively impacts prognosis. Whilst encephalopathy may be due to common systemic causes, such as hypoxia, COVID-19 has also been associated with more prolonged encephalopathy due to less common but nevertheless severe complications, such as inflammation of the brain parenchyma, cerebrovascular involvement and seizures, which may be disproportionate to COVID-19 severity and which require specific management. The aim of this review is to provide pragmatic guidance on the management of COVID-19 encephalopathy through a consensus agreement of the Global COVID-19 Neuro-Research Coalition. A systematic literature search of Medline, MedRxiv, and BioRx was conducted between 1st January 2020 and 11th June 2021 with additional review of references cited within the identified bibliographies. A modified Delphi-approach was then undertaken to develop recommendations along with a parallel approach to score the strength of both the recommendation and the supporting evidence. This manuscript presents analysis of contemporaneous evidence for definition, epidemiology, and pathophysiology of COVID-19 encephalopathy and practical guidance for clinical assessment, investigation, and acute and long-term management.

Summary Background The COVID-19 pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is of a scale not seen since the 1918 influenza pandemic. Although the predominant clinical presentation is with respiratory disease, neurological manifestations are being recognised increasingly. On the basis of knowledge of other coronaviruses, especially those that caused the severe acute respiratory syndrome and Middle East respiratory syndrome epidemics, cases of CNS and peripheral nervous system disease caused by SARS-CoV-2 might be expected to be rare. Recent developments A growing number of case reports and series describe a wide array of neurological manifestations in 901 patients, but many have insufficient detail, reflecting the challenge of studying such patients. Encephalopathy has been reported for 93 patients in total, including 16 (7%) of 214 hospitalised patients with COVID-19 in Wuhan, China, and 40 (69%) of 58 patients in intensive care with COVID-19 in France. Encephalitis has been described in eight patients to date, and Guillain-Barre syndrome in 19 patients. SARS-CoV-2 has been detected in the CSF of some patients. Anosmia and ageusia are common, and can occur in the absence of other clinical features. Unexpectedly, acute cerebrovascular disease is also emerging as an important complication, with cohort studies reporting stroke in 2–6% of patients hospitalised with COVID-19. So far, 96 patients with stroke have been described, who frequently had vascular events in the context of a pro-inflammatory hypercoagulable state with elevated C-reactive protein, D-dimer, and ferritin. Where next? Careful clinical, diagnostic, and epidemiological studies are needed to help define the manifestations and burden of neurological disease caused by SARS-CoV-2. Precise case definitions must be used to distinguish non-specific complications of severe disease (eg, hypoxic encephalopathy and critical care neuropathy) from those caused directly or indirectly by the virus, including infectious, para-infectious, and post-infectious encephalitis, hypercoagulable states leading to stroke, and acute neuropathies such as Guillain-Barre syndrome. Recognition of neurological disease associated with SARS-CoV-2 in patients whose respiratory infection is mild or asymptomatic might prove challenging, especially if the primary COVID-19 illness occurred weeks earlier. The proportion of infections leading to neurological disease will probably remain small. However, these patients might be left with severe neurological sequelae. With so many people infected, the overall number of neurological patients, and their associated health burden and social and economic costs might be large. Health-care planners and policy makers must prepare for this eventuality, while the many ongoing studies investigating neurological associations increase our knowledge base.

Background Linezolid was recently re‐classified as a Group A drug by the World Health Organization (WHO) for treatment of multi‐drug resistant tuberculosis (MDR‐TB) and extensively drug‐resistant tuberculosis (XDR‐TB), suggesting that it should be included in the regimen for all patients unless contraindicated. Linezolid use carries a considerable risk of toxicity, with the optimal dose and duration remaining unclear. Current guidelines are mainly based on evidence from observational non‐comparative studies. Objectives To assess the efficacy of linezolid when used as part of a second‐line regimen for treating people with MDR and XDR pulmonary tuberculosis, and to assess the prevalence and severity of adverse events associated with linezolid use in this patient group. Search methods We searched the following databases: the Cochrane Infectious Diseases Specialized Register; CENTRAL; MEDLINE; Embase; and LILACS up to 13 July 2018. We also checked article reference lists and contacted researchers in the field. Selection criteria We included studies in which some participants received linezolid, and others did not. We included randomized controlled trials (RCTs) of linezolid for MDR and XDR pulmonary tuberculosis to evaluate efficacy outcomes. We added non‐randomized cohort studies to evaluate adverse events. Primary outcomes were all‐cause and tuberculosis‐associated death, treatment failure, and cure. Secondary outcomes were treatment interrupted, treatment completed, and time to sputum culture conversion. We recorded frequency of all and serious adverse events, adverse events leading to drug discontinuation or dose reduction, and adverse events attributed to linezolid, particularly neuropathy, anaemia, and thrombocytopenia. Data collection and analysis Two review authors (BS and DC) independently assessed the search results for eligibility and extracted data from included studies. All review authors assessed risk of bias using the Cochrane ‘Risk of bias' tool for RCTs and the ROBINS‐I tool for non‐randomized studies. We contacted study authors for clarification and additional data when necessary. We were unable to perform a meta‐analysis as one of the RCTs adopted a study design where participants in the study group received linezolid immediately and participants in the control group received linezolid after two months, and therefore there were no comparable data from this trial. We deemed meta‐analysis of non‐randomized study data inappropriate. Main results We identified three RCTs for inclusion. One of these studies had serious problems with allocation of the study drug and placebo, so we could not analyse data for intervention effect from it. The remaining two RCTs recruited 104 participants. One randomized 65 participants to receive linezolid or not, in addition to a background regimen; the other randomized 39 participants to addition of linezolid to a background regimen immediately, or after a delay of two months. We included 14 non‐randomized cohort studies (two prospective, 12 retrospective), with a total of 1678 participants. Settings varied in terms of income and tuberculosis burden. One RCT and 7 out of 14 non‐randomized studies commenced recruitment in or after 2009. All RCT participants and 38.7% of non‐randomized participants were reported to have XDR‐TB. Dosing and duration of linezolid in studies were variable and reported inconsistently. Daily doses ranged from 300 mg to 1200 mg; some studies had planned dose reduction for all participants after a set time, others had incompletely reported dose reductions for some participants, and most did not report numbers of participants receiving each dose. Mean or median duration of linezolid therapy was longer than 90 days in eight of the 14 non‐randomized cohorts that reported this information. Duration of participant follow‐up varied between RCTs. Only five out of 14 non‐randomized studies reported follow‐up duration. Both RCTs were at low risk of reporting bias and unclear risk of selection bias. One RCT was at high risk of performance and detection bias, and low risk for attrition bias, for all outcomes. The other RCT was at low risk of detection and attrition bias for the primary outcome, with unclear risk of detection and attrition bias for non‐primary outcomes, and unclear risk of performance bias for all outcomes. Overall risk of bias for the non‐randomized studies was critical for three studies, and serious for the remaining 11. One RCT reported higher cure (risk ratio (RR) 2.36, 95% confidence interval (CI) 1.13 to 4.90, very low‐certainty evidence), lower failure (RR 0.26, 95% CI 0.10 to 0.70, very low‐certainty evidence), and higher sputum culture conversion at 24 months (RR 2.10, 95% CI 1.30 to 3.40, very low‐certainty evidence), amongst the linezolid‐treated group than controls, with no differences in other primary and secondary outcomes. This study also found more anaemia (17/33 versus 2/32), nausea and vomiting, and neuropathy (14/33 versus 1/32) events amongst linezolid‐receiving participants. Linezolid was discontinued early and permanently in two of 33 (6.1%) participants who received it. The other RCT reported higher sputum culture conversion four months after randomization (RR 2.26, 95% CI 1.19 to 4.28), amongst the group who received linezolid immediately compared to the group who had linezolid initiation delayed by two months. Linezolid was discontinued early and permanently in seven of 39 (17.9%) participants who received it. Linezolid discontinuation occurred in 22.6% (141/624; 11 studies), of participants in the non‐randomized studies. Total, serious, and linezolid‐attributed adverse events could not be summarized quantitatively or comparatively, due to incompleteness of data on duration of follow‐up and numbers of participants experiencing events. Authors' conclusions We found some evidence of efficacy of linezolid for drug‐resistant pulmonary tuberculosis from RCTs in participants with XDR‐TB but adverse events and discontinuation of linezolid were common. Overall, there is a lack of comparative data on efficacy and safety. Serious risk of bias and heterogeneity in conducting and reporting non‐randomized studies makes the existing, mostly retrospective, data difficult to interpret. Further prospective cohort studies or RCTs in high tuberculosis burden low‐income and lower‐middle‐income countries would be useful to inform policymakers and clinicians of the efficacy and safety of linezolid as a component of drug‐resistant TB treatment regimens., Linezolid for managing people with drug‐resistant tuberculosis What is drug‐resistant tuberculosis, and how might linezolid work? Tuberculosis is caused by infection with Mycobacterium tuberculosis bacteria. When there are symptoms or signs of illness, this is called active tuberculosis. An estimated one‐third of the world's population are infected with tuberculosis, and around 1.4 million people died from active tuberculosis in 2015. Bacteria that cause tuberculosis can develop resistance to the drugs most commonly used to treat tuberculosis, also called first‐line antibiotics. This is an increasing problem that makes treatment more difficult, because second‐line tuberculosis treatment drugs are less powerful against the bacteria, and more likely to cause harmful effects. Standard treatment for drug‐resistant tuberculosis requires patients to take multiple antibiotics for nearly two years. Linezolid is a second‐line drug that laboratory studies have found to be good at killing bacteria that cause tuberculosis, but that can also cause frequent, serious harmful effects. The review question Recent international guidelines recommend trying to include linezolid in the treatment of all patients with multi‐drug resistant tuberculosis, but there is concern about whether enough good evidence exists to tell us how well it works, what dose is best, and how safe it is for people who take it. Study characteristics We searched for evidence up to 13 July 2018. We analysed data from two trials, one of which randomly allocated 65 people with drug‐resistant tuberculosis to either a linezolid‐containing or linezolid‐free drug combination, and another that randomly allocated 39 participants to receive linezolid as part of their treatment from the start or have it added after a delay of two months. We also included 14 studies, including 1678 people, in which some participants received linezolid but others did not, but this was not determined at random. What are the main results of the review? One trial showed a higher likelihood of cure and lower risk of treatment failure in participants receiving linezolid compared to those who did not. The second trial showed that participants who received linezolid immediately had a higher chance of tuberculosis being cleared from their sputum four months after the start of the study than those who added linezolid after a two‐month delay. When they examined safety, the first trial found a higher risk of developing low red blood cell counts, nausea and vomiting, and nerve damage in people receiving linezolid. From 11 of the non‐randomized studies that reported this, 22.6% of people had to stop linezolid due to adverse effects (side effects), though further comparisons of harmful effects were not possible due to incomplete reporting in the non‐randomized studies. Overall, although there is some evidence of benefit, we have very low certainty in its accuracy. More high‐quality studies are required before we can be certain how effective and safe linezolid is for drug‐resistant tuberculosis. How up‐to‐date is this review? This review is current up to 13 July 2018.

To the Editor,We read with interest a recent report on voriconazole, a relatively new broad-spectrum triazole, for therapeutic use in 16 cases of cryptococcal meningitis [1]. At follow-up, all pati...

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:\ud \ud To assess the efficacy of linezolid when used as part of a second-line regimen for treating people with multidrug-resistant (MDR-) and extensively drug-resistant (XDR-) pulmonary tuberculosis (TB), and to assess the prevalence and severity of adverse events associated with linezolid use in this patient group

It is not always possible to administer antituberculosis pharmacotherapy orally for reasons that may be a direct consequence of tuberculosis itself. To our knowledge, no published literature is available regarding antituberculosis drug absorption via feeding tube. We present the case of a patient with tuberculosis meningitis who required medication administration via percutaneous endoscopic jejunostomy (PEJ) tube. Blood samples were collected during the continuation phase of antituberculosis therapy, immediately before dose administration, and then at 1, 2, 4, and 6 hours after dose administration for quantification of serum rifampin concentrations. Assaying these concentrations by high-pressure liquid chromatography demonstrated a peak serum rifampin level (C(max)) of 18 μg/ml and total rifampin exposure (area under the curve from 0-6 hours [AUC(0-6)]) of 50.1 μg/ml. These are high compared with rifampin C(max) and AUC(0-6) values reported in patients after oral rifampin administration; C(max) tends to range between 4.0-10.5 μg/ml and AUC(0-6) 7.0-52.9 μg/ml after oral administration of 600 mg at steady state. Based on our patient's results, therefore, rifampin administered by PEJ tube appears to be well absorbed, with preservation of adequate C(max) and AUC values. It is worth noting that this was in the context of drug administration in the fasted state. In the absence of any published evidence of adequate absorption via jejunal feeding tube in the nonfasted state, it would seem prudent to ensure that patients are fasted when rifampin is administered via PEJ tube, just as patients are when oral rifampin is administered. This report represents the first documented evidence, to our knowledge, of adequate rifampin absorption when administered via PEJ tube and provides important reassurance for health care providers, patients, and families facing similar clinical scenarios.

Setting All India Institute of Medical Sciences and Rajan Babu Institute of Pulmonary Medicine and Tuberculosis, New Delhi, India. Objective To investigate the association of vitamin D receptor (VDR) polymorphisms and serum 25(OH)D with susceptibility to, and response to treatment of, multidrug-resistant tuberculosis (MDR-TB) in comparison with drug-susceptible pulmonary TB (DS-PTB) and healthy controls. Design Cross-sectional study. Methods A total of 897 participants from northern India were consecutively enrolled into three groups (MDR-TB 354, DS-PTB 338, controls 205). Genotypic and allelic frequencies of FokI, BsmI and TaqI VDR polymorphisms, and serum 25(OH)D, calcium and intact parathyroid hormone were measured in all participants. In those with active TB, disease severity, time to sputum smear and culture conversion were correlated with VDR genotype and biochemical parameters. Results FokI Ff genotype and TaqI t allele correlated positively with MDR-TB; Ff genotype and f allele of FokI frequency were higher in both TB groups. BsmI Bb genotype correlated inversely with MDR-TB. Serum 25(OH)D concentrations were significantly lowest in MDR-TB, correlating inversely with time to sputum smear conversion. Conclusions VDR gene polymorphisms and hypovitaminosis D may predispose to MDR-TB. Lower serum 25(OH)D may increase time to MDR-TB sputum smear negativity.

While allergic bronchopulmonary aspergillosis and mycosis are well recognised, no cases have been described related to Alternaria spp. Alternaria is a common sensitising fungus in asthmatics and related to thunderstorm asthma. We report a case of an asthmatic who presented with worsening asthma control, mild eosinophilia on high dose inhaled corticosteroids (800 μg/day), a total IgE of 3800 KIU/L, an Alternaria-specific IgE of 21.3 KUa/L and positive skin prick test, negative specific IgE and skin prick test to Aspergillus fumigatus, Penicillium spp., Cladosporium spp., Trichophyton spp. and a normal CT scan of the thorax. He responded well to a short course of oral prednisolone and then oral itraconazole, given over 17 months but relapsed 1 month after stopping it.

Introduction and Objectives BTS guidelines suggest the diagnostic test for pneumonia (in hospital) is a CXR. Since management should be commenced within 4 h of arrival the initial interpretation of the CXR is most often performed by junior doctors. Consultants review patients and their CXRs within 24 h of admission and a radiologist9s report is issued at a later time point but diagnosis dependent decisions—whether to admit, risk stratification and whether to give antibiotics—fall to junior doctors. We measured the inter-observer agreement within groups of doctors involved at key points in CAP diagnosis and management. Methods 24 admission CXRs from patients attending a large teaching hospital between February and April 2011 with a suspected diagnosis of CAP were collected on a radiology computer workstation. Eleven reporting radiologists, eight attending consultants and twenty-two junior doctors from a range of acute medical specialties were recruited. All 41 recruits independently interpreted the CXRs, answering “yes” or “no” for presence of pneumonic infiltrate. Agreement within groups was tested using the Fleiss-Cuzick extension of Cohen9s κ statistic (abbreviated here as κ). Results Agreement (κ scores) for each group of doctors are shown in Abstract P251 figure 1. Radiologists had moderate agreement (κ 0.52, CI 0.49 to 0.55), junior doctors had moderate agreement (κ 0.47, CI 0.45 to 0.48) and attending consultants fair agreement (κ 0.34, CI 0.30 to 0.38). Conclusions In the context of possible pneumonia, the CXR was not consistently reported by any group. Junior doctors were more consistent than attending consultants and radiologists were most consistent. A possible explanation for these differences is that junior doctors, by necessity, have developed similar ideas of what they will consider pneumonic where as consultants who less frequently make the initial diagnostic decision vary in their criteria for diagnosing pneumonia. This study does not present a “gold standard” interpretation and therefore does not address the issue of accuracy but it does raise questions about to what extent the CXR ever be regarded as a “reliable” diagnostic test.

We read Dr Lim and Dr Woodhead's update on the British Thoracic Society (BTS) 2009/2010 community acquired pneumonia (CAP) audit with interest and noted the high inpatient mortality rate of 18.3%.1 As a contributing site, we received a useful summary of our data in comparison with the national data and local mortality rates for severe CAP (CURB65 3-5) were 21.4% versus 42.6% nationally. This provoked an examination of local severe CAP admissions between December 2009 and …

Background Despite the latest World Health Organization guidelines advocating daily therapy in HIV-TB co-infected individuals, there are few recent studies comparing outcomes of thrice-weekly anti-tuberculosis treatment in HIV-positive and HIV-negative patients with TB. The present study sets out to compare TB treatment outcomes in these two groups in the Indian national programme, which currently involves thrice-weekly therapy for all, regardless of HIV status. Methods HIV-positive and HIV-negative were consecutively screened for enrolment into this prospective observational study, carried out at the All India Institute of Medical Sciences hospital, New Delhi, India, between 2006 and 2010. Patients were given short-course thrice-weekly rifampicin-based therapy, with all HIV-positive patients being started on highly active antiretroviral therapy at least 14 days after commencing TB treatment. Patients were regularly followed-up for 24 months after completion of treatment. Results 150 HIV-positive, 155 HIV-negative patients were enrolled consecutively for the study. Significantly higher treatment success (93.5% vs. 76.7% at end of treatment, p 3) was the only predictor of mortality in HIV-TB patients (odds ratio 8 · 43, p = 0 · 013). Conclusions Thrice-weekly anti-tuberculosis therapy is more effective in HIV-negative than in HIV-positive patients. However, outcomes in this HIV co-infected cohort were found to be similar to those reported previously with daily therapy, with no safety concerns. This should prompt further study into whether intermittent or daily therapy should be used universally in resource-poor settings, using large well executed randomised controlled trials. Trial registration NCT%20No.%2000698334