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The Global Alliance for Genomics and Health (GA4GH) aims to accelerate biomedical advances by enabling the responsible sharing of clinical and genomic data through both harmonized data aggregation and federated approaches. The decreasing cost of genomic sequencing (along with other genome-wide molecular assays) and increasing evidence of its clinical utility will soon drive the generation of sequence data from tens of millions of humans, with increasing levels of diversity. In this perspective, we present the GA4GH strategies for addressing the major challenges of this data revolution. We describe the GA4GH organization, which is fueled by the development efforts of eight Work Streams and informed by the needs of 24 Driver Projects and other key stakeholders. We present the GA4GH suite of secure, interoperable technical standards and policy frameworks and review the current status of standards, their relevance to key domains of research and clinical care, and future plans of GA4GH. Broad international participation in building, adopting, and deploying GA4GH standards and frameworks will catalyze an unprecedented effort in data sharing that will be critical to advancing genomic medicine and ensuring that all populations can access its benefits.

As the global health crisis unfolded, many academic conferences moved online in 2020. This move has been hailed as a positive step towards inclusivity in its attenuation of economic, physical, and legal barriers and effectively enabled many individuals from groups that have traditionally been underrepresented to join and participate. A number of studies have outlined how moving online made it possible to gather a more global community and has increased opportunities for individuals with various constraints, e.g., caregiving responsibilities. Yet, the mere existence of online conferences is no guarantee that everyone can attend and participate meaningfully. In fact, many elements of an online conference are still significant barriers to truly diverse participation: the tools used can be inaccessible for some individuals; the scheduling choices can favour some geographical locations; the set-up of the conference can provide more visibility to well-established researchers and reduce opportunities for early-career researchers. While acknowledging the benefits of an online setting, especially for individuals who have traditionally been underrepresented or excluded, we recognize that fostering social justice requires inclusivity to actively be centered in every aspect of online conference design. Here, we draw from the literature and from our own experiences to identify practices that purposefully encourage a diverse community to attend, participate in, and lead online conferences. Reflecting on how to design more inclusive online events is especially important as multiple scientific organizations have announced that they will continue offering an online version of their event when in-person conferences can resume.

In the replacement of both a radiology information system (RIS) and a picture archiving and communication system (PACS) archive, data were migrated from the prior system to the new system. We report on the process, the time and resources required, and the fidelity of data transfer. We find that for two PACS archives, both organized according to the Digital Imaging and Communications in Medicine (DICOM) information model, data may be transferred with full fidelity, but the time required for transfer is significant. Transfer from off-line backup media was found to be faster than transfer from our robotic tape library. In contrast, the RIS replacement required extensive labor to translate prior data between dissimilar information models, and some data were inevitably lost in the translation. Standards for RIS information models are needed to promote the migration of data without loss of content. Copyright © 2000 by W.B. Saunders Company [ABSTRACT FROM AUTHOR]

Researchers must collaborate globally to rapidly respond to the COVID-19 pandemic. In Europe, the General Data Protection Regulation (GDPR) regulates the processing of personal data, including health data of value to researchers. Even during a pandemic, research still requires a legal basis for the processing of sensitive data, additional justification for its processing, and a basis for any transfer of data outside Europe. The GDPR does provide legal grounds and derogations that can support research addressing a pandemic, if the data processing activities are proportionate to the aim pursued and accompanied by suitable safeguards. During a pandemic, a public interest basis may be more promising for research than a consent basis, given the high standards set out in the GDPR. However, the GDPR leaves many aspects of the public interest basis to be determined by individual Member States, which have not fully or uniformly made use of all options. The consequence is an inconsistent legal patchwork that displays insufficient clarity and impedes joint approaches. The COVID-19 experience provides lessons for national legislatures. Responsiveness to pandemics requires clear and harmonized laws that consider the related practical challenges and support collaborative global research in the public interest. [ABSTRACT FROM AUTHOR]

Background: Tuberculosis in cattle is caused by Mycobacterium tuberculosis complex (MTBC) species. Apart from MTBC, different Nontuberculous Mycobacteria (NTM) species have also been isolated from cattle. The presence of NTM infection in bovines makes the diagnosis of bovine tuberculosis (bTB) a cumbersome task. Therefore, a cross sectional study was conducted to isolate and characterize different Mycobacterium spp. from a slaughterhouse situated in Kolkata, a city in the eastern part of India., Results: Out of 258 morbid samples, 98 isolates were found to be positive for bacterial growth, and 35% (n = 34) were positive for Mycobacterium. 94% of Mycobacterial cultural isolates were NTM (n = 32), and the rest (n = 2) were found to be MTBC. Species-level identification of the isolates by hsp65 sequencing revealed that out of 32 isolates, 24 were M. fortuitum, three were M. abscessus, two each were M. chelonae and M. parascrofulaceum, and one was M. novocastrense. A phylogenetic tree with partial hsp65 gene sequences was also constructed to determine the relatedness of the unknown isolates to the reference strains., Conclusion: Both NTM species and MTBCs were identified from TB-like lesions in cattle that were slaughtered at the Kolkata abattoir. This discovery may indicate that NTM contributes to the development of lesions in cattle. Also, we recommend implication of more specific diagnostic tests for bTB., (© 2024. The Author(s).)

Invasive Aspergillosis (IA) is a potentially lethal infection in high-risk haemato-oncology patients. Since traditional diagnostic methods have many inherent challenges, Polymerase Chain Reaction (PCR) has been used to diagnose IA. This prospective study evaluated a commercial AsperGenius multiplex real-time PCR for its clinical utility in diagnosing IA compared with galactomannan (GM) testing serum samples from haemato-oncology patients with clinically suspected IA. A total of 107 patients were recruited between April 2022 and March 2023. Serum samples (n = 113) collected from those patients for the routine diagnosis by GM Enzyme Linked Immuno-Sorbent Assay (ELISA) were subjected to PCR. The patients were categorised into probable, possible, and no IA based on revised (2020) and previous (2008) European Organization for Research and Treatment of Cancer and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC-MSG) criteria. The performance characteristics of PCR and GM were calculated against the EORTC criteria by combining probable and possible cases as diseased groups. Among the 107 recruited patients, 93 were categorised into probable/possible IA (diseased group) and 14 into no IA group. The PCR was positive in 53 samples from 49 patients. The sensitivity and specificity of single positive PCR and GM were 51.61% [95% confidence interval, 41-62], 92.86% (66.1-99.8) and 26.88% (18.2-37.1), 92.86% (66.1-99.8), respectively. The combination-based strategy (GM and/or PCR positive) exhibited a moderate sensitivity of 62.37% (51-72.2) and a specificity of 85.71% (57.2-98.2). To conclude, the combined strategy of serum GM and/or PCR positivity, along with radiological findings that fulfilled the EORTC/MSG criteria, has improved the diagnosis of probable IA among high-risk haematological patients with clinically suspected IA., (© The Author(s) 2024. Published by Oxford University Press on behalf of The International Society for Human and Animal Mycology.)

Background: Invasive fungal disease (IFD) is a sinister complication encountered in patients with haematological disorders. When occurring in the central nervous system (CNS), IFDs can have catastrophic outcomes., Objectives: To study the clinical presentation, predisposing etiological factors, and prognosis of a CNS-IFD in a patient with a haematological disorder., Patients and Methods: This is a retrospective study focusing on the clinical profile, diagnosis, treatment strategy and outcomes of 43 patients with an underlying haematological disorder, who were diagnosed with CNS-IFD between 2018 and 2022., Results: Of the 43 patients, 18 were chemotherapy recipients, while 23 were stem cell transplant (SCT) recipients and 2 presented with CNS-IFD at diagnosis. AML/MDS (37.2%) and ALL (18.6%) were the predominant underlying diagnoses. A sudden deterioration in sensorium (53.5%) was the earliest clinical sign, while T2 hyperintensities (26.8%), vascular involvement (26.8%) and ring-enhancing lesions (16.3%) were the commonest radiological findings, with all patients exhibiting diffusion restriction in diffusion-weighted images. Microbiological evidence of infection was obtained in all patients; however, culture positivity was established in only 25 patients. Rhizopus spp (23.2%) and Aspergillus spp (20.9%) were implicated in most cases. Overall survival of the cohort was 27.9% at a median follow-up of 6 months. In patients who succumbed, the median time to death was 4 days (0-46)., Conclusion: CNS-IFD is associated with very poor survival in patients undergoing chemotherapy or an SCT, urging the need for prompt diagnosis and initiation of suitable antifungal therapy., (© 2024 Wiley‐VCH GmbH. Published by John Wiley & Sons Ltd.)

Background: Despite causing high mortality worldwide, paediatric tuberculosis is often undiagnosed. We aimed to investigate optimal testing strategies for microbiological confirmation of tuberculosis in children younger than 15 years, including the yield in high-risk subgroups (eg, children younger than 5 years, with HIV, or with severe acute malnutrition [SAM])., Methods: For this secondary analysis, we used data from RaPaed-TB, a multicentre diagnostic accuracy study evaluating novel diagnostic assays and testing approaches for tuberculosis in children recruited from five health-care centres in Malawi, Mozambique, South Africa, Tanzania, and India conducted between Jan 21, 2019, and June 30, 2021. Children were included if they were younger than 15 years and had signs or symptoms of pulmonary or extrapulmonary tuberculosis; they were excluded if they weighed less than 2 kg, had received three or more doses of anti-tuberculosis medication at time of enrolment, were in a condition deemed critical by the local investigator, or if they did not have at least one valid microbiological result. We collected tuberculosis-reference specimens via spontaneous sputum, induced sputum, gastric aspirate, and nasopharyngeal aspirates. Microbiological tests were Xpert MTB/RIF Ultra (hereafter referred to as Ultra), liquid culture, and Löwenstein-Jensen solid culture, which were followed by confirmatory testing for positive cultures. The main outcome of this secondary analysis was categorising children as having confirmed tuberculosis if culture or Ultra positive on any sample, unconfirmed tuberculosis if clinically diagnosed, and unlikely tuberculosis if neither of these applied., Findings: Of 5313 children screened, 975 were enrolled, of whom 965 (99%) had at least one valid microbiological result. 444 (46%) of 965 had unlikely tuberculosis, 282 (29%) had unconfirmed tuberculosis, and 239 (25%) had confirmed tuberculosis. Median age was 5·0 years (IQR 1·8-9·0); 467 (48%) of 965 children were female and 498 (52%) were male. 155 (16%) of 965 children had HIV and 110 (11%) children had SAM. 196 (82%) of 239 children with microbiological detection tested positive on Ultra. 110 (46%) of 239 were confirmed by both Ultra and culture, 86 (36%) by Ultra alone, and 43 (18%) by culture alone. 'Trace' was the most common semiquantitative result (93 [40%] of 234). 481 (50%) of 965 children had only one specimen type collected, 99 (21%) of whom had M tuberculosis detected. 484 (50%) of 965 children had multiple specimens collected, 141 (29%) of whom were positive on at least one specimen type. Of the 102 children younger than 5 years with M tuberculosis detected, 80 (78%) tested positive on sputum. 64 (80%) of 80 children who tested positive on sputum were positive on sputum alone; 61 (95%) of 64 were positive on induced sputum, two (3%) of 64 were positive on spontaneous sputum, and one (2%) was positive on both., Interpretation: High rates of microbiological confirmation of tuberculosis in children can be achieved via parallel sampling and concurrent testing procedures. Sample types and choice of test to be used sequentially should be considered when applying to groups such as children younger than 5 years, living with HIV, or with SAM., Funding: European and Developing Countries Clinical Trials Partnership programme, supported by the EU, the UK Medical Research Council, Swedish International Development Cooperation Agency, Bundesministerium für Bildung und Forschung, the German Center for Infection Research, and Beckman Coulter., Competing Interests: Declaration of interests All authors received grant funding for this work from the second European and Developing Countries Clinical Trials Partnership programme (supported by the EU), the German Center for Infection Research, and Beckman Coulter, paid to their institutions. Cepheid provided Xpert MTB/RIF Ultra testing kits and GeneXpert platforms at no cost to the consortium. HJZ is funded by the South African Medical Research Council. ZF-S receives funding from the South African Medical Research Council. LO was financially supported by a European Society For Paediatric Infectious Diseases fellowship award and a clinical leave stipend from the German Center for Infection Research. ELC has received funding from the Wellcome Trust Senior Fellowship. TDM has received funding, paid to his institution, from the Global Alliance Against Tuberculosis, the European and Developing Countries Clinical Trials Partnership programme, Médecins Sans Frontières, the EU Innovative Medicines Initiative, and Great Ormond Street Hospital charity intramural COVID-19 rapid response; receives personal payment for being Editor in Chief from Annals of Clinical Microbiology and Antimicrobials; and is part of the Chair Acid Fast Club UK. RSo has received funding from the US National Institutes of Health. All other authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background and Objectives: Candidaemia is a potentially life-threatening emergency in the intensive care units (ICUs). Surveillance using common protocols in a large network of hospitals would give meaningful estimates of the burden of candidaemia and central line associated candidaemia in low resource settings. We undertook this study to understand the burden and epidemiology of candidaemia in multiple ICUs of India, leveraging the previously established healthcare-associated infections (HAI) surveillance network. Our aim was also to assess the impact that the pandemic of COVID-19 had on the rates and associated mortality of candidaemia., Methods: This study included adult patients from 67 Indian ICUs in the AIIMS-HAI surveillance network that conducted BSI surveillance in COVID-19 and non-COVID-19 ICUs during and before the COVID-19 pandemic periods. Hospitals identified healthcare-associated candidaemia and central line associated candidaemia and reported clinical and microbiological data to the network as per established and previously published protocols., Results: A total of 401,601 patient days and 126,051 central line days were reported during the study period. A total of 377 events of candidaemia were recorded. The overall rate of candidaemia in our network was 0.93/1000 patient days. The rate of candidaemia in COVID-19 ICUs (2.52/1000 patient days) was significantly higher than in non-COVID-19 ICUs (1.05/patient days) during the pandemic period. The rate of central line associated candidaemia in COVID-19 ICUs (4.53/1000 central line days) was also significantly higher than in non-COVID-19 ICUs (1.73/1000 central line days) during the pandemic period. Mortality in COVID-19 ICUs associated with candidaemia (61%) was higher than that in non-COVID-19 ICUs (41%). A total of 435 Candida spp. were isolated. C. tropicalis (26.7%) was the most common species. C. auris accounted for 17.5% of all isolates and had a high mortality., Conclusion: Patients in ICUs with COVID-19 infections have a much higher risk of candidaemia, CLAC and its associated mortality. Network level data helps in understanding the true burden of candidaemia and will help in framing infection control policies for the country., (© 2024 Wiley‐VCH GmbH. Published by John Wiley & Sons Ltd.)

Objectives: Heteroresistant infections are defined as infections in which a mixture of drug-resistant and drug-susceptible populations are present. In Mycobacterium tuberculosis ( M. tb ), heteroresistance poses a challenge in diagnosis and has been linked with poor treatment outcomes. We compared the analytical sensitivity of molecular methods, such as GeneXpert and whole genome sequencing (WGS) in detecting heteroresistance when compared with the 'gold standard' phenotypic assay: the agar proportion method (APM)., Methods: Using two rounds of proficiency surveys with defined monoresistant BCG strains and mixtures of susceptible/resistant M. tb , we determined the limit of detection (LOD) of known resistance associated mutations., Results: The LOD for rifampin-R (RIF-R) detection was 1% using APM, 60% using GeneXpert MTB/RIF, 10% using GeneXpert MTB/RIF Ultra and 10% using WGS. While WGS could detect mutations beyond those associated with RIF resistance, the LOD for these other mutations was also 10%. Additionally, we observed instances where laboratories did not report resistance in the majority population, yet the mutations were present in the raw sequence data., Conclusion: The gold standard APM detects minority resistant populations at a lower proportion than molecular tests. Mycobacterium bovis BCG strains with defined resistance and extracted DNA from M. tb provided concordant results and can serve in quality control of laboratories offering molecular testing for resistance. Further research is required to determine whether the higher LOD of molecular tests is associated with negative treatment outcomes., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: To describe clinicoradiological features and surgical outcomes in a series of nine patients with rhino-orbito-cerebral mucormycosis (ROCM) who presented with Pott's puffy tumor (ROCM-PPT)., Methods: The records of nine patients with ROCM-PPT seen between March 2020 and December 2021 were analysed. Clinical features, radiology, histopathology, operative findings, management and outcome were noted. Frontal sinus pneumatisation and outflow tract configuration was compared between patients and controls with ROCM and no PPT., Results: ROCM-PPT was diagnosed in 9 of 284 (3.2 %) patients with ROCM seen during the study period. There were six (66.7 %) males and the median age was 54 (IQR 46-60) years. Eight (88.9 %) patients had diabetes mellitus and seven (77.8 %) had been COVID-19 positive. Radiological features of osteomyelitis, subperiosteal abscess formation and dural enhancement were seen in all patients. No significant differences in pneumatisation or frontal sinus outflow tract configuration were noted between patients and controls. All patients underwent a craniectomy with frontal bone debridement and frontal sinus exteriorisation. All patients were treated with anti-fungal agents for several months. All patients had symptomatic improvement at a median follow-up of 21 (IQR 18-23) months. Repeat CT/MRI scans showed disease regression/resolution in six out of eight (75 %) patients with follow-up imaging, and stable disease in two others., Conclusions: ROCM-PPT is a rare, delayed complication of mucormycosis that was seen in larger numbers during the recent COVID-19 pandemic. Aggressive debridement of osteomyelitic bone and antifungal therapy results in a good outcome., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

Competing Interests: There are no conflicts of interest.

We aimed to compare the demography, clinical profile, histopathology, fungal culture, radiology, surgery performed, medical therapy and outcomes of patients with acute invasive fungal sinusitis seen during the first and second waves of the COVID-19 pandemic by retrospectively reviewing their case records. Of 238 patients, 43(18.1%) presented during the first wave and 195(81.9%) during the second wave. Patients seen during the first wave were older (p = 0.04) and more likely to have visual impairment (p = 0.004), frozen eye (p = 0.012), altered sensorium (p = 0.007) and stage 3 disease (p = 0.03). Those seen during the second wave were more often COVID-19 positive and had newly diagnosed diabetes mellitus (p = 0.04)and stage 1 disease (p = 0.03). Most patients had a positive culture for Rhizopus species during both waves. Histopathology showed broad aseptate hyphae in all patients but angioinvasion was seen more often during the first wave (p = 0.04). The majority of patients were treated with endoscopic+/- open debridement followed by intravenous amphotericin B and oral posaconazole. While the overall survival rate was similar (first wave 65.1%; second wave 79%; p = 0.106), mortality after discharge was greater during the first wave (11.6% vs 1.5%; p = 0.001). Mortality was higher in patients with stage 3 disease (p = 0.003). Significant differences in clinical presentation, histopathology, radiological stage of disease and post-discharge survival were noted between the two waves of the COVID-19 pandemic, the causes for which were multi-factorial., Competing Interests: Conflict of interestThere is no conflict of interest for any of the authors listed above., (© Association of Otolaryngologists of India 2023. Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.)

Background: Childhood tuberculosis remains a major cause of morbidity and mortality in part due to missed diagnosis. Diagnostic methods with enhanced sensitivity using easy-to-obtain specimens are needed. We aimed to assess the diagnostic accuracy of the Cepheid Mycobacterium tuberculosis Host Response prototype cartridge (MTB-HR), a candidate test measuring a three-gene transcriptomic signature from fingerstick blood, in children with presumptive tuberculosis disease., Methods: RaPaed-TB was a prospective diagnostic accuracy study conducted at four sites in African countries (Malawi, Mozambique, South Africa, and Tanzania) and one site in India. Children younger than 15 years with presumptive pulmonary or extrapulmonary tuberculosis were enrolled between Jan 21, 2019, and June 30, 2021. MTB-HR was performed at baseline and at 1 month in all children and was repeated at 3 months and 6 months in children on tuberculosis treatment. Accuracy was compared with tuberculosis status based on standardised microbiological, radiological, and clinical data., Findings: 5313 potentially eligible children were screened, of whom 975 were eligible. 784 children had MTB-HR test results, of whom 639 had a diagnostic classification and were included in the analysis. MTB-HR differentiated children with culture-confirmed tuberculosis from those with unlikely tuberculosis with a sensitivity of 59·8% (95% CI 50·8-68·4). Using any microbiological confirmation (culture, Xpert MTB/RIF Ultra, or both), sensitivity was 41·6% (34·7-48·7), and using a composite clinical reference standard, sensitivity was 29·6% (25·4-34·2). Specificity for all three reference standards was 90·3% (95% CI 85·5-94·0). Performance was similar in different age groups and by malnutrition status. Among children living with HIV, accuracy against the strict reference standard tended to be lower (sensitivity 50·0%, 15·7-84·3) compared with those without HIV (61·0%, 51·6-69·9), although the difference did not reach statistical significance. Combining baseline MTB-HR result with one Ultra result identified 71·2% of children with microbiologically confirmed tuberculosis., Interpretation: MTB-HR showed promising diagnostic accuracy for culture-confirmed tuberculosis in this large, geographically diverse, paediatric cohort and hard-to-diagnose subgroups., Funding: European and Developing Countries Clinical Trials Partnership, UK Medical Research Council, Swedish International Development Cooperation Agency, Bundesministerium für Bildung und Forschung; German Center for Infection Research (DZIF)., Competing Interests: Declaration of interests All authors declare receiving grant funding for this work from the second European and Developing Countries Clinical Trials Partnership programme (EDCTP2), the German Center for Infection Research (DZIF), and Beckman Coulter to their respective institutions. Cepheid provided testing kits at no cost. ZF-S and HJZ declare funding from the SA-MRC Unit on Child and Adolescent Health to their institution. TDM received funding to his institution from Médicins Sans Frontières 2017–23, GOSH Charity Intramural COVID-19 Rapid Response Funding, Global Alliance Against Tuberculosis, and EU Innovative Medicines Initiative for other research activities. TDM receives personal payment in his function as Editor in Chief of Annals of Clinical Microbiology and Antimicrobials., (Copyright © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background: Rapid detection of tuberculosis (TB) and its resistance are essential for the prompt initiation of correct drug therapy and for stopping the spread of drug-resistant TB. There is an urgent need for increased use of rapid diagnostic tests to control the threat of increased TB and multidrug-resistant TB (MDR-TB)., Methods: EMPE Diagnostics has developed a multiplex molecular diagnostic platform called mfloDx™ by combining nucleotide-specific padlock probe-dependent rolling circle amplification with sensitive lateral flow biosensors, providing visual signals, similar to a COVID-19 test. The first test kit of this platform, mfloDx™ MDR-TB can identify Mycobacterium tuberculosis (MTB) complex and its clinically significant mutations in the rpoB and katG genes and in the inhA promotor contributing resistance to rifampicin (RIF) and isoniazid (INH), causing MDR-TB., Results: We have evaluated the performance of the mfloDx™ MDR-TB test on 210 sputum samples (110 from suspected TB cases and 100 from TB-negative controls) received from a tertiary care center in India. The clinical sensitivity for detecting MTB compared to acid-fast microscopy and mycobacteria growth indicator tube (MGIT) cultures was 86.4% and 84.9%, respectively. All the 100 control samples were negative indicating excellent specificity. In smear-positive sputum samples, the mfloDx™ MDR-TB test showed a sensitivity of 92.5% and 86.4% against MGIT culture and Xpert MTB/RIF, respectively. The clinical sensitivity for the detection of RIF and INH resistance in comparison with MGIT drug susceptibility testing was 100% and 84.6%, respectively, while the clinical specificity was 100%., Conclusion: From the above evaluation, we find mfloDx™ MDR-TB to be a rapid and efficient test to detect TB and its multidrug resistance in 3 h at a low cost making it suitable for resource-limited laboratories., (Copyright © 2024 Copyright: © 2024 International Journal of Mycobacteriology.)

Objective: Early surgical debridement is vital for favorable outcomes in acute invasive fungal sinusitis (AIFS). Our study aimed to propose guidelines with tailored, conservative surgical procedures based on areas of involvement and evaluate their usefulness in avoiding repeated debridement., Methods: This retrospective observational study was conducted on 150 AIFS patients operated on with the proposed surgical guidelines from May to June 2021 at a tertiary care hospital. Data including demography, comorbidities, surgical procedures, revision surgery, and outcome were collected and analyzed., Results: All 150 patients underwent bilateral endoscopic sinonasal debridement. Among them, 108 patients (72%) had current or recent coronavirus disease (COVID) infection. Ninety-two patients (61.3%) required additional procedures based on disease extent. Twenty patients (15.4%) required revision debridement because of progressive or recurrent disease. Mean age of this group was 46.15 (standard deviation ±11.2) years with a strong male predominance (9:1). Seventeen had diabetes mellitus, 12 suffered from active COVID-19 infection and six had received corticosteroids. None of the 31 patients who had recovered from COVID-19 or had no comorbidities required revision surgery. Age, gender, and comorbidities were not significant predictors for revision surgery. Fourteen patients (70%) underwent second surgery within one month of primary surgery. Predominant disease locations were alveolus and palate (55% each), and in 80% the site was uninvolved at primary surgery. The most common revision procedure was inferior partial maxillectomy (60%). At follow-up, all were asymptomatic with no evidence of disease., Conclusion: The proposed surgical guidelines for AIFS allow for adequate surgical debridement with preservation of optimum functional status. Low revision surgery rates and good outcomes with minimal morbidity validate its usefulness., Competing Interests: Conflict of Interest: The authors have no conflicts of interest to declare., (©Copyright 2023 by Turkish Otorhinolaryngology-Head and Neck Surgery Society / Turkish Archives of Otorhinolaryngology is published by Galenos Publishing House.)

Background: Few treatment options exist for patients with severe central nervous system (CNS) tuberculosis (TB) worsening due to inflammatory lesions, despite optimal antitubercular therapy (ATT) and steroids. Data regarding the efficacy and safety of infliximab in these patients are sparse., Methods: We performed a matched retrospective cohort study based on Medical Research Council (MRC) grading system and modified Rankin Scale (mRS) scores comparing 2 groups of adults with CNS TB. Cohort A received at least 1 dose of infliximab after optimal ATT and steroids between March 2019 and July 2022. Cohort B received only ATT and steroids. Disability-free survival (mRS score ≤2) at 6 months was the primary outcome., Results: Baseline MRC grades and mRS scores were similar between the cohorts. Median duration before initiation of infliximab therapy from start of ATT and steroids was 6 (IQR: 3.7-13) months and for neurological deficits was 4 (IQR: 2-6.2) months. Indications for infliximab were symptomatic tuberculomas (20/30; 66.7%), spinal cord involvement with paraparesis (8/30; 26.7%), and optochiasmatic arachnoiditis (3/30; 10%), worsening despite adequate ATT and steroids. Severe disability (5/30 [16.7%] and 21/60 [35%]) and all-cause mortality (2/30 [6.7%] and 13/60 [21.7%]) at 6 months were lower in cohort A versus cohort B, respectively. In the combined study population, only exposure to infliximab was positively associated (aRR: 6.2; 95% CI: 2.18-17.83; P = .001) with disability-free survival at 6 months. There were no clear infliximab-related side effects noted., Conclusions: Infliximab may be an effective and safe adjunctive strategy among severely disabled patients with CNS TB not improving despite optimal ATT and steroids. Adequately powered phase 3 clinical trials are required to confirm these early findings., Competing Interests: Potential conflicts of interest. The authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Introduction: Mucormycosis is an acute invasive fungal disease (IFD) seen mainly in immunocompromised hosts and in patients with uncontrolled diabetes. The incidence of mucormycosis increased exponentially in India during the SARS-CoV-2 (henceforth COVID-19) pandemic. Since there was a lack of data on molecular epidemiology of Mucorales causing IFD during and after the COVID-19 pandemic, whole genome analysis of the Rhizopus spp. isolated during this period was studied along with the detection of mutations that are associated with antifungal drug resistance., Materials and Methods: A total of 50 isolates of Rhizopus spp. were included in this prospective study, which included 28 from patients with active COVID-19 disease, 9 from patients during the recovery phase, and 13 isolates from COVID-19-negative patients. Whole genome sequencing (WGS) was performed for the isolates, and the de novo assembly was done with the Spades assembler. Species identification was done by extracting the ITS gene sequence from each isolate followed by searching Nucleotide BLAST. The phylogenetic trees were made with extracted ITS gene sequences and 12 eukaryotic core marker gene sequences, respectively, to assess the genetic distance between our isolates. Mutations associated with intrinsic drug resistance to fluconazole and voriconazole were analyzed., Results: All 50 patients presented to the hospital with acute fungal rhinosinusitis. These patients had a mean HbA1c of 11.2%, and a serum ferritin of 546.8 ng/mL. Twenty-five patients had received steroids. By WGS analysis, 62% of the Rhizopus species were identified as R. delemar . Bayesian analysis of population structure (BAPS) clustering categorized these isolates into five different groups, of which 28 belong to group 3, 9 to group 5, and 8 to group 1. Mutational analysis revealed that in the CYP51 A gene, 50% of our isolates had frameshift mutations along with 7 synonymous mutations and 46% had only synonymous mutations, whereas in the CYP51B gene, 68% had only synonymous mutations and 26% did not have any mutations., Conclusion: WGS analysis of Mucorales identified during and after the COVID-19 pandemic gives insight into the molecular epidemiology of these isolates in our community and establishes newer mechanisms for intrinsic azole resistance., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Michael, Venkatesan, Ninan, Solaimalai, Sumanth, Varghese, Kurien, Varghese and C.)

Objectives: To evaluate the efficacy and safety of short-course intravenous amphotericin B followed by sustained release posaconazole tablets for diabetes or COVID-19-associated rhino-orbito-cerebral mucormycosis., Methods: This prospective, pragmatic study included adults with diabetes or COVID-19-associated rhino-orbito-cerebral mucormycosis. Patients received short (7-14 days) or long (15-28 days) intravenous antifungal therapy (short intravenous antifungal treatment [SHIFT] or long intravenous antifungal treatment [LIFT], respectively) depending on the presence or absence of brain involvement. All patients received step-down posaconazole tablets, debridement, and glycemic control. The primary outcome was the treatment success at week 14, which was determined by assessing survival and the absence of disease progression through clinical evaluation and nasal endoscopy. Log-binomial regression analysis (risk ratio and 95% CI) was performed to assess factors associated with the primary outcome., Results: Intravenous therapy was administered to 251 participants: SHIFT, 205 (median duration, 13 days); LIFT, 46 (median duration, 22 days). Treatment success at 3 months was 88% (217/248; 95% CI, 83-91%): SHIFT group, 93% (189/203; 89-96%); LIFT group, 62% (28/45; 47-76%). All-cause mortality was 12% (30/251): SHIFT group, 6% (13/205); LIFT group, 37% (17/46). Age (aRR [95% CI]: 1.02 [1.00-1.05]; p 0.027), diabetic ketoacidosis at presentation (2.32 [1.20-4.46]; p 0·012), glycated haemoglobin A1c (1.19 [1.03-1.39]; p 0.019), stroke (3.93 [1.94-7.95]; p 0·0001), and brain involvement (5.67 [3.05-10.54]; p < 0.0001) were independently associated with unsuccessful outcomes., Discussion: Short intravenous amphotericin B with step-down posaconazole tablets should be further studied as primary treatment option for diabetes or COVID-19-associated mucormycosis in randomized controlled trials., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Introduction: An estimated 1.2 million children develop tuberculosis (TB) every year with 240,000 dying because of missed diagnosis. Existing tools suffer from lack of accuracy and are often unavailable. Here, we describe the scientific and clinical methodology applied in RaPaed-TB, a diagnostic accuracy study., Methods: This prospective diagnostic accuracy study evaluating several candidate tests for TB was set out to recruit 1000 children <15 years with presumptive TB in 5 countries (Malawi, Mozambique, South Africa, Tanzania, India). Assessments at baseline included documentation of TB signs and symptoms, TB history, radiography, tuberculin skin test, HIV testing and spirometry. Respiratory samples for reference standard testing (culture, Xpert Ultra) included sputum (induced/spontaneous) or gastric aspirate, and nasopharyngeal aspirate (if <5 years). For novel tests, blood, urine and stool were collected. All participants were followed up at months 1 and 3, and month 6 if on TB treatment or unwell. The primary endpoint followed NIH-consensus statements on categorization of TB disease status for each participant. The study was approved by the sponsor's and all relevant local ethics committees., Discussion: As a diagnostic accuracy study for a disease with an imperfect reference standard, Rapid and Accurate Diagnosis of Pediatric Tuberculosis Disease (RaPaed-TB) was designed following a rigorous and complex methodology. This allows for the determination of diagnostic accuracy of novel assays and combination of testing strategies for optimal care for children, including high-risk groups (ie, very young, malnourished, children living with HIV). Being one of the largest of its kind, RaPaed-TB will inform the development of improved diagnostic approaches to increase case detection in pediatric TB., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

Objective: We aimed to study the literature on chronic granulomatous invasive fungal sinusitis to elucidate the changing trends in the management of the disease., Data Sources: Using specific keywords, we searched the PubMed, PubMed Central, and Scopus databases over the past 50 years, which yielded 938 articles in the English language., Review Methods: Scrutiny of 147 relevant articles revealed 15 homogenous case series (255 cases of histologically proven chronic granulomatous fungal sinusitis alone) and 8 heterogeneous case series (patients with other types of fungal sinusitis included), which were analyzed in detail (all with >5 cases each)., Conclusions: The disease typically affected middle-aged adults with immunocompetence. Most reports were from Sudan, India, and Saudi Arabia. A slowly progressive orbital, cheek, or palatal mass with proptosis (88.2%) or sinonasal symptoms (39.2%) was typical. Ethmoid (57.2%) and maxillary (51.4%) sinuses were chiefly affected with intracranial extension in 35.1%. Aspergillus flavus (64%) was the most frequent isolate reported. Endoscopic excision (78.8%) followed by azole therapy was the preferred treatment in recent reports. Orbital exenteration and craniotomy were infrequently performed. Complete resolution or improvement was reported in 91.3% of patients. Mortality ranged from 5.9% to 22.2%. There is a trend in the literature toward less radical and disfiguring surgery and preferential use of azoles, with good outcomes even in advanced cases., Implications for Practice: Chronic granulomatous fungal sinusitis should be diagnosed on the basis of well-defined histopathologic features. A combination of endoscopic sinus surgery and azole therapy usually yields good outcomes., (© 2022 American Academy of Otolaryngology-Head and Neck Surgery Foundation.)

Paradoxical reactions (PRs) are poorly studied complex immunological phenomena, among patients with tuberculosis (TB). When PRs involves critical structures like the central nervous system (CNS), immunomodulatory therapy is often required. Predictors for PRs in TB to pre-empt appropriate treatment strategies in high-risk groups are lacking. TT genotype of Leukotriene A4 hydrolase (LTA4H) promoter region rs17525495 polymorphisms are associated with exaggerated immune responses in Tuberculous meningitis (TBM), the most severe form of extrapulmonary tuberculosis (EPTB). The association of these polymorphisms with PRs is not known. We evaluated this plausibility among 113 patients with EPTB, at high risk of PRs. Majority [81 (71.7%)] had disseminated tuberculosis with prominent CNS [54 (47.8%)] and lymph node involvement [47 (41.6%)]. Human immunodeficiency Virus (HIV) co-infection was seen among 23 (20.3%) patients. PRs were noted in 38.9% patients, at a median duration of 3 months (IQR 2-4). LTA4H rs17525495 single nucleotide polymorphism (SNP) analysis showed 52 (46%) patients had CC, 43 (38.1%) had CT and 18 (15.9%) had TT genotypes. There was no statistically significant difference in occurrence [CC 38.5% vs CT 39.5% vs TT 38.7%] and time of onset [median (IQR)] of PRs across the genotypes [CC 3 (1-4.7), CT 3 (2-5), TT 2 (2-3)]. PRs was shown to be significantly linked with HIV co-infection (RR 0.6, 95% CI 0.29-1.28), culture positivity (RR 0.5, 95% CI 0.28-1.14), TB Lymphadenitis (RR 0.7, 95% CI 0.44-1.19) and CNS involvement RR 2.1, 95% CI 1.27-3.49) in the univariate analysis (p < 0.2). On multivariate analysis, CNS involvement alone was associated with PRs (aRR 3.8 (1.38-10.92); p < 0.01). PRs were associated with CNS involvement but not with LTA4H rs17525495 polymorphisms., (© 2023. The Author(s).)

Objective: To document changes in evaluation protocols for acute invasive fungal sinusitis during the coronavirus disease 2019 pandemic, and to analyse concordance between clinical and histopathological diagnoses based on new practice guidelines., Methods: Protocols for the evaluation of patients with suspected acute invasive fungal sinusitis both prior and during the coronavirus disease 2019 period are described. A retrospective analysis of patients presenting with suspected acute invasive fungal sinusitis from 1 May to 30 June 2021 was conducted, with assessment of the concordance between clinical and final diagnoses., Results: Among 171 patients with high clinical suspicion, 160 (93.6 per cent) had a final histopathological diagnosis of invasive fungal sinusitis, concordant with the clinical diagnosis, with sensitivity of 100 per cent, positive predictive value of 93.6 per cent and negative predictive value of 100 per cent., Conclusion: The study highlights a valuable screening tool with good accuracy, involving emphasis on 'red flag' signs in high-risk populations. This could be valuable in situations demanding the avoidance of aerosol-generating procedures and in resource-limited settings facilitating early referral to higher level care centres.

Background: Rhino-orbito-cerebral-mucormycosis (ROCM), a rare and potentially fatal disease was seen in increasing numbers during the COVID-19 pandemic. This study describes and compares the patient characteristics and outcomes in COVID-19 associated mucormycosis (CAM) and non-COVID-19 mucormycosis (non-CAM)., Methodology: CAM patients (24 cases) were recruited from the COVID-19 period and non-CAM (24 controls) from the pre-COVID-19 period. Clinical data of the CAM group was collected retrospectively with 3 month outcomes prospectively. The non-CAM group data was collected retrospectively. Patient characteristics were compared and risk factors for mortality in ROCM were assessed., Results: Orbital symptoms [altered vision, restricted eye movements, ptosis] and intracranial involvement were higher in CAM patients on presentation. Similarly, the radiological involvement of orbit (orbital apex, superior orbital fissure) and intracranial cavity (intracranial thrombosis, cavernous sinus) was also higher in CAM patients. Newly detected diabetes was found only in CAM patients (29.2%). Although univariate analysis suggested an increased mortality risk in ROCM patients with orbital involvement, the multivariate analysis showed no increased risk with any of the parameters assessed, including COVID-19 positivity., Conclusions: Compared to the non-CAM, the disease presentation was severe in CAM with higher frequency of orbital and intracranial involvement. However, with early detection and treatment, the short term survival was comparable in both groups.

Background: Bacille Calmette-Guérin (BCG) adenitis is an uncommon complication following BCG vaccination. In rare cases, infants can develop other complications. Controversy exists regarding the diagnosis and management of these cases. Not much information is available in literature regarding their microbiological and immunological characteristics., Methods: Electronic medical records of children presenting to the Pediatric Infectious Diseases clinic in a tertiary care hospital from January 2011-December 2020 with a diagnosis of BCG adenitis were retrospectively reviewed. Their clinical, microbiological, treatment and follow-up data were noted and analyzed., Findings: During the study period, 40 infants presented with a probable diagnosis of BCG adenitis with or without disseminated BCG. Median age at symptom onset was 4(2.5-5.9) months. Nine infants had disseminated disease at presentation. Fifteen infants were suspected to have underlying immune deficiency of whom 12 had proven defects in immune function. On multivariable logistic regression analysis, presence of disseminated disease was the only factor predictive of underlying immunodeficiency. Isoniazid monoresistance was seen in seven cases (32%) of the 22 samples sent for TB cultures., Conclusions: Though BCG adenitis runs a benign course, it could rarely be the first manifestation of an underlying immune defect. There is sizable isoniazid monoresistance, hence sending tissue samples for microbiologic evaluation is necessary to guide anti-tubercular therapy., (© The Author(s) [2022]. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Nocardiosis is a clinical and diagnostic challenge. This was a retrospective study carried out on cases of pulmonary nocardiosis presenting over 15 years. Clinical data was retrieved using the electronic patient records. Vitek MS 3.2 (MALDI TOF MS) was carried out on 22 isolates and sequencing on another 9 isolates. Of 71 patients presenting with pulmonary nocardiosis, 58 (81.6%) were on immunosuppressant therapy, 26 (46%) had a previous lung pathology, 11 (8%) were HIV associated. Disseminated disease was seen in 6 (8.4%). There were 8 (11.26%) deaths in this cohort of patients. Of 31/71 identified to species, the most common were Nocardia cyriacigeorgica (n ​= ​11) followed by Nocardia farcinica (n ​= ​9)., Competing Interests: Declaration of competing interest The authors have no conflicts to disclose., (Copyright © 2022 Indian Association of Medical Microbiologists. Published by Elsevier B.V. All rights reserved.)

Background: India is endemic for Tuberculosis (TB), contributing to the world's highest number of active cases. Diabetes (DM), with its increasing burden in India, could contribute to adverse outcomes among patients with TB., Methods: Consecutive patients with sputum smear positive pulmonary tuberculosis were included in the study. We defined cases as those patients with diabetes at recruitment. Controls were non diabetics (NDM). Sputum samples for AFB smears, AFB culture and Xpert PCR along with blood samples for glycosylated Haemoglobin and glucose levels were collected at recruitment and at 6 months from patients with sputum positive pulmonary TB. Blood glucose levels and sputum smears were repeated at 2 months and monthly till they tested negative. The primary outcome studied was mortality at 6 month follow-up. The secondary outcomes included the time to conversion of sputum smears and cure rates between cases and controls., Results: We recruited 124 patients of which 68 were cases. Mortality after therapy was 15% in cases and 7% in controls, however, the difference was not statistically significant. Equal proportions in each group (Diabetics: 9% vs. NDM 9%) had persistent smear positivity at 2 months. There was no association between delayed sputum conversion and uncontrolled diabetes. Only about 57% of cases and 50% of controls were documented to have completed treatment or been cured. A significant reduction in HbA1c after 6 months of Antituberculous therapy was noted among the cases. [Mean difference - 1.76, P-value - 0.001, 95% CI of difference - (1.01 - 2.52)]., Conclusions: Diabetes did not have adverse outcomes in the form of increased mortality or delayed sputum conversion rates. The high proportion of loss to follow-up seems to be a trend of concern, which should be addressed emergently., Competing Interests: None

Objective: Glioblastoma has been known to be resistant to chemotherapy and radiation, whereas the underlying mechanisms of resistance have not been fully elucidated. The authors studied the role of the transcription factor ZEB1 (zinc finger E-box-binding homeobox 1 protein), which is associated with epithelial-mesenchymal transition (EMT) and is central to the stemness of glioblastoma, to determine its role in therapeutic resistance to radiation and chemotherapy. The authors previously demonstrated that ZEB1 is deleted in a majority of glioblastomas., Methods: The authors explored resistance to therapy in the context of ZEB1 loss and overexpression in glioma stem cells (GSCs) and in patient data., Results: Patients with ZEB1 loss had a shorter survival time than patients with wild-type ZEB1 in both the high- and low-MGMT groups. Consistent with the clinical data, mice implanted with ZEB1 knockdown GSCs showed shortened survival compared with mice inoculated with nonsilencing control (NS) short-hairpin RNA (shRNA) GSC glioblastoma. ZEB1-deleted GSCs demonstrated increased tumorigenicity with regard to proliferation and invasion. Importantly, GSCs that lose ZEB1 expression develop enhanced resistance to chemotherapy, radiotherapy, and combined chemoradiation. ZEB1 loss may lead to increased HER3 expression through the HER3/Akt pathway associated with this chemoresistance. Conversely, overexpression of ZEB1 in GSCs that are ZEB1 null leads to increased sensitivity to chemoradiation., Conclusions: The study results indicate that ZEB1 loss in cancer stem cells confers resistance to chemoradiation and uncovers a potentially targetable cell surface receptor in these resistant cells.

Objectives: The value of the "trace" result in Xpert Ultra for diagnosing active tuberculosis (TB) remains unclear. Our study evaluated the diagnostic accuracy of Xpert MTB/RIF Ultra (Xpert Ultra) (Cepheid, Sunnyvale, USA) over Xpert MTB/RIF (Xpert) (Cepheid, Sunnyvale, USA) and mycobacterial culture when compared with a composite reference standard (CRS)., Methods: A retrospective single-center observational study was conducted in a tertiary care hospital in South India. Over three months, patients (aged ≥15 years) data on Xpert Ultra tests and mycobacterial culture of pulmonary and extrapulmonary samples were extracted from their electronic medical records. Patients were defined as TB cases based on the CRS criteria. Sensitivity, specificity, positive and negative predictive values of diagnostic tests were calculated by comparing them to the CRS., Results: Xpert Ultra was more sensitive (87.8%) than Xpert (72.1%) and culture (44.1%). The specificity of Xpert Ultra was lower (98.1%) than those of Xpert (100%) and culture (100%). The sensitivity (92%) and specificity (100%) of Xpert Ultra were highest when performed on pus samples., Conclusions: Xpert Ultra with the trace category is superior to the conventional Xpert, and mycobacterial culture in identifying TB., Competing Interests: Conflict of interest The authors have no competing interests to declare., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)