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Archana A Nair, Avni P Finn, Paul Sternberg Jr Vanderbilt Eye Institute, Vanderbilt University Medical Center, Nashville, TN, USACorrespondence: Paul Sternberg Jr, Chair and G. W. Hale Professor of Ophthalmology and Visual Sciences, Vanderbilt Eye Institute, Vanderbilt University Medical Center, 2311 Pierce Avenue, Nashville, TN, 37232, USA, Email Paul.sternberg@vumc.orgAbstract: The advent of anti-vascular endothelial growth factor (VEGF) agents has revolutionized the treatment of retinal neovascular diseases including neovascular age-related macular degeneration (nAMD), a leading cause of irreversible blindness. Multiple agents and methods for drug delivery are emerging to increase the duration of treatment effect and treatment interval, reducing the overall treatment burden on patients and clinicians. The newest agent on the market is faricimab. This medication targets two distinct pathways in retinal angiogenesis, VEGF-A and Ang-2, to create a more durable effect. Phase 3 trials for this drug compared treatment intervals up to 16 weeks against aflibercept dosed at 8-week intervals for both nAMD and diabetic macular edema (DME). While the drug shows similar functional and anatomic outcomes with a low adverse effect profile and trial data demonstrating increased treatment duration, its exact place in the VEGF marketplace is yet to be determined. In this article, we discuss the mechanism of action, pivotal clinical trials leading to approval, and the anticipated role for faricimab in the treatment of retinal neovascular disease.Keywords: neovascular age-related macular degeneration, nAMD, macular degeneration, anti-vascular endothelial growth factor, anti-VEGF, faricimab, choroidal neovascularization, CNVM

Recognizing the challenges posed by chemotherapy, specifically the hepatotoxic effects of drugs like cisplatin, this study aimed to examine the hepatoprotective potential of dapagliflozin to mitigate cisplatin-induced hepatotoxicity in a rat model. This study focused on repurposing drugs such as dapagliflozin and natural agents like silymarin as potential interventions to address cisplatin-induced hepatotoxicity. Thirty adult female Wistar rats were distributed into five groups and treated with cisplatin alone, silymarin, dapagliflozin, or a combination of dapagliflozin and silymarin accordingly for 45 days. Body weight, fasting blood glucose levels, liver function tests, and histopathological analysis were conducted to evaluate the hepatoprotective effects. Cisplatin-induced hepatotoxicity significantly ( p < 0.05) increased the serum levels of ALT, AST, TB, and reduced the TP and albumin levels. Dapagliflozin administration led to significant reductions in ALT, AST, TB, and increased albumin levels. Silymarin demonstrated comparable effects. Combining dapagliflozin and silymarin showed synergistic effects, further reducing the liver enzymes and improving albumin levels. Histopathological examination supported these findings, revealing the restoration of liver structure with dapagliflozin and silymarin treatment. Dapagliflozin and silymarin exhibited substantial hepatoprotective benefits against cisplatin-induced hepatotoxicity in rats. The combination therapy demonstrated synergistic effects, highlighting a potential therapeutic approach for mitigating chemotherapy-induced liver damage. Further research into molecular mechanisms and clinical translation is warranted, offering hope for improved clinical outcomes in cancer patients undergoing cisplatin-based chemotherapy.

Differentiation of cardiac fibroblasts to myofibroblasts is necessary for matrix remodeling and fibrosis in heart failure. We previously reported that mitochondrial calcium signaling drives α-ketoglutarate-dependent histone demethylation, promoting myofibroblast formation. Here we investigate the role of ATP-citrate lyase (ACLY), a key enzyme for acetyl-CoA biosynthesis, in histone acetylation regulating myofibroblast fate and persistence in cardiac fibrosis. We show that inactivation of ACLY prevents myofibroblast differentiation and reverses myofibroblasts towards quiescence. Genetic deletion of Acly in post-activated myofibroblasts prevents fibrosis and preserves cardiac function in pressure-overload heart failure. TGFβ stimulation enhances ACLY nuclear localization and ACLY-SMAD2/3 interaction, and increases H3K27ac at fibrotic gene loci. Pharmacological inhibition of ACLY or forced nuclear expression of a dominant-negative ACLY mutant prevents myofibroblast formation and H3K27ac. Our data indicate that nuclear ACLY activity is necessary for myofibroblast differentiation and persistence by maintaining histone acetylation at TGFβ-induced myofibroblast genes. These findings provide targets to prevent and reverse pathological fibrosis., (© 2024. The Author(s).)

Objective: Our study examined the change in repeat opioid analgesic prescription trends in children and adolescents experiencing acute pain between 2013 and 2018., Methods: Eligible individuals were children and adolescents between 1 and 17 years of age enrolled in a Medicaid Managed Care plan and filled an incident opioid analgesic prescription from 2013 to 2018. A repeat opioid prescription was defined as receiving a subsequent opioid prescription within 30 days from the end of the incident opioid prescription. A generalized linear regression analysis was conducted to examine changes in repeat opioid analgesic dispensing over time at quarterly intervals from January 1, 2013, to December 31, 2018., Results: The cohort comprised 17,086 children and adolescents receiving an incident opioid analgesic. Of these, 1780 (10.4%) filled a repeat opioid analgesic prescription. There was a significant decline in the repeat opioid analgesic trend from 11.5% in Q1 2013 to 9.6% in Q4 2018. Stratified analyses by age, sex, and race and ethnicity in a sub-cohort of patients undergoing surgical procedures showed that a significant decline in repeat opioid utilization over time has been observed in all racial/ethnic groups stratified by age and sex, with the most significant decline found in non-Hispanic White children and Hispanic adolescents. At the end of the 6-year follow-up, the racial and ethnic variations in repeat opioid utilization associated with surgical procedures had significantly reduced in children yet persisted among adolescents., Conclusions: Approximately 10% of incident pediatric opioid analgesic recipients received a repeat opioid prescription. There has been a moderate but steady decline (∼7% per quarter) in repeat opioid analgesic utilization between 2013 and 2018., Competing Interests: Declaration of Competing Interest The authors indicate that there is no potential conflict of interest to disclose., (Copyright © 2024 Academic Pediatric Association. Published by Elsevier Inc. All rights reserved.)

This report describes a male in his late 20s who presented with a 2-month history of recurrent haemoptysis and chest pain. A chronic infection, such as tuberculosis, was suspected. He had undergone surgical resection of an intrapericardial hydatid cyst in the past. His blood investigations showed peripheral eosinophilia, and his chest X-ray showed a cystic oval lesion in the left upper zone. A CT pulmonary angiogram revealed filling defects in the bilateral segmental and subsegmental arteries with a cystic lesion in the left upper lobe. Further workup, including bronchoalveolar lavage culture and MRI of the thorax, confirmed the diagnosis of a hydatid cyst of pulmonary echinococcosis. This case illustrates the presentation of multisystemic echinococcosis in a young male with no other risk factors, initially treated with surgical resection and antihelminthic therapy. The disease later recurred, which required prolonged medications, which brought the patient into remission., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Bronchial Dieulafoy's disease (BDD), remains poorly understood, with only 88 cases reported globally. Herein, we present the largest case series ( n  = 7) from a single centre, between 2017 and 2023, retrospectively reviewed, detailing clinical presentations, diagnoses, management and up to 4-year follow-up outcomes. Diagnosis relied on characteristic lesions detected through white light bronchoscopy with or without endobronchial ultrasound (EBUS) or narrow band imaging (NBI), along with computed tomography (CT) scans or bronchial angiography. Identification of aberrant vessels beneath lesions and bronchoscopy details were documented. Treatment modalities and follow-up outcomes until December 2023 were noted. All patients were non-smokers. Review of imaging findings by an experienced radiologist was crucial in suspected cases due to risk of bleeding and often unconclusive results from biopsy. Management of BDD varied, with six patients undergoing bronchial artery embolization (BAE) and one requiring lobectomy; four patients received additional endobronchial therapy, one died due to malignancy, none experienced recurrence of haemoptysis. Identifying patients with large volume haemoptysis disproportionate to parenchymal disease in CT scans is important. A bronchoscopic surveillance is crucial to avoid biopsy; it can be confirmed using EBUS of NBI. While no established guidelines exist, BAE and endobronchial therapy emerge as valuable interventions, with surgical resection reserved for recurrent cases., Competing Interests: None declared., (© 2024 The Author(s). Respirology Case Reports published by John Wiley & Sons Australia, Ltd on behalf of The Asian Pacific Society of Respirology.)

Although previous studies have shown increased health risks of particulate matters, few have evaluated the long-term health impacts of ultrafine particles (UFPs or PM 0.1 , ≤ 0.1 µm in diameter). This study assessed the association between long-term exposure to UFPs and mortality in New York State (NYS), including total non-accidental and cause-specific mortalities, sociodemographic disparities and seasonal trends. Collecting data from a comprehensive chemical transport model and NYS Vital Records, we used the interquartile range (IQR) and high-level UFPs (≥75 % percentile) as indicators to link with mortalities. Our modified difference-in-difference model controlled for other pollutants, meteorological factors, spatial and temporal confounders. The findings indicate that long-term UFPs exposure significantly increases the risk of non-accidental mortality (RR=1.10, 95 % CI: 1.05, 1.17), cardiovascular mortality (RR=1.11, 95 % CI: 1.05, 1.18) particularly for cerebrovascular (RR=1.21, 95 % CI: 1.10, 1.35) and pulmonary heart diseases (RR=1.33, 95 % CI: 1.13, 1.57), and respiratory mortality (borderline significance, RR=1.09, 95 % CI: 1.00, 1.18). Hispanics (RR=1.13, 95 % CI: 1.00, 1.29) and non-Hispanic Blacks (RR=1.40, 95 % CI: 1.16, 1.68) experienced significantly higher mortality risk after exposure to UFPs, compared to non-Hispanic Whites. Children under five, older adults, non-NYC residents, and winter seasons are more susceptible to UFPs' effects., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Shao Lin and Fangqun Yu reports financial support was provided by New York State Energy Research and Development Authority (NYSERDA) and National Institute on Aging of the National Institutes of Health. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Background and Objective: We investigated the reliability of near-infrared reflectance (NIR) imaging as a method of assessing severity of diabetic retinopathy (DR)., Patients and Methods: One hundred ninety-five NIR images were reviewed by two graders for the number of hyporeflective foci, presence or absence of vascular abnormalities, and presumptive DR stage; these were correlated to fundus photography-defined DR stage. Interrater reliability was confirmed via one-way random effects model of intraclass correlation coefficients. Analysis of variance was used in subgroup analysis, receiver operating characteristic (ROC) curves were created to validate reliability of the model, and logistic regression was used to model foci and vascular abnormalities as predictors for moderate or worse disease., Results: A statistically significant difference in mean number of hyporeflective foci was found between no DR and moderate non-proliferative DR (NPDR; P < 0.0001), no DR and severe NPDR ( P < 0.001), no DR and proliferative DR (PDR; P < 0.0001), mild and moderate NPDR ( P = 0.008), mild and severe NPDR ( P < 0.001), and mild NPDR and PDR ( P < 0.001). The area under the ROC curve was 0.849 (CI: 0.792 to 0.905). The threshold for detection of moderate NPDR or worse was 4.75 foci, with a sensitivity of 79.0% and a false positive rate of 20.0%. Multivariate logistic regression model incorporating hyporeflective foci with vascular abnormalities (odds ratio [OR] = 1.592, 95% CI: 1.381 to 1.835; P < 0.001) was able to accurately predict moderate disease or worse, just moderate disease (OR = 1.045, 95% CI: 1.003 to 1.089; P = 0.035), severe disease (OR = 1.050, 95% CI: 1.006 to 1.096; P = 0.027), and proliferative disease (OR = 1.050, 95% CI: 1.008 to 1.095; P = 0.018)., Conclusions: NIR imaging may be an adjunct tool in screening for DR. [ Ophthalmic Surg Lasers Imaging Retina 2024;55:318-325.] .

Pleural effusion is a common problem in our country, and most of these patients need invasive tests as they can't be evaluated by blood tests alone. The simplest of them is diagnostic pleural aspiration, and diagnostic techniques such as medical thoracoscopy are being performed more frequently than ever before. However, most physicians in India treat pleural effusion empirically, leading to delays in diagnosis, misdiagnosis and complications from wrong treatments. This situation must change, and the adoption of evidence-based protocols is urgently needed. Furthermore, the spectrum of pleural disease in India is different from that in the West, and yet Western guidelines and algorithms are used by Indian physicians. Therefore, India-specific consensus guidelines are needed. To fulfil this need, the Indian Chest Society and the National College of Chest Physicians; the premier societies for pulmonary physicians came together to create this National guideline. This document aims to provide evidence based recommendations on basic principles, initial assessment, diagnostic modalities and management of pleural effusions., (Copyright © 2024 Copyright: © 2024 Indian Chest Society.)

Legionnaires' disease (LD) is a severe form of pneumonia (∼10-25% fatality rate) caused by inhalation of aerosols containing Legionella , a pathogenic gram-negative bacteria. These bacteria can grow, spread, and aerosolize through building water systems. A recent dramatic increase in LD incidence has been observed globally, with a 9-fold increase in the United States from 2000 to 2018, and with disproportionately higher burden for socioeconomically vulnerable subgroups. Despite the focus of decades of research since the infamous 1976 outbreak, substantial knowledge gaps remain with regard to source of exposure and the reason(s) for the dramatic increase in LD incidence. Here, we rule out factors indicated in literature to contribute to its long-term increases and identify a hitherto unexplored explanatory factor. We also provide an epidemiological demonstration that the occurrence of LD is linked with exposure to cooling towers (CTs). Our results suggest that declining sulfur dioxide air pollution, which has many well-established health benefits, results in reduced acidity of aerosols emitted from CTs, which may prolong the survival duration of Legionella in contaminated CT droplets and contribute to the increase in LD incidence. Mechanistically associating decreasing aerosol acidity with this respiratory disease has implications for better understanding its transmission, predicting future risks, and informed design of preventive and interventional strategies that consider the complex impacts of continued sulfur dioxide changes., (© The Author(s) 2024. Published by Oxford University Press on behalf of National Academy of Sciences.)

Purpose: Our study examined the association between outpatient postsurgical analgesic prescription and risk of insufficiently managed pain characterized by pain-associated hospital admission and emergency room (ER) visit., Methods: Eligible individuals were children 1-17 years of age who filled an incident analgesic following an outpatient surgery during 2013-2018. Pain-associated hospital admission or ER visit were measured within 30 days following the outpatient surgical procedure. A hierarchical multivariable logistic regression model with patients nested under prescribers was fitted to test the association between incident analgesic prescription and risk of having pain-associated hospital admission or ER visit., Results: Of 14 277 children meeting the inclusion criteria, 6224 (43.6%) received an incident opioid and 8053 (56.4%) received an incident non-opioid analgesic prescription respectively. There were a total of 523 (3.7%) children undergoing surgical procedures that had pain-related hospital admissions or ER visits with 5.1% initiated on non-opioid analgesics and 1.8% on opioid analgesics. The multilevel model indicated that initial opioid analgesic recipients were 32% less likely of having a pain-associated hospital admission or ER visit [aOR: 0.68 (95% CI: 0.3-0.8)]., Conclusion: Majority of postsurgical patients do not require additional pain management strategies. In the 3.7% of patients requiring additional pain management strategies, those initiated on non-opioid analgesics are more likely to have a pain-associated hospital admission or ER visit compared with their opioid recipient counterparts., (© 2024 John Wiley & Sons Ltd.)

Objectives: To describe the characteristics of primary Sjögren's syndrome (pSS) patients with interstitial lung disease (ILD) and to assess treatment response., Methods: All patients of pSS from 2010 to 2019 were retrospectively identified. Lung function tests, high resolution computed tomography (HRCT) findings, and treatment outcomes were analysed., Results: Out of 550 patients with pSS, ILD was detected in 33 patients (frequency of 6 %). The mean(±SD) age at the diagnosis of pSS was 50 (± 9.3) years. 28/33(84.8%) were females. ILD onset preceded pSS diagnosis in 2 (6%) patients, simultaneously diagnosed in 21 (63.6%) patients and developed after pSS onset in 10 (30.3%) patients. 5 patients (15.15 %) were asymptomatic for ILD. Non-specific interstitial pneumonia (NSIP) accounted for the most frequent ILD subtype, in 15 patients (45.5%). Mycophenolate mofetil (MMF) was the most frequently used steroid sparing agent, in 25 patients (75.7%). 7 patients were lost to follow up. Response was seen in 22 patients, whereas 3 patients were non responders. There was one mortality due to lower respiratory tract infection-related sepsis. Presence of sicca symptoms [91.5% vs 8.7% (p<0.001)], NSIP pattern of ILD [90% vs 10% (p = 0.002)], and absence of Raynaud's phenomenon [91.7% vs 8.3% (p<0.001)] were significantly associated with responder status when compared to non-responders., Conclusion: ILD in primary Sjögren's syndrome is not an uncommon entity, and immunosuppression with steroids along with steroid-sparing agents led to good clinical outcomes of ILD in a majority of the patients in our cohort., Competing Interests: The authors declare no conflicts of interest., (© 2024 The Mediterranean Journal of Rheumatology (MJR).)

Background: Tracheobronchopathia osteochondroplastica (TPO) is a rare idiopathic disease involving the tracheobronchial tree. It is mostly an incidental finding with non-specific clinical manifestations. It has typical bronchoscopic, radiological features and biopsy is usually considered non-essential. The study aimed to determine whether biopsy makes a difference in the management of patients., Methods: All patients diagnosed with TPO in our institution over 15 years (2005 to 2020) were included in this study. Their medical records, chest computed tomography (CT), and bronchoscopy reports were retrospectively reviewed, and data were analysed. All the CT images were reviewed by a senior chest radiologist., Results: From the 20,000 bronchoscopies and 260,000 CT thorax images obtained, 28 cases were diagnosed as TPO based on either bronchoscopy or radiology or both. Among the 19 cases diagnosed through bronchoscopy, 16 underwent a biopsy. In addition to TPO features, biopsy showed additional diagnoses in 6 cases. In 9 cases, TPO was not initially diagnosed by CT but by bronchoscopy. In 8 patients, TPO was diagnosed incidentally on CT performed for other reasons. On follow-up with the treatment of underlying/co-existing concomitant aetiologies, clinical improvement was noted in all patients. None of them progressed to respiratory failure or airway obstruction until the last follow-up., Conclusion: Among patients who underwent bronchoscopic biopsy of TPO lesions, 38% had biopsy results showing an alternative aetiology, which led to changes in the treatment plan for all these patients. Hence, a bronchoscopic biopsy of TPO lesions should be performed to rule out other aetiologies., Competing Interests: Disclosure: There is no conflict of interest or other disclosures., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: The spatiotemporal and demographic disparities in exposure to ultrafine particles (UFP; number concentrations of particulate matter (PM) with diameter ≤0.1 μm), a key subcomponent of fine aerosols (PM 2.5 ; mass concentrations of PM ≤ 2.5 μm), have not been well studied., Objective: To quantify and compare the aerosol pollutant exposure disparities for UFP and PM 2.5 by socio-demographic factors in New York State (NYS)., Methods: Ambient atmospheric UFP and PM 2.5 were quantified using a global three-dimensional model of chemical transport with state-of-the-science aerosol microphysical processes validated extensively with observations. We matched these to U.S. census demographic data for varied spatial scales (state, county, county subdivision) and derived population-weighted aerosol exposure estimates. Aerosol exposure disparities for each demographic and socioeconomic (SES) indicator, with a focus on race-ethnicity and income, were quantified for the period 2013-2020., Results: The average NYS resident was exposed to 4451 #·cm -3 UFP and 7.87 μg·m -3 PM 2.5 in 2013-2020, but minority race-ethnicity groups were invariably exposed to greater daily aerosol pollution (UFP: +75.0% & PM 2.5 : +16.2%). UFP has increased since 2017 and is temporally and seasonally out-of-phase with PM 2.5 . Race-ethnicity exposure disparities for PM 2.5 have declined over time; by -6% from 2013 to 2017 and plateaued thereafter despite its decreasing concentrations. In contrast, these disparities have increased (+12.5-13.5%) for UFP. The aerosol pollution exposure disparities were the highest for low-income minorities and were more amplified for UFP than PM 2.5. DISCUSSION: We identified large disparities in aerosol pollution exposure by urbanization level and socio-demographics in NYS residents. Jurisdictions with higher proportions of race-ethnicity minorities, low-income residents, and greater urbanization were disproportionately exposed to higher concentrations of UFP and PM 2.5 than other NYS residents. These race-ethnicity exposure disparities were much larger, more disproportionate, and unabating over time for UFP compared to PM 2.5 across various income strata and levels of urbanicity., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Fangqun Yu reports financial support was provided by New York State Energy Research Development Authority. Shao Lin reports financial support was provided by National Institutes of Health., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Haemoptysis is a frequently encountered presentation in thoracic surgery practice. Most of the patients present with chronic haemoptysis while 5% of them will present with life-threatening acute haemoptysis. Emergency surgery used to be the first-line management in acute life-threatening haemoptysis which resulted in significant morbidity and mortality. With advancements in interventional procedures, most of these acute presentations are now being managed conservatively by interventionists. In a country like India with a high incidence of tuberculosis and other infectious diseases of the lungs, haemoptysis is even more common. While interventional procedures help to tide over the crisis and earn valuable time to stabilise a haemorrhaging patient, surgical resection is the definitive management most of the time. This review will endeavour to establish the definition, aetiology, emergency, and definitive management of a patient who presents with haemoptysis., Competing Interests: Conflict of interestThere was no conflict of interest in this study., (© Indian Association of Cardiovascular-Thoracic Surgeons 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.)

Lipoblastoma-like tumor (LLT) is a benign soft tissue tumor demonstrating mixed morphologic features of lipoblastoma, myxoid liposarcoma, and spindle cell lipoma but lacking genetic alterations associated with those tumors. LLT was originally thought to be specific to the vulva but has since been reported in the paratesticular region. The morphologic features of LLT overlap with those of "fibrosarcoma-like lipomatous neoplasm" (FLLN), a rare, indolent adipocytic neoplasm considered by some to form part of the spectrum of atypical spindle cell and pleomorphic lipomatous tumor. We compared the morphologic, immunohistochemical, and genetic features of 23 tumors previously classified as LLT (n = 17) and FLLN (n = 6). The 23 tumors occurred in 13 women and 10 men (mean age, 42 years; range, 17 to 80 years). Eighteen (78%) cases arose in the inguinogenital region, whereas 5 tumors (22%) involved noninguinogenital soft tissue, including the flank (n = 1), shoulder (n = 1), foot (n = 1), forearm (n = 1), and chest wall (n = 1). Microscopically, the tumors were lobulated and septated, with variably collagenized fibromyxoid stroma, prominent thin-walled vessels, scattered univacuolated or bivacuolated lipoblasts, and a minor component of mature adipose tissue. Using immunohistochemistry, 5 tumors (42%) showed complete RB1 loss, with partial loss in 7 cases (58%). RNA sequencing, chromosomal microarray, and DNA next-generation sequencing study results were negative for significant alterations. There were no clinical, morphologic, immunohistochemical, or molecular genetic differences between cases previously classified as LLT or FLLN. Clinical follow-up (11 patients [48%]; range, 2-276 months; mean, 48.2 months) showed all patients were alive without disease, and only one patient had experienced a single local recurrence. We conclude that LLT and FLLN represent the same entity, for which "LLT" seems most appropriate. LLT may occur in either sex and any superficial soft tissue location. Careful morphologic study and appropriate ancillary testing should allow for the distinction of LLT from its potential mimics., (Copyright © 2023 United States & Canadian Academy of Pathology. Published by Elsevier Inc. All rights reserved.)

Background: Hypertrophic cardiomyopathy (HCM) is characterized by asymmetric left ventricular hypertrophy. Currently, hypertrophy pathways responsible for HCM have not been fully elucidated. Their identification could serve as a nidus for the generation of novel therapeutics aimed at halting disease development or progression. Herein, we performed a comprehensive multi-omic characterization of hypertrophy pathways in HCM., Methods: Flash-frozen cardiac tissues were collected from genotyped HCM patients (n=97) undergoing surgical myectomy and tissue from 23 controls. RNA sequencing and mass spectrometry-enabled deep proteome and phosphoproteomic assessment were performed. Rigorous differential expression, gene set enrichment, and pathway analyses were performed to characterize HCM-mediated alterations with emphasis on hypertrophy pathways., Results: We identified transcriptional dysregulation with 1246 (8%) differentially expressed genes and elucidated downregulation of 10 hypertrophy pathways. Deep proteomic analysis identified 411 proteins (9%) that differed between HCM and controls with strong dysregulation of metabolic pathways. Seven hypertrophy pathways were upregulated with antagonistic upregulation of 5 of 10 hypertrophy pathways shown to be downregulated in the transcriptome. Most upregulated hypertrophy pathways encompassed the rat sarcoma-mitogen-activated protein kinase signaling cascade. Phosphoproteomic analysis demonstrated hyperphosphorylation of the rat sarcoma-mitogen-activated protein kinase system suggesting activation of this signaling cascade. There was a common transcriptomic and proteomic profile regardless of genotype., Conclusions: At time of surgical myectomy, the ventricular proteome, independent of genotype, reveals widespread upregulation and activation of hypertrophy pathways, mainly involving the rat sarcoma-mitogen-activated protein kinase signaling cascade. In addition, there is a counterregulatory transcriptional downregulation of the same pathways. Rat sarcoma-mitogen-activated protein kinase activation may serve a crucial role in hypertrophy observed in HCM.

New particle formation (NPF) and subsequent growth can contribute upwards of 50 % of the global cloud condensation nuclei (CCN) budget. It is also a significant source of ultrafine aerosols (PM 0.1 ) with health implications. Ammonia (NH 3 ) can play a significant role in enhancing NPF and contributing to the growth of nucleated particles. Understanding these processes are vital for air quality and climate. Here, we examine the role of NH 3 in NPF and consequent effects on aerosol number concentrations (including CCN) and size distributions during springtime over the United States (US). We use the GEOS-Chem chemistry transport model coupled with the size-resolved Advanced Particle Microphysics (APM) Model. We also employ measurements of particle number size distributions, CN10 (condensation nuclei > 10 nm), CCN0.4 (CCN at 0.4 % supersaturation), and aerosol composition (SO 4 , NO 3 , NH 4 , Organics) at the Southern Great Plains site (SGP). The impact of NH 3 in ion-mediated nucleation is the improved capturing of the occurrence of almost all springtime (March-April) NPF events observed at SGP during 2015-2020. Furthermore, this brings the magnitude and temporal variations of particle number concentrations in stronger agreement with observations; mean fractional bias for modeled CN10(CCN0.4) reducing from -1.26 to -0.27 (-0.75 to -0.54) and overall good-agreement (∣FractionalBias ∣ < 0.6) improving from 8.5 to 54 % (31 to 42 %). The contribution of NH 3 in new particle formation is important for springtime abundance of ultrafine aerosols (explaining 63 ± 15 % of CN10) and CCN (16 ± 10 % of CCN0.4) over the US. Our analysis shows that the deviation of CCN0.4 is strongly correlated with PM 1 -NH 4 + deviations, suggesting the importance of improved model representation of ammonium for more accurate quantification of potential cloud forming particles., Competing Interests: Declaration of competing interest 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., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Objective: Our study evaluated the association between initial opioid prescription duration and receipt of a repeat opioid prescription in children., Methods: Eligible individuals were children between 1 and 17 years of age who enrolled in a Medicaid Managed Care plan and filled an incident opioid prescription during 2013 to 2018. An incident prescription was defined as receipt of an opioid analgesic without a prior use for 12 months. A repeat opioid prescription was defined as receipt of a subsequent opioid prescription within 30 days since the end of incident opioid prescription. A hierarchical multivariable logistic regression model was fitted to test the association between incident opioid prescription duration and the likelihood of receiving a repeat prescription., Results: The cohort consisted of 17,086 children receiving an incident opioid prescription in which 6272 (36.7%) received 1 to 3 days' supply, 8442 (49.4%) received 4 to 7 days' supply, 1434 (8.4%) received 8 to 10 days' supply, and 938 (5.5%) received >10 days' supply. Of these incident opioid recipients, 1780 (10.4%) filled a repeat opioid prescription. The multilevel model results indicated that, children receiving 4 to 7 days' supply (adjusted odds ratio [aOR]: 0.98 {0.9-1.1}), 8 to 10 days' supply (aOR: 1.03 [0.8-1.3]), and >10 days' supply (aOR: 0.85 [0.7-1.1]) had comparable likelihoods of receiving a repeat prescription as those receiving 1 to 3 days' supply., Discussion: Nearly 10% of children who filled an opioid prescription for acute pain received a repeat prescription. Initial prescription duration was not associated with the risk of receiving a repeat prescription., (Copyright © 2022 Academic Pediatric Association. Published by Elsevier Inc. All rights reserved.)

Purpose: To study patient follow-up after they engage in a teleretinal screening program and to understand potential barriers to care. Methods: This was a retrospective analysis and a prospective study of telephone-based patient interviews of outpatients screened for diabetic retinopathy (DR) through a teleretinal referral system. Results: Of 2761 patients screened through a teleretinal referral program, 123 (4.5%) had moderate nonproliferative DR (NPDR), 83 (3.0%) had severe NPDR, and 31 (1.1%) had proliferative DR. Of the 114 patients with severe NPDR or worse, 67 (58.8%) saw an ophthalmologist within 3 months of referral. Eighty percent of interviewed patients reported they were not aware of the need for follow-up eye appointments. Conclusions: Of patients with severe retinopathy or worse, 58.8% presented for in-person evaluation and treatment within 3 months of screening. Although this result was negatively affected by factors related to the COVID-19 pandemic, key elements of patient education and improved referral strategies to facilitate in-person treatment are essential to improving follow-up after patients engage in telescreening., Competing Interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Dr. Parikh is a consultant to Blue Cross Blue Shield, Anthem. Dr. Colby is a consultant to WL Gore Inc. Dr. Modi is a consultant to Alimera, Alcon, Allergan, Bausch + Lomb, Genentech, Iveric Bio, Thea, and Zeiss., (© The Author(s) 2023.)

Machine Learning (ML) models have been developed to predict perioperative clinical parameters. The objective of this study was to determine if ML models can serve as decision aids to improve anesthesiologists' prediction of peak intraoperative glucose values and postoperative opioid requirements. A web-based tool was used to present actual surgical case and patient information to 10 practicing anesthesiologists. They were asked to predict peak glucose levels and post-operative opioid requirements for 100 surgical patients with and without presenting ML model estimations of peak glucose and opioid requirements. The accuracies of the anesthesiologists' estimates with and without ML estimates as reference were compared. A questionnaire was also sent to the participating anesthesiologists to obtain their feedback on ML decision support. The accuracy of peak glucose level estimates by the anesthesiologists increased from 79.0 ± 13.7% without ML assistance to 84.7 ± 11.5% (< 0.001) when ML estimates were provided as reference. The accuracy of opioid requirement estimates increased from 18% without ML assistance to 42% (p < 0.001) when ML estimates were provided as reference. When ML estimates were provided, predictions of peak glucose improved for 8 out of the 10 anesthesiologists, while predictions of opioid requirements improved for 7 of the 10 anesthesiologists. Feedback questionnaire responses revealed that the anesthesiologist primarily used the ML estimates as reference to modify their clinical judgement. ML models can improve anesthesiologists' estimation of clinical parameters. ML predictions primarily served as reference information that modified an anesthesiologist's clinical estimate., (© 2022. The Author(s), under exclusive licence to Springer Nature B.V.)

Objective: There are altered mucosal functions in irritable bowel syndrome with diarrhoea (IBS-D); ~30% of patients with IBS-D have abnormal bile acid (BA) metabolism (ABAM) and diarrhoea (summarised as BAD)., Aim: To compare biochemical parameters, gastrointestinal and colonic transit, rectal sensation and pathobiological mechanisms in IBS-D without ABAM and in BAD (serum 7C4>52 ng/mL)., Design: In patients with Rome III criteria of IBS-D, we compared biochemical features, colonic transit, rectal sensation, deep genotype of five BA-related genes, ileal and colonic mucosal mRNA (differential expression (DE) analysis) and stool dysbiosis (including functional analysis of microbiome). Results in BAD were compared with IBS-D without ABAM., Results: Compared with 161 patients with IBS-D without ABAM, 44 patients with BAD had significantly faster colonic transit, lower microbial alpha diversity, different compositional profile (beta diversity) and higher Firmicutes to Bacteroidetes ratio with evidence of decreased expression of bile acid thiol ligase (involved in transformation of primary to secondary BAs) and decreased sulfatases. In BAD (compared with IBS-D without ABAM), terminal ileal biopsies showed downregulation of SLC44A5 (a BA transporter), and ascending colon biopsies showed upregulation in barrier-weakening genes ( CLDN2 ), serine protease inhibitors, immune activation, cellular differentiation and a cellular transporter ( FABP6 ; BA binding). No DE of genes was documented in descending colon biopsies. The two groups had similar rectal sensation., Conclusion: Though sharing clinical symptoms with IBS-D, BAD is associated with biological differences and mechanisms that have potential to enhance diagnosis and treatment targeting barrier dysfunction, inflammatory and microbial changes., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: To describe cases of unilateral cone-rod dysfunction presenting in two middle-aged females., Methods: This case series highlights two middle-aged female patients with progressive visual decline in one eye. Fundus photography, fundus autofluorescence (FAF), spectral-domain optical coherence tomography (SD-OCT), multi-focal electroretinogram (mfERG), full-field electroretinogram(ffERG), and genetic testing were obtained., Results: In the first patient, mfERG showed an extinguished response and ffERG demonstrated markedly reduced a-wave and b-wave amplitudes (more pronounced under photopic conditions) in the right eye. SD-OCT showed attenuation of the ellipsoid zone of the right eye. Similar findings were appreciated in the second patient. Genetic testing in the first patient identified three heterozygous variants in PRPH2, RCBTB1, and USH2A. The second patient was found to have heterozygous variants in BBS1 and ABCA4., Conclusion: These two cases add to the literature of case reports of unilateral cone-rod and rod-cone dystrophies. However, the underlying etiology of the unilateral pattern of cone-rod dysfunction and the significance of the heterozygous mutations found in both cases remains uncertain., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

A male patient in his 20s presented with a cough and a small volume of haemoptysis that lasted a year. He had no other constitutional symptoms and a respiratory examination was suggestive of a consolidation. A chronic infection, such as tuberculosis, was suspected. The routine evaluation showed peripheral eosinophilia with raised serum total IgE. Sputum examination for tuberculosis was negative; hence, a high-resolution CT of the thorax was performed, which revealed bilateral bronchiectasis with high-attenuation mucus plugging. The imaging and blood profiles were in favour of allergic bronchopulmonary aspergillosis, but there was no history suggestive of asthma, and the pulmonary function test was normal. The patient underwent a skin prick test and an allergen-specific IgE test for Aspergillus fumigatus , and both were positive. His bronchoalveolar lavage cultures also grew A. fumigatus , and he responded well to antifungal therapy. This case illustrates the presentation of a rare entity-allergic bronchopulmonary aspergillosis sans asthma., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Systemic corticosteroids are used to treat people with COVID-19 because they counter hyper-inflammation. Existing evidence syntheses suggest a slight benefit on mortality. Nonetheless, size of effect, optimal therapy regimen, and selection of patients who are likely to benefit most are factors that remain to be evaluated., Objectives: To assess whether and at which doses systemic corticosteroids are effective and safe in the treatment of people with COVID-19, to explore equity-related aspects in subgroup analyses, and to keep up to date with the evolving evidence base using a living systematic review approach., Search Methods: We searched the Cochrane COVID-19 Study Register (which includes PubMed, Embase, CENTRAL, ClinicalTrials.gov, WHO ICTRP, and medRxiv), Web of Science (Science Citation Index, Emerging Citation Index), and the WHO COVID-19 Global literature on coronavirus disease to identify completed and ongoing studies to 6 January 2022., Selection Criteria: We included randomised controlled trials (RCTs) that evaluated systemic corticosteroids for people with COVID-19. We included any type or dose of systemic corticosteroids and the following comparisons: systemic corticosteroids plus standard care versus standard care, different types, doses and timings (early versus late) of corticosteroids. We excluded corticosteroids in combination with other active substances versus standard care, topical or inhaled corticosteroids, and corticosteroids for long-COVID treatment., Data Collection and Analysis: We followed standard Cochrane methodology. To assess the risk of bias in included studies, we used the Cochrane 'Risk of bias' 2 tool for RCTs. We rated the certainty of the evidence using the GRADE approach for the following outcomes: all-cause mortality up to 30 and 120 days, discharged alive (clinical improvement), new need for invasive mechanical ventilation or death (clinical worsening), serious adverse events, adverse events, hospital-acquired infections, and invasive fungal infections., Main Results: We included 16 RCTs in 9549 participants, of whom 8271 (87%) originated from high-income countries. A total of 4532 participants were randomised to corticosteroid arms and the majority received dexamethasone (n = 3766). These studies included participants mostly older than 50 years and male. We also identified 42 ongoing and 23 completed studies lacking published results or relevant information on the study design. Hospitalised individuals with a confirmed or suspected diagnosis of symptomatic COVID-19 Systemic corticosteroids plus standard care versus standard care plus/minus placebo We included 11 RCTs (8019 participants), one of which did not report any of our pre-specified outcomes and thus our analyses included outcome data from 10 studies. Systemic corticosteroids plus standard care compared to standard care probably reduce all-cause mortality (up to 30 days) slightly (risk ratio (RR) 0.90, 95% confidence interval (CI) 0.84 to 0.97; 7898 participants; estimated absolute effect: 274 deaths per 1000 people not receiving systemic corticosteroids compared to 246 deaths per 1000 people receiving the intervention (95% CI 230 to 265 per 1000 people); moderate-certainty evidence). The evidence is very uncertain about the effect on all-cause mortality (up to 120 days) (RR 0.74, 95% CI 0.23 to 2.34; 485 participants). The chance of clinical improvement (discharged alive at day 28) may slightly increase (RR 1.07, 95% CI 1.03 to 1.11; 6786 participants; low-certainty evidence) while the risk of clinical worsening (new need for invasive mechanical ventilation or death) may slightly decrease (RR 0.92, 95% CI 0.84 to 1.01; 5586 participants; low-certainty evidence). For serious adverse events (two RCTs, 678 participants), adverse events (three RCTs, 447 participants), hospital-acquired infections (four RCTs, 598 participants), and invasive fungal infections (one study, 64 participants), we did not perform any analyses beyond the presentation of descriptive statistics due to very low-certainty evidence (high risk of bias, heterogeneous definitions, and underreporting). Different types, dosages or timing of systemic corticosteroids We identified one RCT (86 participants) comparing methylprednisolone to dexamethasone, thus the evidence is very uncertain about the effect of methylprednisolone on all-cause mortality (up to 30 days) (RR 0.51, 95% CI 0.24 to 1.07; 86 participants). None of the other outcomes of interest were reported in this study. We included four RCTs (1383 participants) comparing high-dose dexamethasone (12 mg or higher) to low-dose dexamethasone (6 mg to 8 mg). High-dose dexamethasone compared to low-dose dexamethasone may reduce all-cause mortality (up to 30 days) (RR 0.87, 95% CI 0.73 to 1.04; 1269 participants; low-certainty evidence), but the evidence is very uncertain about the effect of high-dose dexamethasone on all-cause mortality (up to 120 days) (RR 0.93, 95% CI 0.79 to 1.08; 1383 participants) and it may have little or no impact on clinical improvement (discharged alive at 28 days) (RR 0.98, 95% CI 0.89 to 1.09; 200 participants; low-certainty evidence). Studies did not report data on clinical worsening (new need for invasive mechanical ventilation or death). For serious adverse events, adverse events, hospital-acquired infections, and invasive fungal infections, we did not perform analyses beyond the presentation of descriptive statistics due to very low-certainty evidence. We could not identify studies for comparisons of different timing and systemic corticosteroids versus other active substances. Equity-related subgroup analyses We conducted the following subgroup analyses to explore equity-related factors: sex, age (&lt; 70 years; ≥ 70 years), ethnicity (Black, Asian or other versus White versus unknown) and place of residence (high-income versus low- and middle-income countries). Except for age and ethnicity, no evidence for differences could be identified. For all-cause mortality up to 30 days, participants younger than 70 years seemed to benefit from systemic corticosteroids in comparison to those aged 70 years and older. The few participants from a Black, Asian, or other minority ethnic group showed a larger estimated effect than the many White participants. Outpatients with asymptomatic or mild disease There are no studies published in populations with asymptomatic infection or mild disease., Authors' Conclusions: Systemic corticosteroids probably slightly reduce all-cause mortality up to 30 days in people hospitalised because of symptomatic COVID-19, while the evidence is very uncertain about the effect on all-cause mortality up to 120 days. For younger people (under 70 years of age) there was a potential advantage, as well as for Black, Asian, or people of a minority ethnic group; further subgroup analyses showed no relevant effects. Evidence related to the most effective type, dose, or timing of systemic corticosteroids remains immature. Currently, there is no evidence on asymptomatic or mild disease (non-hospitalised participants). Due to the low to very low certainty of the current evidence, we cannot assess safety adequately to rule out harmful effects of the treatment, therefore there is an urgent need for good-quality safety data. Findings of equity-related subgroup analyses should be interpreted with caution because of their explorative nature, low precision, and missing data. We identified 42 ongoing and 23 completed studies lacking published results or relevant information on the study design, suggesting there may be possible changes of the effect estimates and certainty of the evidence in the future., (Copyright © 2022 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

Competing Interests: Competing interests: None declared.

Purpose: To identify risk factors for the development of new-onset, postoperative diplopia following orbital decompression surgery based on patient demographics, clinical exam characteristics, radiographic parameters, and surgical techniques., Methods: We conducted a multi-center retrospective chart review of patients who underwent orbital decompression for thyroid eye disease (TED). Patient demographics, including age, gender, smoking history, preoperative exophthalmometry, clinical activity score (CAS), use of peribulbar and/or systemic steroids, and type of orbital decompression were reviewed. Postoperative diplopia was determined at a minimum of 3 months postoperatively and before any further surgeries. Cross-sectional area ratios of each extraocular muscle to orbit and total fat to orbit were calculated from coronal imaging in a standard fashion. All measurements were carried out using PACS imaging software. Multivariable logistic regression modeling was performed using Stata 14.2 (StataCorp, College Station, TX)., Results: A total of 331 patients without preoperative diplopia were identified. At 3 months postoperatively, 249 patients had no diplopia whereas 82 patients developed diplopia. The average postoperative follow-up was 22 months (range 3-156) months. Significant preoperative clinical risk factors for postoperative diplopia included older age at surgery, proptosis, use of peribulbar or systemic steroids, elevated clinical activity score, and presence of preoperative compressive optic neuropathy. Imaging findings of enlarged cross-sectional areas of each rectus muscle to the overall orbital area also conferred a significant risk of postoperative diplopia. Regarding surgical factors, postoperative diplopia was more common among those undergoing medial wall decompression, bilateral orbital surgery, and balanced decompression, whereas endoscopic medial wall decompression was found to be relatively protective., Conclusions: This study identifies risk factors associated with the development of diplopia following orbital decompression using multivariable data. This study demonstrates that several characteristics including age, clinical activity score, the cross-sectional muscle to orbit ratios, in addition to the type of orbital decompression surgery, are predictive factors for the development of new-onset postoperative diplopia., Competing Interests: D.O.K. and B.S.K. Consultant for Horizon Therapeutics. The other authors have no conflicts of interest to disclose., (Copyright © 2022 The American Society of Ophthalmic Plastic and Reconstructive Surgery, Inc.)

Objective: To study the outcomes of noninvasive ventilation (NIV) administered through a tabletop device for coronavirus disease 2019 acute respiratory distress syndrome in the respiratory intermediate care unit (RIMCU) at a tertiary care hospital in India., Patients and Methods: We retrospectively studied a cohort of hospitalized patients deteriorating despite low-flow oxygen support who received protocolized management with positive airway pressure using a tabletop NIV device in the RIMCU as a step-up rescue therapy from July 30, 2020 to November 14, 2020. Treatment was commenced on the continuous positive airway pressure mode up to a pressure of 10 cm of H 2 O, and if required, inspiratory pressures were added using the bilevel positive air pressure mode. Success was defined as weaning from NIV and stepping down to the ward, and failure was defined as escalation to the intensive care unit, the need for intubation, or death., Results: In total, 246 patients were treated in the RIMCU during the study period. Of these, 168 received respiratory support via a tabletop NIV device as a step-up rescue therapy. Their mean age was 54 years, and 83% were men. Diabetes mellitus (78%) and hypertension (44%) were the commonest comorbidities. Treatment was successful with tabletop NIV in 77% (129/168) of the patients; of them, 41% (69/168) received treatment with continuous positive airway pressure alone and 36% (60/168) received additional increased inspiratory pressure via the bilevel positive air pressure mode., Conclusion: Respiratory support using the tabletop NIV device was an effective and economical treatment for coronavirus disease 2019 acute respiratory distress syndrome. Further studies are required to assess the appropriate time of initiation for maximal benefits and judicious utilization of resources., (© 2022 The Authors.)

Worldwide, diabetic foot lesions are a major medical, social and economic problem and are the leading cause of hospitalization for patients with diabetes. The organisms causing the ulcers vary from different geographical regions and initiation of empiric antibiotics depends on the prevalence of the local pathogens and their sensitivity pattern, With this background the present study was carried out to evaluate the bacterial diversity and their culture sensitivity patterns in diabetic foot ulcers., Material: Medical records of 65 cases of diabetes mellitus with diabetic foot ulcer admitted to hospital during the period from January 2019 to December 2020 were retrieved from the Medical Records Department. Demographic, clinical profile and microbiological profile with antibiotic sensitivity pattern were analyzed., Observation: Out of 65 cases (n=65), 54 (83.07%) were male and 11 (16.92%) were female. Age range of the patients was from 39 years to 80 years with mean age of 59=/-9.65years. The mean duration of diabetes was 9.4=/-5.7 years and 52.4% had diabetes for more than 10 years. Hypertension was present in 84.5% of the cases. Nearly 62.5% had lesions for 3 months before presenting to the hospital. Peripheral neuropathy was present in all the cases. More than 60% cases were surgically treated with debridement. Osteomyelitis was present in 44.5% cases. Out of 65 cases, 64 were culture positive. Pseudomonas aeruginosa was the leading pathogen in 23.3% cases (n=15), Staphylococcus aureus, E.coli, Acinetobacter baumannii and Klebsiella pneumoniae were isolated in 15.38% cases each followed by Burkholderia cepacia which constituted 10% of all cases. Multiple organisms were isolated in 11 cases (16.92%)., Conclusion: Burkholderia cepacia, which was earlier an uncommon infection in Diabetic foot ulcer, was found in significant (10%) number of cases. This may be due to improper waste management and change in environmental conditions., (© Journal of the Association of Physicians of India 2011.)

Drug resistant malaria represents a challenging health problem in developing countries like India. The failure of drug artemisinin, which is the cornerstone of malaria therapy will rapidly compromise the treatment and prognosis of malaria. Resistance should be suspected if inspite of full treatment with Artesunate Combination Therapy and with no history of vomiting or diarrhoea, there is no clinical or parasitological response in the patient after 72 hours. The emergence of partial artemisinin resistant parasites were previously reported from West Bengal in the form of resistance to drugs. Presence of mutations in molecular markers was reported from different parts of India (Uttar Pradesh,Andhra Pradesh,Odisha and Jharkhand)., Material: We report four cases of complicated malaria in Eastern India between January 2020 and July 2021, with apparent treatment failure with artemisinin drugs. Case1 A 45 old male known diabetic and hypertensive presenting with fever with loose stools since 5 days and seizures since 1 day. Case 2 A 59 year old male patient, known diabetic admitted with fever,black stools and decreased urination for 10 days. Case 3 A 35 year old male patient admitted with fever, headache, vomiting and hematuria for 5 days. Case 4 A 25 year old pregnant female admitted with complaints of bleeding per vaginum since 10 days with fever and vomiting for 6 days. In all cases malaria was confirmed with rapid card test and peripheral smears showed ring forms of plasmodium falciparum.Parasite levels were estimated to be between 30% to 45% in all cases.The patients were treated with injectable artesunate and once they tolerated oral medication they were started on oral artesunate combination therapy., Observation: After 4 days repeat peripheral smears showed persistence of parasites. Organ dysfunction did not subside. Hence Injectable Quinine and clindamycin was started in all cases. On day 7 all obtained microscopic parasite clearance. Cases 2 and 4 attained complete recovery,but the other two cases developed multiorgan dysfunction followed by septic shock and succumbed on 11th and 14th day of admission respectively. We could not confirm artemisinin resistance in any of these cases due to lack of availability of gene testing in our area., Conclusion: This report emphasizes the need for increased surveillance to identify artemisinin resistance in India. It will aid the treating physician for more selective use of drug-combinations which are less likely to foster resistance., (© Journal of the Association of Physicians of India 2011.)

Background: Inhaled corticosteroids are well established for the long-term treatment of inflammatory respiratory diseases such as asthma or chronic obstructive pulmonary disease. They have been investigated for the treatment of coronavirus disease 2019 (COVID-19). The anti-inflammatory action of inhaled corticosteroids might have the potential to reduce the risk of severe illness resulting from hyperinflammation in COVID-19., Objectives: To assess whether inhaled corticosteroids are effective and safe in the treatment of COVID-19; and to maintain the currency of the evidence, using a living systematic review approach., Search Methods: We searched the Cochrane COVID-19 Study Register (which includes CENTRAL, PubMed, Embase, ClinicalTrials.gov, WHO ICTRP, and medRxiv), Web of Science (Science Citation Index, Emerging Citation Index), and the WHO COVID-19 Global literature on coronavirus disease to identify completed and ongoing studies to 7 October 2021., Selection Criteria: We included randomised controlled trials (RCTs) evaluating inhaled corticosteroids for COVID-19, irrespective of disease severity, age, sex, or ethnicity. We included the following interventions: any type or dose of inhaled corticosteroids. We included the following comparison: inhaled corticosteroids plus standard care versus standard care (with or without placebo). We excluded studies examining nasal or topical steroids., Data Collection and Analysis: We followed standard Cochrane methodology. For risk of bias assessment, we used the Cochrane RoB 2 tool. We rated the certainty of evidence using the GRADE approach for the outcomes of mortality, admission to hospital or death, symptom resolution, time to symptom resolution, serious adverse events, adverse events, and infections., Main Results: Inhaled corticosteroids plus standard care versus standard care (with/without placebo) - People with a confirmed diagnosis of moderate-to-severe COVID-19 We found no studies that included people with a confirmed diagnosis of moderate-to-severe COVID-19. - People with a confirmed diagnosis of asymptomatic SARS-CoV-2 infection or mild COVID-19 We included three RCTs allocating 3607 participants, of whom 2490 had confirmed mild COVID-19. We analysed a subset of the total number of participants recruited to the studies (2171, 52% female) as some trials had a platform design where not all participants were allocated to treatment groups simultaneously. The included studies were community-based, recruiting people who were able to use inhaler devices to deliver steroids and relied on remote assessment and self-reporting of outcomes. Most people were older than 50 years and had co-morbidities such as hypertension, lung disease, or diabetes. The studies were conducted in high-income countries prior to wide-scale vaccination programmes. A total of 1057 participants were analysed in the inhaled corticosteroid arm (budesonide: 860 participants; ciclesonide: 197 participants), and 1075 participants in the control arm. No studies included people with asymptomatic SARS-CoV-2 infection. With respect to the following outcomes, inhaled corticosteroids compared to standard care: - may result in little to no difference in all-cause mortality (at up to day 30) (risk ratio (RR) 0.61, 95% confidence interval (CI) 0.22 to 1.67; 2132 participants; low-certainty evidence). In absolute terms, this means that for every nine deaths per 1000 people not receiving inhaled corticosteroids, there were six deaths per 1000 people who did receive the intervention (95% CI 2 to 16 per 1000 people); - probably reduces admission to hospital or death (at up to 30 days) (RR 0.72, 95% CI 0.51 to 0.99; 2025 participants; moderate-certainty evidence); - probably increases resolution of all initial symptoms at day 14 (RR 1.19, 95% CI 1.09 to 1.30; 1986 participants; moderate-certainty evidence); - may reduce the duration to symptom resolution (at up to day 30) (by -4.00 days, 95% CI -6.22 to -1.78 less than control group rate of 12 days; 139 participants; low-certainty evidence); - the evidence is very uncertain about the effect on serious adverse events (during study period) (RR 0.51, 95% CI 0.09 to 2.76; 1586 participants; very low-certainty evidence); - may result in little to no difference in adverse events (at up to day 30) (RR 0.78, 95% CI 0.47 to 1.31; 400 participants; low-certainty evidence); - may result in little to no difference in infections (during study period) (RR 0.88, 95% CI 0.30 to 2.58; 400 participants; low-certainty evidence). As studies did not report outcomes for subgroups (e.g. age, ethnicity, sex), we did not perform subgroup analyses., Authors' Conclusions: In people with confirmed COVID-19 and mild symptoms who are able to use inhaler devices, we found moderate-certainty evidence that inhaled corticosteroids probably reduce the combined endpoint of admission to hospital or death and increase the resolution of all initial symptoms at day 14. Low-certainty evidence suggests that corticosteroids make little to no difference in all-cause mortality up to day 30 and may decrease the duration to symptom resolution. We do not know whether inhaled corticosteroids increase or decrease serious adverse events due to heterogeneity in the way they were reported across the studies. There is low-certainty evidence that inhaled corticosteroids may decrease infections. The evidence we identified came from studies in high-income settings using budesonide and ciclesonide prior to vaccination roll-outs. We identified a lack of evidence concerning quality of life assessments, serious adverse events, and people with asymptomatic infection or with moderate-to-severe COVID-19. The 10 ongoing and four completed, unpublished RCTs that we identified in trial registries address similar settings and research questions as in the current body of evidence. We expect to incorporate the findings of these studies in future versions of this review. We monitor newly published results of RCTs on inhaled corticosteroids on a weekly basis and will update the review when the evidence or our certainty in the evidence changes., (Copyright © 2022 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

BACKGROUND: In the United States, asthma occurs in a vast proportion of children and adolescents. Asthma exacerbation is an acute episodic event typically characterized by difficulty in breathing, chest tightness, coughing, or wheezing. Severe asthma exacerbation can be life-threatening and lead to service utilizations such as hospitalizations and emergency department (ED) visits. Opioid analgesic use can trigger an asthma exacerbation through 2 pharmacological mechanisms. Despite the potential mechanisms, there is lack of empirical evidence to determine the risk of asthma exacerbation and its association with opioid use. OBJECTIVE: To evaluate the risk of asthma exacerbation in children with current asthma receiving an opioid vs a nonopioid analgesic. METHODS: Eligible individuals aged under 18 years with current asthma and receiving an incident analgesic prescription were identified from a large Medicaid managed care database during 2013-2018. Current asthma was defined as receipt of an asthma diagnosis and an antiasthmatic medication in the 12 months before analgesic medication initiation. Asthma exacerbation was defined as a hospitalization or ED visit with asthma as either the primary or secondary diagnosis within 3 days of receipt of an analgesic prescription. A weighted multivariable logistic regression using inverse probability treatment weighting was performed to test the association between use of analgesic medication and risk of asthma exacerbation. RESULTS: This study included 13,359 children with current asthma who filled either an incident opioid (n = 5,363, 40.1%) or nonopioid analgesic (n = 7,996, 59.9%) prescription. Asthma exacerbation was observed in 24 (0.5%) opioid analgesic recipients and 22 (0.3%) nonopioid analgesic recipients within 3 days of analgesic initiation. Weighted logistic regression results showed that children receiving opioid analgesics (adjusted odds ratio = 1.6, 95% CI = 0.9-2.9) did not have a statistically significantly higher risk of asthma exacerbation than their nonopioid analgesic recipient counterparts in the propensity score-weighted multivariable analysis. CONCLUSIONS: Asthma exacerbation associated with analgesic use in children with current asthma was an uncommon event, and the risk was comparable among children receiving opioid vs nonopioid analgesics. DISCLOSURES: This study was supported and funded by the Agency for Healthcare Research and Quality (AHRQ), Project Number: 1R03HS026790-01A1. The study content was solely the responsibility of the authors, and AHRQ had no role in the design and conduct of the study. The authors have nothing to disclose.

Behavioral Health (BH) screening is critical for early diagnosis and treatment of pediatric mental disorders. The objective of this study was to assess the impact of geographic access to primary care providers (PCP) on pediatric BH screening in children with different race/ethnicity. A retrospective cohort study was conducted using the 2013-2016 administrative claims data from a large pediatric Medicaid Managed Care Plan that have been linked to 2010 US Census data and the 2017 National Provider Identifier (NPI) Registry. Geographic access was defined as the actual travel distance to nearest PCP and the PCP density within 10-mile travel radius from each individual's residence. Stratified multivariate logistic regression was conducted to examine the association between the geographic access to PCP and the likelihood of receiving screening for behavioral disorders within each racial/ethnic group. BH screening rate was 12.6% among 402,655 children and adolescents who met the inclusion criteria. Multivariable analysis stratified by individual race/ethnicity revealed that Hispanic and Black children were more vulnerable to the geographic access barriers than their non-Hispanic White counterparts. The increase in travel distance to the nearest PCP was negatively associated with screening uptake only among Hispanics (10-20 miles vs. 0-10 miles: OR = 0.78, 95% CI [0.71-0.86]; 20-30 miles vs. 0-10 miles: OR = 0.35, 95% CI [0.23-0.54]). In a subgroup that had access to at least one PCP within 10 miles of travel distance, the variation in PCP density had a greater impact on the screening uptake among Hispanics and Blacks than that in non-Hispanic Whites., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Purpose: Opioid analgesics are frequently dispensed in children despite its known risk in children with a compromised airway function. The objectives of the study were to assess the prevalence of opioid analgesic dispensing in children with current asthma and to identify patient and prescriber factors associated with the dispensing of opioid versus non-opioid analgesics., Methods: Children <18 years of age, having current asthma and receiving an incident analgesic prescription were identified from a large Medicaid Managed Care Plan during years 2013 through 2018. Current asthma was defined as both receiving an asthma diagnosis and filling an anti-asthmatic medication during the 12-month period prior to the analgesic medication initiation. A scoring algorithm was applied to associate analgesic prescription with procedures and diagnoses according to perceived need for analgesia and time proximity., Results: Of the 9529 children meeting the inclusion criteria, 2681 (28.1%) received an opioid prescription. Opioid analgesic dispensing was most common among children who had an outpatient surgery/procedure (29.4%), trauma (19.4%) dental procedure (18.4%), and respiratory infection (10.6%). Multivariable analysis indicated that non-Hispanic Black (AOR: 0.39[0.3-0.5]) and Hispanic (AOR: 0.51[0.4-0.6]) children were less likely to receive an opioid analgesic compared to their non-Hispanic White counterparts. Children with prior history of asthma-related emergency department visit (AOR: 1.24[1.0-1.5]) and short acting beta agonist overuse (AOR: 1.33[1.1-1.7]) were more likely to fill an opioid analgesic prescription than those without., Conclusion: Opioid analgesics are frequently dispensed to children with asthma. A higher dispensing rate was observed among non-Hispanic White children and among those with a history of uncontrolled asthma., (© 2021 John Wiley & Sons Ltd.)

Desmoplastic small round cell tumor (DSRCT) is a high-grade round cell sarcoma that typically arises in the abdominopelvic cavity of young males, co-expresses keratins and desmin, and carries a pathognomonic EWSR1-WT1 gene fusion. The EWSR1-WT1 gene fusion is generally considered specific for DSRCT, although there are two reports of this fusion in tumors otherwise lacking features of DSRCT. We report three female genital tract tumors with EWSR1-WT1 fusions but showing morphologic and immunohistochemical features incompatible with DSRCT. The tumors occurred in the uterine cervix, uterine corpus/ovaries, and vagina, respectively, of 46, 30, and 20-year-old women. Two tumors consisted of a sheet-like to fascicular proliferation of relatively uniform spindled to occasionally more epithelioid cells arrayed about thick-walled, hyalinized, and capillary-sized vessels, with distinctive areas of pseudovascular change, and absence of desmoplastic stroma. The third tumor resembled a monomorphic spindle cell sarcoma with necrosis. All had diffuse desmin and variable but more limited keratin expression, two of three expressed smooth muscle actin, and all were negative for h-caldesmon, CD10, estrogen receptor, myogenin, N-terminus WT-1, and S100 protein. One patient received neoadjuvant chemotherapy and radiation therapy followed by resection and is disease-free 42 months after diagnosis. Another patient was managed by resection only and is disease-free 9 months after initial diagnosis. The remaining patient recently underwent resection of multifocal pelvic disease. Comprehensive differential gene expression analysis on two tumors compared to two classic DSRCTs with known EWSR1-WT1 fusions resulted in 1726 genes that were differentially expressed (log2 fold change >2 or < -2) and statistically significant (FDR < 5%). In combination with previous reports, our findings suggest pleiotropy of the EWSR1-WT1 fusion is possible and not limited to DSRCT. Subsets of non-DSRCT EWSR1-WT1 positive tumors may represent discrete entities, but further study is necessary., (© 2021. The Author(s), under exclusive licence to United States & Canadian Academy of Pathology.)

Polymorphous low-grade neuroepithelial tumor of the young (PLNTY) is a recently described epileptogenic tumor characterized by oligodendroglioma-like components, aberrant CD34 expression, and frequent mitogen-activated protein kinase (MAPK) pathway activation. We molecularly profiled 13 cases with diagnostic histopathological features of PLNTY (10 female; median age, 16 years; range, 5-52). Patients frequently presented with seizures (9 of 12 with available history) and temporal lobe tumors (9 of 13). MAPK pathway activating alterations were identified in all 13 cases. Fusions were present in the 7 youngest patients: FGFR2-CTNNA3 (n = 2), FGFR2-KIAA1598 (FGFR2-SHTN1) (n = 1), FGFR2-INA (n = 1), FGFR2-MPRIP (n = 1), QKI-NTRK2 (n = 1), and KIAA1549-BRAF (n = 1). BRAF V600E mutation was present in 6 patients (17 years or older). Two fusion-positive cases additionally harbored TP53/RB1 abnormalities suggesting biallelic inactivation. Copy number changes predominantly involving whole chromosomes were observed in all 10 evaluated cases, with losses of chromosome 10q occurring with FGFR2-KIAA1598 (SHTN1)/CTNNA3 fusions. The KIAA1549-BRAF and QKI-NTRK2 fusions were associated respectively with a 7q34 deletion and 9q21 duplication. This study shows that despite its name, PLNTY also occurs in older adults, who frequently show BRAF V600E mutation. It also expands the spectrum of the MAPK pathway activating alterations associated with PLNTY and demonstrates recurrent chromosomal copy number changes consistent with chromosomal instability., (© 2021 American Association of Neuropathologists, Inc. All rights reserved.)

Background: Smartphones and mobile applications have seen a surge in popularity in recent years, a pattern that has also been reflected in the health care system. Despite increased reliance among clinicians however, limited research has been conducted on the uptake and impact of smartphone usage in medical practice, especially outside the Western world., Objective: This study aimed to identify the usage of smartphones and medical apps by doctors in the clinical setting in 2 culturally distinct countries: King Hamad University Hospital (KHUH), Bahrain and Queen Mary Hospital (QMH), Hong Kong., Methods: A cross-sectional, comparative study was conducted where doctors in both hospitals were asked to take part in a 15-item online survey. The questions were categorized into the following groups: demographics of the study population, ownership and main use of smartphones, number and names of medical apps currently owned, rating usage of smartphones for medical purposes, time spent on a smartphone related to clinical use, clinical reliance on smartphones, and views on further integration of smartphones. The results were then tabulated and analyzed using SPSS Statistics 25 for Mac (IBM Corp Inc, Armonk, NY)., Results: A total of 200 doctors were surveyed, with a total of 99.0% (99/100) of the doctors owning a smartphone in both KHUH and QMH; 58% (57/99) and 55% (54/99) of the doctors from KHUH and QMH, respectively, identified communication as their main use of smartphones in the clinical setting (P=.004). Doctors from KHUH were likely to spend more time on medical apps than doctors from QMH (P=.002). According to the overall results of both hospitals, 48% (32/67) of the junior doctors claimed high reliance on smartphones, whereas only 32.3% (41/127) of the senior doctors said the same (P=.03). Of doctors in KHUH and QMH, 78.0% (78/100) and 69.0% (69/100), respectively, either strongly agreed or agreed that smartphones need to be integrated into the clinical setting. In terms of preferences for future apps, 48% (48/100) and 56% (56/100) of the doctors in KHUH and QMH, respectively, agreed that more medical applications need to be created in order to support smartphone use in the clinical setting., Conclusions: These results suggest a substantial acceptance of smartphones by doctors in the clinical setting. It also elicits the need to establish policies to officially integrate smartphone technology into health care in accordance with ethical guidelines. More emphasis should be placed on creating medical applications that aid health care professionals in attaining their information from accurate sources and also regulate a system to monitor the usage of mobile devices within hospitals to prevent a breach of patient privacy and confidentiality., (©Anjali Ajay Nair, Samreen Afroz, Bushra Urooj Ahmed, Uzma Urooj Ahmed, Chi Chung Foo, Hind Zaidan, Martin Corbally. Originally published in JMIR mHealth and uHealth (https://mhealth.jmir.org), 10.05.2021.)

Tumor mutation burden (TMB) is an emerging biomarker of immunotherapy response. RNA sequencing in FFPE tissue samples was used for determining TMB in microsatellite-stable (MSS) and microsatellite instability-high (MSI-H) tumors in patients with colorectal or endometrial cancer. Tissue from tumors and paired normal tissue from 46 MSI-H and 12 MSS cases were included. Of the MSI-H tumors, 29 had defective DNA mismatch-repair mutations, and 17 had MLH1 promoter hypermethylation. TMB was measured using the expressed somatic nucleotide variants (eTMB). A method of accurate measurement of eTMB was developed that removes FFPE-derived artifacts by leveraging mutation signatures. There was a significant difference in the median eTMB values observed between MSI-H and MSS cases: 27.3 versus 6.7 mutations/megabase (mut/Mb) (P = 3.5 × 10 -9 ). Among tumors with defective DNA-mismatch repair, those with mismatch-repair mutations had a significantly higher median eTMB than those with hypermethylation: 28.1 versus 17.5 mut/Mb (P = 0.037). Multivariate analysis showed that MSI status, tumor type (endometrial or colorectal), and age were significantly associated with eTMB. Additionally, using whole-exome sequencing in a subset of these patients, it was determined that DNA TMB correlated well with eTMB (Spearman correlation coefficient, 0.83). These results demonstrate that RNA sequencing can be used for measuring eTMB in FFPE tumor specimens., (Copyright © 2021 Association for Molecular Pathology and American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Importance: The American Academy of Ophthalmology (AAO) indicated that urgent or emergent vitreoretinal surgical procedures should continue during the coronavirus disease 2019 (COVID-19) pandemic. Although decreases in the frequency of critical procedures have been reported outside the field of ophthalmology, analyses are limited by volume, geography, and time., Objective: To evaluate whether the frequency of ophthalmic surgical procedures deemed urgent or emergent by the AAO changed across the United States during the COVID-19 pandemic., Design, Setting, and Participants: Vitreoretinal practices from 17 institutions throughout the US participated in this multicenter cross-sectional study. The frequency of 11 billed vitreoretinal Current Procedural Terminology (CPT) codes across respective weeks was obtained from each practice between January 1, 2019, and May 31, 2020. Data were clustered into intravitreal injections (code 67028), lasers and cryotherapy (codes 67141, 67145, and 67228), retinal detachment (RD) repairs (codes 67107, 67108, 67110, and 67113), and other vitrectomies (codes 67036, 67039, and 67040). Institutions were categorized by region (Northeast, Midwest, South, and West Coast), practice setting (academic [tax-exempt] or private [non-tax-exempt]), and date of respective statewide stay-at-home orders., Main Outcomes and Measures: Nationwide changes in the frequency of billing for urgent or emergent vitreoretinal surgical procedures during the COVID-19 pandemic., Results: A total of 526 536 CPT codes were ascertained: 483 313 injections, 19 257 lasers or cryotherapy, 14 949 RD repairs, and 9017 other vitrectomies. Relative to 2019, a weekly institutional decrease in injections was observed from March 30 to May 2, 2020, with a maximal 38.6% decrease (from a mean [SD] of 437.8 [436.3] to 273.8 [269.0] injections) from April 6 to 12, 2020 (95% CI, -259 to -69 injections; P = .002). A weekly decrease was also identified that spanned a longer interval, at least until study conclusion (March 16 to May 31, 2020), for lasers and cryotherapy, with a maximal 79.6% decrease (from a mean [SD] of 6.6 [7.7] to 1.5 [2.0] procedures) from April 6 to 12, 2020 (95% CI, -6.8 to -3.3 procedures; P < .001), for RD repairs, with a maximal 59.4% decrease (from a mean [SD] of 3.5 [4.0] to 1.6 [2.2] repairs) from April 13 to 19, 2020 (95% CI, -2.7 to -1.4 repairs; P < .001), and for other vitrectomies, with a maximal 84.3% decrease (from a mean [SD] of 3.0 [3.1] to 0.4 [0.8] other vitrectomies) from April 6 to 12, 2020 (95% CI, -3.3 to -1.8 other vitrectomies; P < .001). No differences were identified by region, setting, or state-level stay-at-home order adjustment., Conclusions and Relevance: Although the AAO endorsed the continued performance of urgent or emergent vitreoretinal surgical procedures, the frequency of such procedures throughout the country experienced a substantial decrease that may persist after the COVID-19 pandemic's initial exponential growth phase. This decrease appears independent of region, setting, and state-level stay-at-home orders. It is unknown to what extent vitreoretinal intervention would have decreased without AAO recommendations, and how the decrease is associated with outcomes. Although safety is paramount during the COVID-19 pandemic, practices should consider prioritizing availability for managing high-acuity conditions until underlying reasons for the reduction are fully appreciated.

Purpose: The purpose was to establish the position of the fovea centralis to the optic nerve via en-face, near-infrared spectral domain optical coherence tomography (NIR-OCT) in healthy patients. This may shed light on physiological variability and be used for studying subtle cases of foveal ectopia in macular pathology and after retinal detachment., Methods: SD-OCT data of 890 healthy eyes were retrospectively analyzed. Exclusion criteria included axial myopia causing tilting of the optic disc, peripapillary atrophy >1/3 the width of the disc, macular images excluding greater than half of the optic disc, and patients unable to maintain vertical head positioning. Two independent reviewers measured the horizontal and vertical distance from the fovea to the optic disc center and optic disc diameter via cross-sectional and en-face scanning laser ophthalmoloscopy OCT imaging., Results: 890 eyes were included in the study. The right and left eyes differed in the horizontal distance from the fovea to the disc center (4359 vs. 4248 µm, P < 0.001) and vertical distance from the fovea to the disc center (464 µm vs. 647, P < 0.001). This corresponded to a smaller angle between the right and left eyes (6.07° vs. 8.67°, P < 0.001). Older age was associated with a larger horizontal (P = 0.008) and vertical distance (0.025). These differences persisted after correcting for axial length in the 487 patients with axial-length data., Conclusions: This study compares the position of the fovea centralis among individuals without macular pathology on a micron level basis. The significant variability between right and left eyes indicates that contralateral eye evaluation cannot be reliably used. Rather, true foveal ectopia requires assessments of preoperative and postoperative NIR-OCT scans. This finding is relevant to retinal detachment cases and evaluation of subtle foveal ectopia., Translational Relevance: This finding is relevant to retinal detachment cases and evaluation of subtle foveal ectopia.