A 59-year-old male was diagnosed with JAK2-positive Polycythemia Vera. Subsequently, further lab testing revealed elevated ferritin and iron saturation. Genetic testing for HFE gene mutation screen revealed that the patient was positive for heterozygous C282Y mutation. The patient was ultimately diagnosed with both Polycythemia Vera and Hereditary Hemochromatosis.

Ecologists often rely on observational data to understand causal relationships. Although observational causal inference methodologies exist, model selection based on information criterion (e.g., AIC) remains a common approach used to understand ecological relationships. However, such approaches are meant for predictive inference and is not appropriate for drawing causal conclusions. Here, we highlight the distinction between predictive and causal inference and show how model selection techniques can lead to biased causal estimates. Instead, we encourage ecologists to apply the backdoor criterion, a graphical rule that can be used to determine causal relationships across observational studies.

COVID-19 vaccines and the role of other potential allergenic components different from PEG. A reply to: “Other excipients than PEG might cause serious hypersensitivity reactions in COVID-19 vaccines”

Across the globe, ecological communities are confronted with multiple global environmental change drivers, and they are responding in complex ways ranging from behavioural, physiological, and morphological changes within populations to changes in community composition and food web structure with consequences for ecosystem functioning. A better understanding of global change-induced alterations of multitrophic biodiversity and the ecosystem-level responses in terrestrial ecosystems requires holistic and integrative experimental approaches to manipulate and study complex communities and processes above and below the ground. We argue that mesocosm experiments fill a critical gap in this context, especially when based on ecological theory and coupled with microcosm experiments, field experiments, and observational studies of macroecological patterns. We describe the design and specifications of a novel terrestrial mesocosm facility, the iDiv Ecotron. It was developed to allow the setup and maintenance of complex communities and the manipulation of several abiotic factors in a near-natural way, while simultaneously measuring multiple ecosystem functions. To demonstrate the capabilities of the facility, we provide a case study. This study shows that changes in aboveground multitrophic interactions caused by decreased predator densities can have cascading effects on the composition of belowground communities. The iDiv Ecotrons technical features, which allow for the assembly of an endless spectrum of ecosystem components, create the opportunity for collaboration among researchers with an equally broad spectrum of expertise. In the last part, we outline some of such components that will be implemented in future ecological experiments to be realized in the iDiv Ecotron. Key words: food webs, biodiversity and ecosystem functioning, mesocosms, biotic interactions, lysimeters, climate chambers

Guidelines state there is no Abstract for Correspondence: Our Experience

Aortic valve and root replacements require an in-depth understanding of the aortic root and annulus. Both structures can be asymmetric at times, and this needs to be recognized and taken into consideration when peforming valve-sparing operations or other root-replacement procedures. Moreover, the geometry of the aortic annulus can be altered, and when performing an aortic root replacement this can distort the geometry of a neo-aortic valve for instance, and lead to valve dysfunction, which is difficult to reverse. We are describing an altered aortic annulus, which required modification through annulus elevation before proceeding with aortic root replacement with a graft-reinforced pulmonary-autograft.

Progressive knowledge of allergenic structures resulted in a broad availability of allergenic molecules for diagnosis. Component resolved diagnosis allowed a better understanding of patient sensitization patterns, facilitating allergen immunotherapy decisions. In parallel to the discovery of allergenic molecules, there was a progressive development of a regulation framework that affected both in vitro diagnostics and Allergen Immunotherapy products. With a progressive understanding of underlying mechanisms associated to Allergen immunotherapy and an increasing experience of application of molecular diagnosis in daily life, we focus in analyzing the evidences of the value provided by molecular allergology in daily clinical practice, with a focus on Allergen Immunotherapy decissions.

Benzalkonium chloride (BAC) is a quaternary ammonium compound commonly employed as a preservative in several multidose eye drops. Its use is associated with several adverse events, particularly when used chronically. Topically instilled BAC acts not only on superficial structures but also reaches deeper tissues (trabecular meshwork, optic nerve) and can be deleterious in patient under chronic treatment. In glaucomatous patients, BAC is the primary cause of ocular surface disease (OSD), and it can lead to significant morbidity, influence treatment compliance, quality of life, and surgical outcomes. Clinical and experimental evidence demonstrates that BAC causes instability of the tear layer, loss of goblet cells, apoptosis, subclinical neuroinflammation, and antibiotic resistance. Considering the validity of the alternative formulations (alternative preservatives or preservative-free formulations) it is unreasonable to persist in using such toxic compounds and, perhaps it is time for a moratorium on the use of BAC in eye drops.

DECIPHER (https://www.deciphergenomics.org) is a free web platform for sharing anonymised phenotype-linked variant data from rare disease patients. Its dynamic interpretation interfaces contextualise genomic and phenotypic data to enable more informed variant interpretation, incorporating international standards for variant classification. DECIPHER supports almost all types of germline and mosaic variation in the nuclear and mitochondrial genome: sequence variants, short tandem repeats, copy-number variants and large structural variants. Patient phenotypes are deposited using Human Phenotype Ontology (HPO) terms, supplemented by quantitative data, which is aggregated to derive gene-specific phenotypic summaries. It hosts data from >250 projects from ~40 countries, openly sharing ~40,000 patient records containing >51,000 variants and >172,000 phenotype terms. The rich phenotype-linked variant data in DECIPHER drives rare disease research and diagnosis by enabling patient matching within DECIPHER and with other resources, and has been cited in >2,600 publications. In this paper, we describe the types of data deposited to DECIPHER, the variant interpretation tools, and patient matching interfaces which make DECIPHER an invaluable rare disease resource.

Anode-free Li-metal batteries (AFLBs) are of significant interest to energy storage industries due to their intrinsically high energy. However, the accumulative Li dendrites and dead Li continuously consume active Li during cycling. That results in a short lifetime and low Coulombic efficiency (CE) of AFLBs. Introducing effective electrolyte additives can improve the Li deposition homogeneity and solid-state interphase (SEI) stability for AFLBs. Herein, we reveal that introducing dual additives, composed of LiAsF6 and FEC, into a commercial carbonate electrolyte will boost the cycle life and average CE of NCM||Cu AFLBs. The NCM||Cu AFLBs with the dual additives exhibit a capacity retention of about 75% after 50 cycles, much higher than those with bare electrolytes (35%). The average CE of the NCM||Cu AFLBs with additives can maintain 98.3% over 100 cycles. In contrast, the average CE without additives rapidly decline to 97% after only 50 cycles. In situ Raman measurements reveal that the prepared dual additives facilitate denser and smoother Li morphology during Li deposition. The dual additives significantly suppress the Li dendrite growth, enabling stable SEI formation on anode and cathode surfaces. Our results provide a broad view of developing low-cost and high-effective functional electrolytes for high-energy and long-life AFLBs.

The large majority of germline alterations identified in the DNA mismatch repair (MMR) gene PMS2, a low-penetrance gene for the cancer predisposition Lynch Syndrome (LS, OMIM 120435), represent variants of unknown significance (VUS). The inability to assess pathogenicity of such VUS interferes with personalized healthcare. The complete in vitro MMR activity (CIMRA) assay, that only requires sequence information on the VUS, provides a functional analysis-based tool suited for VUS classification. To derive a formula that translates CIMRA assay results for PMS2 VUS into the odds of pathogenicity (OddsPath), we used a set of clinically classified PMS2 variants, supplemented by inactivating variants generated by an in cellulo genetic screen, as proxies for pathogenic variants. Validation of this OddsPath revealed very high predictive values for PMS2 VUS. We conclude that this OddsPath provides an integral metric that, similar to the other, higher penetrance, MMR proteins MSH2, MLH1 and MSH6, can be incorporated into the upcoming criteria for MMR gene VUS classification of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP). This will represent a seminal step forward in enabling personalized healthcare for individuals suspected of LS and their relatives.

Guillain- Barre Syndrome (GBS), an autoimmune neurological disease of peripheral nerves has been causally associated with COVID-19 vaccination in adults. However, no such report has been published so far in children. We describe a 13-year old female child who presented to emergency department with complaints of bilateral upper limb, lower limb and truncal weakness over three days following first dose of recombinant protein subunit COVID-19 vaccine (Corbevax). Clinical examination and nerve conduction studies showed pure motor axonal polyneuropathy with absent compound muscle action potential (CMAP) in all sampled nerves of upper and lower limbs which was consistent with the diagnosis of GBS after ruling out possible alternative aetiologies. A temporal association between first dose of protein subunit COVID-19 vaccine administered a day prior and symptom onset was noted. The causality assessment using World Health Organization (WHO) tool for adverse event following immunization (AEFI) assessment indicated vaccine-product related reaction categorized as A1. Patient’s clinical condition improved after seven sessions of plasmapheresis. The purpose of this report is to create awareness among the health care professionals about COVID-19 vaccine induced GBS in children as early diagnosis and management can be critical in avoiding complications and improving patient outcomes.

Purpose:There have been concerted efforts towards cataloging rare and deleterious variants in different world population using high throughput genotyping and sequencing based methods. The Indian populations are underrepresented or its information w.r.t. clinically relevant variants are sparse in public datasets. The aim of this study was to estimate the burden of monogenic disease causing variants in Indian populations. Towards this, we have assessed the frequency profile of monogenic phenotype associated ClinVar variants. Methods: The study utilized genotype dataset (global-screening-array, Illumina) from 2795 individuals (multiple in-house genomics cohorts) representing diverse ethnic and geographically distinct Indian populations. Results: Of the analyzed variants from GSA, ~12% were found to be informative and were either not known earlier or underrepresented in public databases in terms of their frequencies. These variants were linked to disorders, viz. Inborn-errors of Metabolism, Monogenic-diabetes, hereditary cancers and various other hereditary conditions. We have also shown that our study cohort is genetically better representatives of Indian populations than its representation in1000 genome project (South-Asians). Conclusion: We have created a database, ClinIndb [(http://clinindb.igib.res.in) and (https://databases.lovd.nl/shared/variants?search_owned_by_=%3D%22Mohamed%20Faruq%22)], to help clinicians and researchers in diagnosis, counseling and development of appropriate genetic screening tools relevant to the Indian populations and Indians living abroad.

Few seroprevalence studies were performed on coronavirus disease (COVID-19) in Nepal. Here, we aimed to estimate seroprevalence and assess risk factors for infection in the general population of Nepal by conducting two rounds of sampling. The first round in October 2020 at the peak of the first generalized wave of COVID-19 and the second round in July-August 2021 following the peak of the wave caused by the delta variant of SARS-COV-2. We used cross-sectional probability-to-size (PPS)-based multistage cluster sampling to estimate the seroprevalence in the general population of Nepal at the national and provincial levels. We tested for the presence of anti-SARS-CoV-2 total antibody using the WANTAI SARS-CoV-2 Ab ELISA kit. In Round 1, the overall national seroprevalence was 14.4%, with provincial estimates ranging from 5.3% in Sudurpaschim to 27.3% in Madesh province. In Round 2, the estimated national seroprevalence was 70.7%, with the highest estimated seroprevalence in Madesh Province (84.8%) and the lowest in the Gandaki Province (62.9%). Seroprevalence was comparable between males and females (Round 1, 15.8% vs 12.2% and Round 2, 72.3% vs. 68.7%). The seroprevalence in the ecozones—terai, hills, and mountains—was 76.3%, 65.3%, and 60.5% in Round 2 and 17.7%, 11.7%, and 4.6% in Round 1, respectively. In Nepal, COVID-19 vaccination was introduced in January, 2021. At the peak of the first generalized wave of COVID-19, most of the population of Nepal remained unexposed to SARS-COV-2 and towards the end of the second generalized wave in April 2021, two-thirds of the population was exposed.

TITLE PAGE Title: Letter to the Editor: Minimally invasive aortic valve repair using geometric ring annuloplastyArticle type: Letter to the editorCorrespondence : 1. Bilawal NadeemContact: +92-3137562580 Email: [email protected]: King Edward Medical University, LahoreAddress: Mianwal Ranjha Dera Allah Wadhaya Tehsil and District Mandi Bahauddin, 50400Words count: 418Conflict of interest: noneDisclosure: noneFunding: none

Various neurological symptoms have been reported as the side effect of COVID-19 vaccines. Vaccine-associated acute Cerebellitis is very uncommon. Here, we report a 45-year-old female with acute onset cerebellitis, beginning 10 days after administration of Sinopharm vaccine. Her CSF COVID-19 PCR was found to be positive, with no pulmonary symptoms.

Inhaled nebulised unfractionated heparin (UFH) has a strong scientific and biological rationale that warrants urgent investigation of its therapeutic potential in patients with COVID-19. UFH has antiviral effects and prevents the SARS-CoV-2 virus’ entry into mammalian cells. In addition, UFH has significant anti-inflammatory and anti-coagulant properties, which limit progression of lung injury and vascular pulmonary thrombosis. Methods and intervention The INHALEd nebulised unfractionated HEParin for the treatment of hospitalised patients with COVID-19 (INHALE-HEP) meta-trial is a prospective individual patient data analysis of on-going randomised controlled trials and early phase studies. Individual studies are being conducted in multiple countries. Participating studies randomise adult patients admitted to the hospital with confirmed SARS-CoV-2 infection, who do not require immediate mechanical ventilation, to inhaled nebulised UFH or standard care. All studies collect a minimum core dataset. The primary outcome for the meta-trial is intubation (or death, for patients who died before intubation) at day 28. The secondary outcomes are oxygenation, clinical worsening and mortality, assessed in time-to-event analyses. Individual studies may have additional outcomes. Analysis We use a Bayesian approach to monitoring, followed by analysing individual patient data, outcomes and adverse events. All analyses will follow the intention-to-treat principle, considering all participants in the treatment group to which they were assigned, except for cases lost to follow-up or withdrawn. Trial registration, ethics and dissemination The meta-trial is registered at ClinicalTrials.gov ID NCT04635241. Each contributing study is individually registered and has received approval of the relevant ethics committee or institutional review board.

Background: Multiple myeloma accounts for over 15% of hematological malignancies. In attempt to tackle this malady, the FDA approved four drugs in 2015 which has propagated further development of new anti-multiple myeloma since. However, the health safety of these new agents is still ill-defined. The aim of this study is to delineate the cardiovascular adverse events of these drugs. Methods: We searched the cardiac adverse events of the newly approved FDA drugs since 2015 using the U.S. Food and Drug Administration Adverse Events Reporting System database (FAERS). We calculated the reporting odds ratio (ROR) with 95% confidence for four drugs that have the highest incidence of cardiovascular adverse events. Results: Among the medications that have approved for MM Between 2015-2020, four novel drugs showed the highest incidence of cardiotoxicity. ROR (95% CI) for atrial fibrillation due to elotuzumab, Ixazomib, daratumumab, and panobinostat compared to other FAERS drugs was 5.8 (4.4-7.7), 1.9 (1.5-2.3), 4.8 (4.2-5.6), and 5.7 (4.1-8.1), respectively. The ROR (95% CI) for cardiac failure was 8.2 (6.4-10.5), 4.7 (4.1-5.4), 5.8 (4.9-6.7), and 5.6 (3.8-8.1) and ROR (95% CI) for coronary disease was 2.7 (1.9-3.9), 2.7 (2.3-3.2), 2.3 (1.9-2.8), and 4.6 (3.2-6.6) due to elotuzumab, Ixazomib, daratumumab, and panobinostat versus all other drugs in FAERS. Conclusions: Our results demonstrated that the newly approved antimyeloma therapy (elotuzumab, Ixazomib, daratumumab, panobinostat) are significantly associated previously unknow cardiotoxicity. These results warrant further studies and highlight the importance of considering the cardiac history of patients with multiple myeloma when utilizing these novel agents.