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Suicide remains a leading cause of death in the United States, and recent data suggest suicide deaths involving opioids are increasing. Given unprecedented increases in drug-poisoning deaths, suicidality, and suicide deaths in recent years, an updated examination of the trends in suicide deaths involving opioids is warranted. In this descriptive epidemiologic analysis, we leverage final and provisional mortality data from the US Centers for Disease Control and Prevention's WONDER database to examine trends in suicide deaths involving opioid poisoning from 1999 to 2021 by biological sex. Results reveal complex changes over time: the number and age-adjusted rate of suicide deaths involving opioid poisoning among male and female residents tended to track together, and both increased through 2010, but then diverged, with the number and rate of suicide deaths involving opioid poisoning among female residents outpacing that of male residents. However, the number and rate of suicide deaths involving opioid poisoning among male residents then began to stabilize, while that of female residents declined, closing the sex-based gap. Across all years of data, the proportion of suicide deaths that involved opioid poisoning was consistently higher among female decedents (5.8%-11.0%) compared with male decedents (1.4%-2.8%). Findings have implications for improved suicide prevention and harm reduction efforts. This article is part of a Special Collection on Mental Health., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objective: Intellectual disability is often the outcome of neurodevelopmental disorders and is characterized by significant impairments in intellectual and adaptive functioning. X-linked intellectual disability (XLID) is a subset of these disorders caused by genetic defects on the X chromosome, affecting about 2 out of 1,000 males. In syndromic form, it leads to a broad range of cognitive, behavioral, ocular, and physical disabilities., Methods: Employing exome or genome sequencing, here we identified 4 missense variants (c.475C > G; p.H159D, c.1373C > A; p.T458N, and c.1585G > A; p.E529K, c.953C > T; p.S318L) and a putative truncating variant (c.1413_1414del; p.Y471*) in the SRPK3 gene in 9 XLID patients from 5 unrelated families. To validate SRPK3 as a novel XLID gene, we established a knockout (KO) model of the SRPK3 orthologue in zebrafish., Results: The 8 patients ascertained postnatally shared common clinical features including intellectual disability, agenesis of the corpus callosum, abnormal eye movement, and ataxia. A ninth case, ascertained prenatally, had a complex structural brain phenotype. Together, these data indicate a pathological role of SRPK3 in neurodevelopmental disorders. In post-fertilization day 5 larvae (free swimming stage), KO zebrafish exhibited severe deficits in eye movement and swim bladder inflation, mimicking uncontrolled ocular movement and physical clumsiness observed in human patients. In adult KO zebrafish, cerebellar agenesis and behavioral abnormalities were observed, recapitulating human phenotypes of cerebellar atrophy and intellectual disability., Interpretation: Overall, these results suggest a crucial role of SRPK3 in the pathogenesis of syndromic X-linked intellectual disability and provide new insights into brain development, cognitive and ocular dysfunction in both humans and zebrafish. ANN NEUROL 2024;96:914-931., (© 2024 The Author(s). Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Male infertility is a complex multifactorial reproductive disorder with highly heterogeneous phenotypic presentations. Azoospermia is a medically non-manageable cause of male infertility affecting ∼1% of men. Precise etiology of azoospermia is not known in approximately three-fourth of the cases. To explore the genetic basis of azoospermia, we performed whole exome sequencing in two non-obstructive azoospermia affected siblings from a consanguineous Pakistani family. Bioinformatic filtering and segregation analysis of whole exome sequencing data resulted in the identification of a rare homozygous missense variant (c.962G>C, p. Arg321Thr) in YTHDC2, segregating with disease in the family. Structural analysis of the missense variant identified in our study and two previously reported functionally characterized missense changes (p. Glu332Gln and p. His327Arg) in mice showed that all these three variants may affect Mg 2+ binding ability and helicase activity of YTHDC2. Collectively, our genetic analyses and experimental observations revealed that missense variant of YTHDC2 can induce azoospermia in humans. These findings indicate the important role of YTHDC2 deficiency for azoospermia and will provide important guidance for genetic counseling of male infertility., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background and Aims: The advent of 3D printing has revolutionized plastic surgery and prosthetic devices, providing personalized solutions for patients with traumatic injuries, deformities, and appearance-related conditions. This review offers a comprehensive overview of 3D printing's applications, advantages, limitations, and future prospects in these fields., Methods: A literature search was conducted in PubMed, Google Scholar, and Scopus for studies on 3D printing in plastic surgery., Results: 3D printing has significantly contributed to personalized medical interventions, with benefits like enhanced design flexibility, reduced production time, and improved patient outcomes. Using computer-aided design (CAD) software, precise models tailored to a patient's anatomy can be created, ensuring better fit, functionality, and comfort. 3D printing allows for intricate geometries, leading to improved aesthetic outcomes and patient-specific prosthetic limbs and orthoses. The historical development of 3D printing, key milestones, and breakthroughs are highlighted. Recent progress in bioprinting and tissue engineering shows promising applications in regenerative medicine and transplantation. The integration of AI and automation with 3D printing enhances surgical planning and outcomes. Emerging trends in patient-specific treatment planning and precision medicine are potential game-changers. However, challenges like technical considerations, economic implications, and ethical issues exist. Addressing these challenges and advancing research in materials, design processes, and long-term outcomes are crucial for widespread adoption., Conclusion: The review underscores the increasing adoption of 3D printing in healthcare and its impact on plastic surgery and prosthetic devices. It emphasizes the importance of evaluating the current state and addressing knowledge gaps through future research to foster further advancements., Competing Interests: The authors declare no conflict of interest., (© 2024 The Author(s). Health Science Reports published by Wiley Periodicals LLC.)

Background: Diabetes, especially Type-2 diabetes mellitus (T2DM), poses a significant global health challenge. Complementary and alternative medicine, such as Unani Medicine, has gained popularity for managing T2DM., Objective: This systematic review aims to evaluate the efficacy and safety of Unani medications in T2DM management., Methods: A comprehensive literature search was conducted across multiple electronic databases to identify relevant clinical trials. Inclusion criteria focused on original research articles examining the efficacy and safety of Unani medications in patients with T2DM. Data extraction and quality assessment were performed using established criteria, and meta-analyses were conducted to assess the efficacy of Unani medications on glycemic control., Results: Five randomized controlled trials met the inclusion criteria. Meta-analyses revealed that Unani medications significantly reduced fasting blood glucose and postprandial blood glucose levels compared to control groups. However, the impact on HbA1c levels was not statistically significant. No adverse effects were reported., Conclusion: The findings of this review suggest that Unani medications hold promise in the management of T2DM, as evidenced by significant reductions in fasting and postprandial blood glucose levels. However, further investigation, particularly focusing on compounds like Qurs Gulnar, is essential to unravel their mechanisms and ascertain their long-term efficacy. Moreover, enhancing study quality would provide valuable insights into the role of Unani Medicine as a complementary or alternative therapy for T2DM. These efforts are critical for establishing Unani Medicine's place in the comprehensive management of T2DM.

Neurodevelopmental disorders (NDDs) are a clinically and genetically heterogeneous group of early-onset pediatric disorders that affect the structure and/or function of the central or peripheral nervous system. Achieving a precise molecular diagnosis for NDDs may be challenging due to the diverse genetic underpinnings and clinical variability. In the current study, we investigated the underlying genetic cause(s) of NDDs in four unrelated Pakistani families. Using exome sequencing (ES) as a diagnostic approach, we identified disease-causing variants in established NDD-associated genes in all families, including one hitherto unreported variant in RELN and three recurrent variants in VPS13B, DEGS1, and SPG11. Overall, our study highlights the potential of ES as a tool for clinical diagnosis., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: The global burden of metabolic disorders is increasing at an alarming rate. These disorders have a huge impact in terms of human suffering and economic implications. There is an urgent need for effective strategies, including the use of traditional systems of medicine, to reduce the burden of these diseases., Objective: The objective of this article is to compile information on preventive strategies for metabolic disorders found in Unani medicine., Methods: A literature survey of classical Unani texts was conducted to understand the conceptual framework in Unani medicine underlying preventive strategies for metabolic disorders. Electronic databases such as PubMed, ScienceDirect, and Google Scholar were searched to obtain the evidence needed to validate the Unani medicine viewpoint., Results: Unani scholars have described a set of clinical conditions caused by the insufficiency of the nutritive faculty. These conditions correlate in many ways with metabolic disorders. Cold dystemperament of the liver is considered to be the cause of insufficiency of nutritive faculty. Therefore, care and protection of the liver is considered as the main preventive approach for metabolic disorders in Unani medicine. Several epidemiological studies have also reported a strong relationship between non-alcoholic fatty liver disease and metabolic syndrome., Conclusion: The broad set of approaches (based on its theoretical foundations) used by Unani scholars to maintain the nutritive faculty in its optimal functional state seems to be an effective measure for the prevention of metabolic disorders.

Medical trainees or junior doctors within the United Kingdom, regardless of their level of training or specialty, are assigned an educational supervisor (ES). The General Medical Council within the United Kingdom defines an ES as "a trainer who is selected and appropriately trained to be responsible for the overall supervision and management of a specified trainee's educational progress during a clinical placement or series of placements." This article critically evaluates the current literature to explore the roles of the ES in supporting and monitoring a trainee's progress while discussing challenges associated with the role. Through clearer delineation of the role of an ES, barriers to improving training can be identified and overcome, thus improving overall satisfaction with training., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Said et al.)

The Objective Structured Clinical Examination (OSCE) is a globally established clinical examination; it is often considered the gold standard in evaluating clinical competence within medicine and other healthcare professionals' educations alike. The OSCE consists of a circuit of multiple stations testing a multitude of clinical competencies expected of undergraduate students at certain levels throughout training. Despite its widespread use, the evidence regarding formative renditions of the examination in medical training is highly variable; thus, its suitability as an assessment has been challenged for various reasons. Classically, Van Der Vleuten's formula of utility has been adopted in the appraisal of assessment methods as means of testing, including the OSCE. This review aims to provide a comprehensive overview of the literature surrounding the formative use of OSCEs in undergraduate medical training, whilst specifically focusing on the constituents of the equation and means of mitigating factors that compromise its objectivity., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Al-Hashimi et al.)

The genetic aetiology of a major fraction of patients with intellectual disability (ID) remains unknown. De novo mutations (DNMs) in protein-coding genes explain up to 40% of cases, but the potential role of regulatory DNMs is still poorly understood. We sequenced 63 whole genomes from 21 ID probands and their unaffected parents. In addition, we analysed 30 previously sequenced genomes from exome-negative ID probands. We found that regulatory DNMs were selectively enriched in fetal brain-specific enhancers as compared with adult brain enhancers. DNM-containing enhancers were associated with genes that show preferential expression in the prefrontal cortex. Furthermore, we identified recurrently mutated enhancer clusters that regulate genes involved in nervous system development ( CSMD1 , OLFM1 , and POU3F3 ). Most of the DNMs from ID probands showed allele-specific enhancer activity when tested using luciferase assay. Using CRISPR-mediated mutation and editing of epigenomic marks, we show that DNMs at regulatory elements affect the expression of putative target genes. Our results, therefore, provide new evidence to indicate that DNMs in fetal brain-specific enhancers play an essential role in the aetiology of ID., (© 2023 De Vas et al.)

Tomato is one of the most significant vegetable crops, which provides several important dietary components. Pakistan has a significant low tomato yield compared to other countries because of low genetic diversity and the absence of improved cultivars. The present study aimed to investigate the genetic variability, heritability, and genetic advance for yield and yield-related traits in tomato. For this purpose, eight tomato parents and their 15 crosses or hybrids were evaluated to study the relevant traits. Significant variation was observed for all studied traits. Higher values of the genotypic coefficient of variability (GCV) and phenotypic coefficient of variability (PCV) were recorded for yield per plant (YP) (kg) (37.62% and 37.79%), as well as the number of fruits per cluster (NFRC) (31.52% and 31.71%), number of flowers per cluster (24.63 and 24.67), and single fruit weight (g) (23.49 and 23.53), which indicated that the selection for these traits would be fruitful. Higher heritability (h 2 ) estimates were observed for the number of flowers per cluster (NFC) (0.99%), single fruit weight (SFW) (g) (0.99%), and yield per plant (YP) (kg) (0.99%). Single fruit weight (SFW) (g) exhibited higher values for all components of variability. High genetic advance as a % of the mean (GAM) coupled with higher heritability (h 2 ) was noted for the yield per plant (YP) (kg) (52.58%) and the number of fruits per cluster (NFRC) (43.91). NFRC and SFW (g) had a highly significant correlation with YP (kg), while FSPC had a significant positive association with YP (kg), and these traits can be selected to enhance YP (kg). Among the 15 hybrids, Nagina × Continental, Pakit × Continental, and Roma × BSX-935 were selected as high-yielding hybrids for further evaluation and analysis. These findings revealed that the best performing hybrids could be used to enhance seed production and to develop high-yielding varieties. The parents could be further tested to develop hybrids suitable for changing climatic conditions. The selection of YP (kg), SFW (g), NFC, and NFRC would be ideal for selecting the best hybrids., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Rasheed, Ilyas, Khan, Mahmood, Riaz, Chattha, Al Kashgry, Binothman, Hassan, Wu and Qari.)

Hereditary neurological disorders (HNDs) are a clinically and genetically heterogeneous group of disorders. These disorders arise from the impaired function of the central or peripheral nervous system due to aberrant electrical impulses. More than 600 various neurological disorders, exhibiting a wide spectrum of overlapping clinical presentations depending on the organ(s) involved, have been documented. Owing to this clinical heterogeneity, diagnosing these disorders has been a challenge for both clinicians and geneticists and a large number of patients are either misdiagnosed or remain entirely undiagnosed. Contribution of genetics to neurological disorders has been recognized since long; however, the complete picture of the underlying molecular bases are under-explored. The aim of this study was to accurately diagnose 11 unrelated Pakistani families with various HNDs deploying NGS as a first step approach. Using exome sequencing and gene panel sequencing, we successfully identified disease-causing genomic variants these families. We report four novel variants, one each in, ECEL1, NALCN, TBR1 and PIGP in four of the pedigrees. In the rest of the seven families, we found five previously reported pathogenic variants in POGZ, FA2H, PLA2G6 and CYP27A1. Of these, three families segregate a homozygous 18 bp in-frame deletion of FA2H, indicating a likely founder mutation segregating in Pakistani population. Genotyping for this mutation can help low-cost population wide screening in the corresponding regions of the country. Our findings not only expand the existing repertoire of mutational spectrum underlying neurological disorders but will also help in genetic testing of individuals with HNDs in other populations., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objectives: This study aimed to find out the association of CT severity score with demographic and clinical characteristics as well as mortality in the patients who were confirmed to have COVID-19 disease in the second wave., Material and Methods: This retrospective study included collection and assessment of the demographic, clinical, laboratory data, and mortality of the patients, suspected with COVID-19 infection who underwent chest HRCT scan during March to April 2021. The findings of the chest HRCT were retrieved manually from the Medical Records section. Determination of the severity was done by the scoring system that involved the visual evaluation of the affected lobes., Results: CT severity score was mild, moderate, and severe in 21.94%, 41.60%, and 30.48% patients, respectively. Mortality rate was 5.70%. Age of the patients with mild, moderate, and severe CT severity score was significantly more than those with normal severity score (50 vs. 50 vs. 50 vs. 31, P =0.0009). When compared to patients with normal score, those with mild, moderate, and severe CT severity score had significantly higher dyspnoea (10.39% vs. 67.81% vs. 97.20% vs. 0%), significantly more cases with diabetes mellitus (16.88% vs. 25.34% vs. 31.78% vs. 9.52%, P =0.044), hypertension (27.27% vs. 21.23% vs. 32.71% vs. 4.76%, P =0.026), and obesity (6.49% vs. 8.90% vs. 23.36% vs. 0%, P =0.0005). Total leucocyte counts, absolute neutrophil counts, creatinine, serum glutamic pyruvic transaminase (SGPT), lactate dehydrogenase (LDH), ferritin, and D-dimer were deranged in significantly more patients of severe score (53.27%, 62.62%, 60.75%, 85.05%, 90.65%, 97.20%, and 95.35%, respectively). Interleukin-6 (IL-6) and C-reactive protein were deranged in significantly more patients with moderate disease (98.18% and 98.63%, respectively). Increasing severity scores were associated with increased mortality (mild vs. moderate vs. severe: 1.30% vs. 1.37 vs. 15.89%, P <.0001). Oxygen saturation (SpO 2 ) was significantly lowest in severe score followed by moderate, mild and normal scores (87 vs. 90 vs. 96 vs. 97, P <.0001). Duration of non-rebreather mask (NRBM), noninvasive ventilation (NIV), high-flow nasal cannula (HFNC), Venture/face mask, and intubation was also associated with increasing severity scores ( P <0.0001)., Conclusion: CT scans play an important role in guiding physicians with their management plans and can serve as a predictor of disease severity and outcomes., Competing Interests: The authors have no conflicts of interest to declare., (© 2022 Published by Scientific Scholar on behalf of Journal of Clinical Imaging Science.)

Introduction: The present study was undertaken to describe and quantify the spectrum of radiographic findings on coronavirus disease 2019 (COVID-19) patients. The study also aimed to analyse the changes in chest X-ray (CXR) with disease progression., Methods: COVID-19 patients admitted between the period of 15 March 2020 and 1 July 2020 were retrospectively enrolled. CXR images were assessed and reported as 'Normal' or 'Abnormal'. A severity score was calculated using Warren et al .'s Radiographic Assessment of Lung Edema scoring. Correlations of the severity score thus calculated were sought with age, sex, clinical manifestations and presence of comorbidities., Results: Five hundred patients (342 males, 158 females) were enrolled, median age being 35 years. Fever and cough were the most common symptoms but significant correlation of an abnormal CXR was found with dyspnoea. CXRs were normal in 67% and abnormal in 33% patients. The commonest comorbidities were diabetes mellitus and cardiovascular disease including hypertension, coronary artery disease and congestive heart failure. Predominant pattern was ground glass opacities, reticular alteration and consolidation peaking in the second week from symptom onset. The most frequent distribution was bilateral, peripheral with middle/lower predominance. Increasing age, male sex, presence of dyspnoea and comorbidities correlated with abnormal findings on CXR. Critical illness and mortality correlated strongly with increasing age, male sex and presence of dyspnoea, less so with presence of comorbidities., Conclusion: In the current scenario with clinicians and radiologists working in tandem, CXR seems to be a promising tool in providing relevant information in a simplified way., Competing Interests: There are no conflicts of interest., (Copyright: © 2022 Journal of Family Medicine and Primary Care.)

Autosomal recessive limb-girdle muscular dystrophy-1 (LGMDR1) is an autosomal recessive disorder characterized by progressive weakness of the proximal limb and girdle muscles. Biallelic mutations in CAPN3 are reported frequently to cause LGMDR1. Here, we describe 11 individuals from three unrelated consanguineous families that present with typical features of LGMDR1 that include proximal muscle wasting, weakness of the upper and lower limbs, and elevated serum creatine kinase. Whole-exome sequencing identified a rare homozygous CAPN3 variant near the exon 2 splice donor site that segregates with disease in all three families. mRNA splicing studies showed partial retention of intronic sequence and subsequent introduction of a premature stop codon (NM&#95;000070.3: c.379 + 3A>G; p.Asp128Glyfs*15). Furthermore, we observe reduced CAPN3 expression in primary dermal fibroblasts derived from an affected individual, suggesting instability and/or nonsense-mediated decay of mutation-bearing mRNA. Genome-wide homozygosity mapping and single-nucleotide polymorphism analysis identified a shared haplotype and supports a possible founder effect for the CAPN3 variant. Together, our data extend the mutational spectrum of LGMDR1 and have implications for improved diagnostics for individuals of Pakistani origin., (© 2021 Wiley Periodicals LLC.)

Osteopetrosis is a genetically heterogenous, fatal bone disorder characterized by increased bone density. Globally, various genetic causes are reported for osteopetrosis with all forms of inheritance patterns. A precise molecular diagnosis is necessary for prognosis and for prescribing treatment paradigms in osteopetrosis. Here we report on thirteen individuals diagnosed with infantile malignant osteopetrosis coming from ten unrelated Pakistani families; nine of whom are consanguineous. We performed whole exome sequencing and Sanger sequencing in all families and identified homozygous variants in genes previously reported for autosomal recessive inheritance of osteopetrosis. All the identified variants are expected to affect the stability or length of gene products except one nonsynonymous missense variant. TCIRG1 was found as a candidate causal gene in majority of the families. We report six novel variants; four in TCIRG1 and one each in CLCN7 and OSTM1. Our combined findings will be helpful in molecular diagnosis and genetic counselling of patients with osteopetrosis particularly in populations with high consanguinity., (© 2021. The Author(s).)

Objectives: Indoor air quality has a significant impact on our health and quality of life, as people spends 80-90% of their time indoors. Fumigation of several medicinal herbs has been recommended by Unani scholars to improve air quality, but their efficacy in air purification is still unknown. Hence, this article aims to discuss the applicability of proposed medicinal herbs in the light of current researches., Methods: A manual literature survey of classical Unani texts was conducted to collect information about the herbs recommended for air purification. In addition, research databases such as PubMed, Google Scholar, and ScienceDirect were extensively searched for evidence on the efficacy and mechanism of action of the suggested herbs in air purification., Results: In classical Unani texts, authors have found descriptions of 26 herbs that have been recommended for improving air quality. In-vitro studies have confirmed the antimicrobial activity of 19 of these herbs. Moreover, the efficacy of Styrax benzoin, Commiphora myrrha and Acorus calamus fumigation on aerial microbes have also been validated by studies., Conclusions: The findings of the literature review clearly demonstrated that the herbs recommended by Unani scholars for air purification have broad-spectrum antimicrobial activity, indicating that these herbs could be a potential candidate for air disinfectant. Therefore, authors recommend the further researches on proposed herbs to validate their efficiency against airborne pathogens in the vapour phase., (© 2021 Walter de Gruyter GmbH, Berlin/Boston.)

Periprosthetic osteolysis remains as a major complication of total joint replacement surgery. Modulation of macrophage polarization with interleukin-4 (IL-4) has emerged as an effective means to limit wear particle-induced osteolysis. The aim of this study was to evaluate the efficacy of local IL-4 delivery in treating preexisting particle-induced osteolysis. To this end, recently established 8 week modification of murine continuous femoral intramedullary particle infusion model was utilized. Subcutaneous infusion pumps were used to deliver polyethylene (PE) particles into mouse distal femur for 4 weeks to induce osteolysis. IL-4 was then added to the particle infusion for another 4 weeks. This delayed IL-4 treatment (IL-4 Del) was compared to IL-4 delivered continuously (IL-4 Cont) with PE particles from the beginning and to the infusion of particles alone for 8 weeks. Both IL-4 treatments were highly effective in preventing and repairing preexisting particle-induced bone loss as assessed by μCT. Immunofluorescence indicated a significant reduction in the number of F4/80 + iNOS + M1 macrophages and increase in the number of F4/80 + CD206 + M2 macrophages with both IL-4 treatments. Reduction in the number of tartrate resistant acid phosphatase + osteoclasts and increase in the amount of alkaline phosphatase (ALP) + osteoblasts was also observed with both IL-4 treatments likely explaining the regeneration of bone in these samples. Interesting, slightly more bone formation and ALP + osteoblasts were seen in the IL-4 Del group than in the IL-4 Cont group although these differences were not statistically significant. The study is a proof of principle that osteolytic lesions can be repaired via modulation of macrophage polarization., (© 2020 Wiley Periodicals LLC.)

Proteins involved in transcriptional regulation harbor a demonstrated enrichment of mutations in neurodevelopmental disorders. The Sin3 (Swi-independent 3)/histone deacetylase (HDAC) complex plays a central role in histone deacetylation and transcriptional repression. Among the two vertebrate paralogs encoding the Sin3 complex, SIN3A variants cause syndromic intellectual disability, but the clinical consequences of SIN3B haploinsufficiency in humans are uncharacterized. Here, we describe a syndrome hallmarked by intellectual disability, developmental delay, and dysmorphic facial features with variably penetrant autism spectrum disorder, congenital malformations, corpus callosum defects, and impaired growth caused by disruptive SIN3B variants. Using chromosomal microarray or exome sequencing, and through international data sharing efforts, we identified nine individuals with heterozygous SIN3B deletion or single-nucleotide variants. Five individuals harbor heterozygous deletions encompassing SIN3B that reside within a ∼230 kb minimal region of overlap on 19p13.11, two individuals have a rare nonsynonymous substitution, and two individuals have a single-nucleotide deletion that results in a frameshift and predicted premature termination codon. To test the relevance of SIN3B impairment to measurable aspects of the human phenotype, we disrupted the orthologous zebrafish locus by genome editing and transient suppression. The mutant and morphant larvae display altered craniofacial patterning, commissural axon defects, and reduced body length supportive of an essential role for Sin3 function in growth and patterning of anterior structures. To investigate further the molecular consequences of SIN3B variants, we quantified genome-wide enhancer and promoter activity states by using H3K27ac ChIP-seq. We show that, similar to SIN3A mutations, SIN3B disruption causes hyperacetylation of a subset of enhancers and promoters in peripheral blood mononuclear cells. Together, these data demonstrate that SIN3B haploinsufficiency leads to a hitherto unknown intellectual disability/autism syndrome, uncover a crucial role of SIN3B in the central nervous system, and define the epigenetic landscape associated with Sin3 complex impairment., (Copyright © 2021 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

The rising episodes of deadly heat waves have intensified the need for a heat protection strategy. The Unani system of medicine offers ways to stay healthy in different climatic conditions. Hence, this article aims to discuss the applicability of health protection measures suggested by Unani scholars for hot weather conditions in the light of current researches. The manual literature survey of classical Unani texts was conducted to collect information on health safety measures for hot weather. A substantial search of scientific databases such as "Google Scholar" and "Medline" for proposed measures in combination with "heat-stroke", "heat exhaustion" and "heat rash" was also conducted to identify their possible activity in heat-related illnesses. The guidelines for summer seasons in the classical Unani literature are described under the title tadābīr-i-mavsam. Unani scholars have discussed in detail the pathophysiological effects of heat and the measures to stay healthy by regulating the body system through lifestyle, diet and herbs. Most of the measures proposed by them are backed up by evidences. However, some measures have not yet been evaluated for their therapeutic or prophylactic efficacy in heat-related illnesses. On the basis of findings, the authors advocate the adoption of evidence-based measures and propose further investigation of those measures that are not well supported by the evidence or have not yet been evaluated., (© 2021 Walter de Gruyter GmbH, Berlin/Boston.)

Studies were undertaken across five field locations in Western Australia to determine the relative changes in disease severity and subsequent field pea yield from up to four foliar pathogens associated with a field pea foliar disease complex (viz. genera Didymella , Phoma , Peronospora , and Septoria ) across four different pea varieties sown at three different times and at three different densities. Delaying sowing of field pea significantly ( P < 0.05) reduced the severity of Ascochyta blight (all five locations) and Septoria blight (one location), increased the severity of downy mildew (four locations), but had no effect on seed yield. In relation to Ascochyta blight severity at 80 days after sowing, at all locations the early time of sowing had significantly ( P < 0.05) more severe Ascochyta blight than the mid and late times of sowing. Increasing actual plant density from 20 to 25 plants m -2 to 58 to 78 plants m -2 significantly ( P < 0.05) increased the severity of the Ascochyta blight (four locations) and downy mildew (one location), and it increased seed yield at four locations irrespective of sowing date and three locations irrespective of variety. Compared with varieties Dundale, Wirrega, and Pennant, variety Alma showed significantly ( P < 0.05) less severe Ascochyta blight, downy mildew, and Septoria blight (one location each). Grain yield was highest for the early time of sowing at three locations. Varieties Alma, Dundale, and Wirrega significantly ( P < 0.05) outyielded Pennant at four locations. The percentage of isolations of individual Ascochyta blight pathogens at 80 days after the first time of sowing varied greatly, with genus Didymella ranging from 25 to 93% and genus Phoma ranging from 6 to 23% across the five field locations. This fluctuating nature of individual pathogen types and proportions within the Ascochyta blight complex, along with variation in the occurrence of pathogens Peronospora and Septoria , highlights the challenges to understand and manage the complexities of co-occurring different foliar pathogens of field pea. While the search for more effective host resistance continues, there is a need for and opportunities from further exploring and exploiting cultural management approaches focusing on crop sequence diversification, intercropping, manipulating time of sowing and stand density, and application of improved seed sanitation and residue/inoculum management practices. We discuss the constraints and opportunities toward overcoming the challenges associated with managing foliar disease complexes in field pea.

Essential tremor (ET) is the most common adult-onset movement disorder. In the present study, we performed whole exome sequencing of a large ET-affected family (10 affected and 6 un-affected family members) and identified a TUB p.V431I variant (rs75594955) segregating in a manner consistent with autosomal-dominant inheritance. Subsequent targeted re-sequencing of TUB in 820 unrelated individuals with sporadic ET and 630 controls revealed significant enrichment of rare nonsynonymous TUB variants (e.g. rs75594955: p.V431I, rs1241709665: p.Ile20Phe, rs55648406: p.Arg49Gln) in the ET cohort (SKAT-O test p-value = 6.20e-08). TUB encodes a transcription factor predominantly expressed in neuronal cells and has been previously implicated in obesity. ChIP-seq analyses of the TUB transcription factor across different regions of the mouse brain revealed that TUB regulates the pathways responsible for neurotransmitter production as well thyroid hormone signaling. Together, these results support the association of rare variants in TUB with ET., Competing Interests: I have read the journal's policy and the authors of this manuscript have the following competing interests: MPS is a co-founder of Personalis, Qbio, Sensomics and January. He is on the scientific advisory of these companies and Genapsys.

Objective: To compare the microleakage around resin modified glass ionomer cement (RMGIC) based sealants and flowable resin based sealants placed with or without ameloplasty in extracted human teeth., Methods: This in-vitro experimental study was conducted at the Operative Dentistry Department, Dow University of Health Sciences, Karachi, Pakistan from June 2017 to December 2018. Sixty extracted human molars and premolars were assigned to four groups (n=15) each, according to the type of fissure sealant (flowable resin based sealant or resin modified glass ionomer based sealant) used and either placed with or without ameloplasty. Specimens were thermocycled and then immersed in 1% methylene blue for 24 hours. Specimens were then sectioned and examined using stereo-microscope (50X) for microleakage that was scored on an ordinal scale. Mann-Whitney U test and Ordinal regression were applied. Level of significance kept at 0.05., Results: There was a statistically significant difference (p-value <0.001) between the two sealant types for the microleakage scores. Sealants placed with ameloplasty demonstrated significantly higher microleakage values (p-value <0.001)., Conclusion: Microleakage was found to be more pronounced in RMGIC based sealants compared to the resin based sealants. Ameloplasty resulted in higher leakage around the sealants irrespective of the chemistry of material., (Copyright: © Pakistan Journal of Medical Sciences.)

Hemophilia (HP), the deficiency of clotting factors such as VIII (FVIII) and IX, is an inherited blood disorder which is due to the lack of clotting protein. Conventional techniques for detecting hemophilia are based on clotting factor tests such as hemostasis assays to determine various types of hemophilia and its severity. In the current study, we propose a new approach involving a spectral technique to discriminate normal controls from hemophilia patients with an accuracy above 80 %. This accuracy is calculated on the normalized relative intensity based on the light measurement of blood components by analyzing a certain set of fluorescent bio molecules. Our results indicated that Red Blood Cells (RBCs) show lower porphyrin content and enzyme deficiencies in hemophilia patients than in normal controls. Therefore, the spectral features in hemophilia patients are different from those of normal controls. Thus, the proposed technique is a good alternative for the detection of hemophilia patients when compared with conventional detection techniques., Competing Interests: Declaration of Competing Interest The Authors declare no conflicts of interest., (Copyright © 2019 Elsevier B.V. All rights reserved.)

The past few decades have seen a significant rise in research into alternative polymer based nanosized unilamellar drug delivery systems, termed polymersomes. The reported benefits of polymersomes over the more traditional liposomes include increased stability, higher encapsulation efficacies, better adaptability and reduced water permeation due to an increased bilayer thickness. Together, these advantages render them suitable for a plethora of therapies. The work presented in this manuscript creates and compares four such drug delivery systems, two based on the traditional liposome and two prepared from amphiphilic polymers. From there we assess these systems in terms of size, stability, encapsulation efficiency, drug release, cellular toxicity and cellular uptake. We can confirm from this comprehensive investigation that the multi-functional synthetic polymersomes are undoubtedly a future contender in this expanding field of nanomedicines. Their ability to encapsulate a cocktail of different compounds, high stability as well as their ease of adaptability will ensure that they feature prominently in the future of advanced drug delivery systems., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2019 Published by Elsevier B.V.)

Purpose: The purpose of this study was to expand the genetic architecture of neurodevelopmental disorders, and to characterize the clinical features of a novel cohort of affected individuals with variants in ZNF142, a C 2 H 2 domain-containing transcription factor., Methods: Four independent research centers used exome sequencing to elucidate the genetic basis of neurodevelopmental phenotypes in four unrelated families. Following bioinformatic filtering, query of control data sets, and secondary variant confirmation, we aggregated findings using an online data sharing platform. We performed in-depth clinical phenotyping in all affected individuals., Results: We identified seven affected females in four pedigrees with likely pathogenic variants in ZNF142 that segregate with recessive disease. Affected cases in three families harbor either nonsense or frameshifting likely pathogenic variants predicted to undergo nonsense mediated decay. One additional trio bears ultrarare missense variants in conserved regions of ZNF142 that are predicted to be damaging to protein function. We performed clinical comparisons across our cohort and noted consistent presence of intellectual disability and speech impairment, with variable manifestation of seizures, tremor, and dystonia., Conclusion: Our aggregate data support a role for ZNF142 in nervous system development and add to the emergent list of zinc finger proteins that contribute to neurocognitive disorders.

Background: This study was conducted to compare the adaptation of resin-based sealants with that of Resin modified glass ionome-based sealants in various tooth fissure morphologies., Methods: It was an in vitro experimental study done at the Dow University and NED University, Karachi, Pakistan. Ten extracted human molars were randomly assigned to two groups, (n=5) each. Fissure sealant material (Resin based sealant or resin modified glass ionomer-based sealant) was applied on the occlusal surface of the tooth according to manufacturer's recommendations. Specimens were thermocycled and then sectioned into three longitudinal parts in the bucco- lingual direction. Specimens were examined using scanning electron microscope for the adaptation of the sealant in the occlusal fissure. Mann-Whitney -U test and Kruskall-Wallis test were applied to compare the adaptability scores of sealant materials in the tooth fissure. Level of significance was kept at 0.05., Results: There were no significant differences in the adaptability scores among U-shaped (p-value=0.35), V-shaped (p-value=0.89), IK-shaped (p-value=0.52), I-shaped (p-value- =0.41) and Y-shaped (p-value=1.00) fissure patterns. Similarly, there were no significant differences observed between the resin-based sealant (p-value=0.95) versus RMGIC based sealant (p-value=0.63) for the adaptability scores in various tooth fissure morphologies., Conclusions: No significant difference was found between resin-based sealants and resin modified glass ionomerbased sealants for the adaptation in various tooth fissure patterns.

[This corrects the article DOI: 10.1186/s12959-017-0143-3.].

Precise genetic counseling and prenatal diagnosis are often hindered by incomplete penetrance of risk variance and complex patterns of inheritance. Here, we performed a clinical and genetic study of a five-generation Pakistani family with a history of multiple cases of childhood brain tumors. Six affected individuals died of brain tumors at very early ages and three were confirmed as having a homozygous mutation in exon 6 of the PMS2 gene (c.543delT). Fifteen members of the family were identified as heterozygous carriers of this mutation with a lack of cancer incidence. Both clinical manifestations and genetic test results of brain tumor patients in the family support the diagnosis of constitutional mismatch repair deficiency (CMMRD) syndrome, a condition in which individuals carry homozygous germline mutations in mismatch repair machinery genes with an early onset of malignancies such as glioma. This information was used to guide prenatal diagnosis with genetic testing on chorionic villus samples for the family. This is the first report of prenatal genetic diagnosis of hereditary brain tumor.

Memory CD8+ T cells in the circulation rapidly infiltrate non-lymphoid tissues following infection and provide protective immunity in an antigen-specific manner. However, the subsequent fate of memory CD8+ T cells after entering non-lymphoid tissues such as the skin during a secondary infection is largely unknown. Furthermore, because expression of CD62L is often used to identify the central memory (TCM) CD8+ T cell subset, uncoupling the physical requirement for CD62L-mediated lymph node homing versus other functional attributes of TCM CD8+ T cells remains unresolved. Here, we show that in contrast to naïve CD8+ T cells, memory CD8+ T cells traffic into the skin independent of CD62L-mediated lymph node re-activation and provide robust protective immunity against Vaccinia virus (VacV) infection. TCM, but not effector memory (TEM), CD8+ T cells differentiated into functional CD69+/CD103- tissue residents following viral clearance, which was also dependent on local recognition of antigen in the skin microenvironment. Finally, we found that memory CD8+ T cells expressed granzyme B after trafficking into the skin and utilized cytolysis to provide protective immunity against VacV infection. Collectively, these findings demonstrate that TCM CD8+ T cells become cytolytic following rapid infiltration of the skin to protect against viral infection and subsequently differentiate into functional CD69+ tissue-residents., Competing Interests: The authors have declared that no competing interests exist.

The use of whole-exome and whole-genome sequencing has been a catalyst for a genotype-first approach to diagnostics. Under this paradigm, we have implemented systematic sequencing of neonates and young children with a suspected genetic disorder. Here, we report on two families with recessive mutations in NCAPG2 and overlapping clinical phenotypes that include severe neurodevelopmental defects, failure to thrive, ocular abnormalities, and defects in urogenital and limb morphogenesis. NCAPG2 encodes a member of the condensin II complex, necessary for the condensation of chromosomes prior to cell division. Consistent with a causal role for NCAPG2, we found abnormal chromosome condensation, augmented anaphase chromatin-bridge formation, and micronuclei in daughter cells of proband skin fibroblasts. To test the functional relevance of the discovered variants, we generated an ncapg2 zebrafish model. Morphants displayed clinically relevant phenotypes, such as renal anomalies, microcephaly, and concomitant increases in apoptosis and altered mitotic progression. These could be rescued by wild-type but not mutant human NCAPG2 mRNA and were recapitulated in CRISPR-Cas9 F0 mutants. Finally, we noted that the individual with a complex urogenital defect also harbored a heterozygous NPHP1 deletion, a common contributor to nephronophthisis. To test whether sensitization at the NPHP1 locus might contribute to a more severe renal phenotype, we co-suppressed nphp1 and ncapg2, which resulted in significantly more dysplastic renal tubules in zebrafish larvae. Together, our data suggest that impaired function of NCAPG2 results in a severe condensinopathy, and they highlight the potential utility of examining candidate pathogenic lesions beyond the primary disease locus., (Copyright © 2018 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)