Haploinsufficiency of the Sin3/HDAC corepressor complex member SIN3B causes a syndromic intellectual disability/autism spectrum disorder.

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.

Exome sequencing in four families with neurodevelopmental disorders: genotype-phenotype correlation and identification of novel disease-causing variants in VPS13B and RELN.

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.

Prior Use of Angiotensin-converting Enzyme Inhibitors or Angiotensin II Receptor Blockers and Clinical Outcomes of Sepsis and Septic Shock: A Systematic Review and Meta-analysis.

ABSTRACT: Sepsis and septic shock are life-threatening conditions that are associated with high mortality and considerable health care costs. The association between prior angiotensin-converting enzyme inhibitors (ACEi) or angiotensin II receptor blockers (ARBs) use and outcomes after sepsis is elusive. The aim of this study was to evaluate the role of the prior use of ACEi or ARBs and outcomes after sepsis and septic shock. A relevant literature review was performed in 4 databases from inception until July 2022. Independent reviewers first screened the title, abstract, and full text, and then, data extraction and analysis were performed. One post hoc analysis of a trial and 6 retrospective cohort studies were included in this review. There were 22% lower odds of in-hospital/30-day mortality among patients who have used ACEi/ARBs in the past [23.83% vs. 37.20%; odds ratio (OR), 0.78, 95% confidence interval (CI), 0.64-0.96], and reduced 90-day mortality (OR, 0.80, 95% CI, 0.69-0.92). ACEi/ARBs users were found to have 31% lesser odds of developing acute kidney injury as compared with nonusers (OR, 0.69, 95% CI, 0.63-0.76). There was no significant difference in the length of hospital stay (MD 1.26, 95% CI, ‒7.89 to 10.42), need for renal replacement therapy (OR, 0.71, 95% CI, 0.13-3.92), mechanical ventilation (OR, 1.10, 95% CI, 0.88-1.37) or use of vasopressors (OR, 1.21, 95% CI, 0.91-1.61). Based on this analysis, prior use of ACEi/ARBs lowers the risk of mortality and adverse renal events in patients with sepsis and septic shock.

Streptomyces enissocaesilis L-82 has broad-spectrum antibacterial activity and promotes growth for Carassius auratus.

Aeromonas is the main pathogen causing bacterial diseases in fish. The disadvantages of chemical drugs to control fish diseases have been highlighted, and it is urgent to find an eco-friendly control method. In this study, an actinomycete strain with antibacterial activity against fish pathogenic bacteria was screened from soil samples. Combined with morphological characteristics, physiological and biochemical characteristics, and gyrB gene and whole genome comparison analysis, it was identified as a new strain of Streptomyces enissocaesilis, named Streptomyces enissocaesilis L-82. The strain has broad-spectrum antibacterial activity against fish pathogens. A substance with a mass-to-charge ratio of 227.20 [M + H] + was isolated and purified by high-performance liquid chromatography and mass spectrometry. It was presumed to be a derivative of 5-dimethylallylindole-3-acetonitrile. The strain is safe and non-toxic to crucian carp, and can stably colonize crucian carp and inhibit the proliferation of A. hydrophila. After feeding the feed containing 1 × 108 CFU/mL strain concentration, the weight growth rate and specific growth rate of crucian carp increased, the activity of ACP and SOD in serum increased, and the survival rate of crucian carp increased after challenge. Genome-wide analysis showed that the strain had strong ability to metabolize and tolerate extreme environments. And has a strong potential for disease resistance. Therefore, the strain is expected to be developed as a feed additive for fish farming. KEY POINTS: • The new Streptomyces enissocaesilis L-82 has a broad spectrum and stable antibacterial activity and meets the safety standards of feed additives. • Strain L-82 can colonize crucian carp, improve the growth, antioxidant, and immune performance of the host, and improve the survival rate after being infected with A. hydrophila. • Genome-wide analysis suggests that the strain has great disease resistance potential and is expected to be developed as a feed additive for fish culture.

Candidate variants in TUB are associated with familial tremor.

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.

Phylogenetic relationships of a novel bat fly species infesting the geographically widespread Old World fruit bat, Rousettus leschenaultii, in Southern Asia.

The global epidemiological significance of bats and their blood-sucking ectoparasites is increasingly recognized. However, relevant data are scarce from Pakistan where the Palearctic and Oriental zoogeographic regions meet. In this study, 200 bats belonging to five species were examined for the presence of ectoparasites in Pakistan. Bat flies were found only on Leschenault's fruit bat (Rousettus leschenaultii). The prevalence of infestation did not correlate with habitat type and host traits including age, reproductive status, and sex. All bat flies represented the same Eucampsipoda species which was shown to be morphologically different from all species of its genus with known south Asian distribution and belonged to a separate phylogenetic group. These results highlight the existence of a hitherto undescribed bat fly species in southern Asia, which is not shared by the fruit bat species (R. leschenaultii) and insectivorous ones (e.g., Rhinopoma microphyllum) thus probably playing a role only in intraspecific transmission of pathogens.

Self-harm and suicidal ideation in Pakistani youth amid COVID-19 pandemic: findings of a large, cross-sectional study.

Suicide is the fourth leading cause of death among young people. COVID-19 pandemic has exacerbated various factors which could lead to suicidal ideation. Therefore, this study was aimed to assess self-harm and suicidal ideation among university students in Pakistan. We conducted an online, cross-sectional study among students of four major Pakistani universities. The generalized anxiety scale and patient health questionnaire were used to screen students for anxiety, depression and suicidal ideation/self-harm. Suicidal ideation/self-harm was determined from the ninth-item (score ≥1) of the patient health questionnaire. Brief-COPE was used to assess coping methods. This study included 1134 respondents (age 21.76 ± 3.48 years; female 70.5%). Around 32% students reported having thoughts of death and/or self-harm in the past 2 weeks (several days 14.8%, over half the days 7.1%, and nearly every day 10.2%). Moreover, these thoughts were equally prevalent among the demographics. Suicidal ideation/self-harm was found to be increased by the severity of generalized anxiety and depression (p < 0.001). In conclusion, the rate of suicidal ideation/self-harm is alarmingly high in Pakistani university students during the COVID-19 pandemic. There is a dire need to initiate the psychological measures to prevent suicidal behaviors in Pakistani youth. Addressing mental health disparities and preparing support systems to mitigate mental health consequences as the pandemic evolves will continue to be needed urgently.

Challenges of having a child with thalassemia in Pakistan: A phenomenological study.

BACKGROUND: Thalassemia is a persistent hemolytic disease and has debilitating effects on patients and their parents. Parents of these children experience pain and suffer from additional emotional strain as they provide daily and lifetime care and are mostly concerned about the health and future of their children. AIM: The study aimed to understand the experiences of parents of children with thalassemia related to their family, financial, social, treatment, and psychological issues in Pakistan. METHODS: This descriptive phenomenological study recruited 21 parents of children with thalassemia through purposive sampling until data saturation was achieved. Analysis of transcribed interviews was performed through Colaizzi's method and themes and subthemes revolving around diagnosis, challenges, and treatment issues were extracted. FINDINGS: A total of 21 Pakistani parents participated in this study. Most of the participants were females (n = 16, 76.19%), housewives/stay-at-home moms (n = 13 (61.90%), and were uneducated (n = 6, 28.57%). Regarding genetic traits, only three (14.28%) parents declared that they had genetic traits of thalassemia. The findings of our study revealed that thalassemia is enormously influenced by psychosocial and economic problems because of this disease in their families. CONCLUSION: Our findings indicated that parents of these children face multi-faceted challenges, such as physical, socio-emotional, financial, and familial. These findings may lead to an adequate understanding of their individual needs and efficient utilization of supportive and care programs. PRACTICE IMPLICATIONS: An understanding of such experiences, involving those distinctive to Pakistani culture, is especially vital to inform the care of these children and enhance their quality of life.

Mutations in NCAPG2 Cause a Severe Neurodevelopmental Syndrome that Expands the Phenotypic Spectrum of Condensinopathies.

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.

NGS-driven molecular diagnosis of heterogeneous hereditary neurological disorders reveals novel and known variants in disease-causing genes.

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.

A recurrent rare intronic variant in CAPN3 alters mRNA splicing and causes autosomal recessive limb-girdle muscular dystrophy-1 in three Pakistani pedigrees.

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_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.

A Virtual Clinic for DDH Pavlik Harness Monitoring.

BACKGROUND: Pavlik harness (PH) treatment is successful in treating over 90% of newborns with developmental dysplasia of the hip (DDH). There is a need for close supervision, frequent adjustments, size changes, and monitoring of complications. This paper aims to provide a safe criterion for remote follow-up of DDH patients treated in a PH to reduce the risk of COVID-19 (coronavirus disease 2019) exposure to patients, parents, and health practitioners. METHODS: All infants with stable hips (Graf I, IIa/b/c/d, treated III/IV) with consenting parents after appropriate counseling were enrolled in a virtual clinic. Clinics were conducted using the NHS "Attend anywhere" virtual link service by an extended scope practitioner-specialist physiotherapist and a clinical nurse specialist. The virtual clinic group was compared with a matched cohort of patients from 2018/2019. RESULTS: A total of 141 patients were referred to the neonatal hip clinic; 45 patients were eligible for harness treatment and 20 patients were selected for virtual clinics. In total, there were 35 virtual clinic appointments. Each of the patients had an average of 1.7 virtual appointments ranging from 1 to 3 (26.3% of total number of clinics). Age at presentation of the treated group was 7±4.2 weeks and control group 5.7±5.5 weeks (P=0.59). PH duration of the study group was 9±2.6 weeks and the control group, 7.8±2.5 weeks (P=0.12). There were no missed complications at the follow-up face-to-face appointment. Patients saved an average of 76 km total travel distance. CONCLUSIONS: This study demonstrates adequate evidence that children requiring routine follow-up appointments involving PH adjustment, skincare, and identification of clinical anomalies, can be treated and followed up safely using virtual clinics. Clinical triage of suitable patients for virtual clinic provision must always be made by experienced clinicians. Children presenting with Graf IIa, IIb, IIc, IId, as well as those with stable and improving Graf III at initial diagnoses, had successful treatment with virtual clinic follow-up appointments in this study. LEVEL OF EVIDENCE: Level IV.

LC Passive Wireless Sensor System Based on Two Switches for Detection of Triple Parameters.

This paper presents the LC-type passive wireless sensing system for the simultaneous and independent detection of triple parameters, featuring three different capacitive sensors controlled by two mechanical switches. The sensor coil was connected with three different capacitors in parallel and two mechanical switches were in series between every two capacitors, which made the whole system have three resonant frequencies. The readout coil was magnetically coupled with the sensor coil to interrogate the sensor wirelessly. The circuit was simulated advanced design system (ADS) software, and the LC sensor system was mathematically analyzed by MATLAB. Results showed that the proposed LC sensing system could test three different capacitive sensors by detecting three different resonant frequencies. The sensitivity of sensors could be determined by the capacitance calculated from the detected resonant frequencies, and the resolution of capacitance was 0.1 PF and 0.2 PF when using the proposed sensor system in practical applications. To validate the proposed scheme, a PCB inductor and three variable capacitors were constructed with two mechanical switches to realize the desired system. Experimental results closely verified the simulation outputs.

Parents' refusal to vitamin-K supplementation among neonates and its association with vaccine refusal: A systematic review and meta-analysis.

OBJECTIVE: This systematic review and meta-analysis aims to estimate the prevalence of neonatal vitamin K prophylaxis refusal among parents and its possible association with subsequent vaccine hesitancy or refusal. METHODS: The databases searched included PubMed, Cochrane Library, Embase via Ovid, CINAHL Plus and Medline via EBSCOhost, ProQuest and PsycINFO from inception to 31 August 2017. Keywords, such as "vitamin K", "refusal", "decline", "hesitancy", and "vaccination" were used to identify potential studies. Analysis of proportions was conducted, while odd ratios and relative risks were estimated using the random effect model. RESULTS: Of the 2216 studies identified, 8(0.36%) were subjected to qualitative analysis; 4(50%) retrospective cohort studies and 4(50%) cross-sectional studies. Overall, 6(75%) studies were of good quality, while 2(25%) were ranked as of fair quality. Of the 273,714 parents, 3,136(1.14%) refused to opt for the vitamin K prophylaxis. Meta-analysis concluded that refusal to vitamin K prophylaxis was significant among the included studies ((p<0.184). CONCLUSIONS: The overall risk of refusal to essential vaccination among vitamin K prophylaxis refusal group was 6.45 times compared to the group that accepted vitamin K prophylaxis.

Advances in Infectious Diseases and Clinical Microbiology during the COVID-19 Pandemic.

Infectious diseases pose substantial challenges to the healthcare system and are associated with significant morbidity and mortality [...].

Dual Molecular Effects of Dominant RORA Mutations Cause Two Variants of Syndromic Intellectual Disability with Either Autism or Cerebellar Ataxia.

RORα, the RAR-related orphan nuclear receptor alpha, is essential for cerebellar development. The spontaneous mutant mouse staggerer, with an ataxic gait caused by neurodegeneration of cerebellar Purkinje cells, was discovered two decades ago to result from homozygous intragenic Rora deletions. However, RORA mutations were hitherto undocumented in humans. Through a multi-centric collaboration, we identified three copy-number variant deletions (two de novo and one dominantly inherited in three generations), one de novo disrupting duplication, and nine de novo point mutations (three truncating, one canonical splice site, and five missense mutations) involving RORA in 16 individuals from 13 families with variable neurodevelopmental delay and intellectual disability (ID)-associated autistic features, cerebellar ataxia, and epilepsy. Consistent with the human and mouse data, disruption of the D. rerio ortholog, roraa, causes significant reduction in the size of the developing cerebellum. Systematic in vivo complementation studies showed that, whereas wild-type human RORA mRNA could complement the cerebellar pathology, missense variants had two distinct pathogenic mechanisms of either haploinsufficiency or a dominant toxic effect according to their localization in the ligand-binding or DNA-binding domains, respectively. This dichotomous direction of effect is likely relevant to the phenotype in humans: individuals with loss-of-function variants leading to haploinsufficiency show ID with autistic features, while individuals with de novo dominant toxic variants present with ID, ataxia, and cerebellar atrophy. Our combined genetic and functional data highlight the complex mutational landscape at the human RORA locus and suggest that dual mutational effects likely determine phenotypic outcome.

Isolation of a new Streptomyces virginiae W18 against fish pathogens and its effect on disease resistance mechanism of Carassius auratus.

The Streptomyces virginiae strain W18 was screened from soil, which exhibited broad-spectrum antibacterial activity against fish pathogens. Safety assays showed that strain W18 had no toxicity to fish. Additionally, strain W18 promoted the growth performance of Carassius auratus after feeding in feed mixed with bacteria for one month. Moreover, the activities of AKP, ACP, and SOD in the serum of C. auratus were significantly increased, while the activity of LZM did not greatly change. To detect the expression levels of the genes related to immune factors in the livers, kidneys, and spleens of C. auratus, qRT-PCR was performed. The expression levels of KEAP1, IL-8, TNF-α, IL-ß, and C3 were upregulated in all three organs compared to the control, but LZM expression was downregulated in the kidney. The challenge experiment illustrated that the probability of infection with Aeromonas veronii was reduced by 60% and 40% when C. auratus was fed with two different doses of strain W18 in advance. The whole genome of strain W18 was sequenced, and the gene clusters of secondary metabolites in strain W18 were analyzed by AntiSMASH. The results showed that strain W18 contained a total of 26 gene clusters, and functional annotation analysis was conducted by using the non-coding databases COG and KEGG. All of the above results indicated that the use of strain W18 as a feed additive could enhance the resistance of C. auratus toward pathogenic bacteria and disease. In conclusion, an antagonistic strain (W18) against fish pathogenic bacteria was obtained in this study, which is of great significance for finding new treatment methods for bacterial diseases in the aquaculture industry.

Study on the mathematical modelling of COVID-19 with Caputo-Fabrizio operator.

In this article we study a fractional-order mathematical model describing the spread of the new coronavirus (COVID-19) under the Caputo-Fabrizio sense. Exploiting the approach of fixed point theory, we compute existence as well as uniqueness of the related solution. To investigate the exact solution of our model, we use the Laplace Adomian decomposition method (LADM) and obtain results in terms of infinite series. We then present numerical results to illuminate the efficacy of the new derivative. Compared to the classical order derivatives, our obtained results under the new notion show better results concerning the novel coronavirus model.

A snapshot of the global policies and practices of medicine use reviews by community pharmacist in chronic diseases: A narrative review.

Medicine use review is a tool to improve medication adherence and safety. Current narrative review was planned to explore global policies and practices of medicine use review by community pharmacists in chronic diseases and its impact and way forward for low- and middle-income countries. Key words, such as ″medicine use review″, ″medication therapy management″ and ″community pharmacy″ were used for search on PubMed and CINAHL databases for articles published from 2004 to 2019. Medicine use review has opened an avenue of ongoing collaboration between community pharmacists and general practitioners. High-income countries have witnessed a gradual yet cautious adoption of these services through effective policy shift. In terms of practices and impact, the situation in high-income countries was promising where on an average ″type-II″ medicine use review was widely in practice and had improved clinical, humanistic and economic outcomes in chronic disease. However, in low- and middle-income countries, a paucity of effective policies was noted. Nevertheless, an emergent recognition of the potential of community pharmacists to contribute to the management of chronic diseases was evident.

Knowledge, Attitude, and Barriers Toward ADRs Reporting Among Health-Care Professionals at Tertiary Care Health Settings in Peshawar, Pakistan: A Web Based Study.

Background: Underreporting of adverse drug reactions (ADRs) is considered a major determinant of poor ADR signal detection in Pakistan. Considering this, the study was proposed to evaluate healthcare professionals' (HCPs) knowledge attitude toward and the barriers that discourse ADRs reporting. Methods: A cross-sectional survey was distributed among HCPs in 3 major tertiary care facilities of Peshawar. A self-administered, 31 items questionnaire was circulated online to collect the required information. Relative index ranking was used to identify the top barriers to the ADR reporting process. Results: HCPs (n = 322) were requested, and over one-third (n = 122) responded. Of the total, 97 (79.5%) were males, and by designation, 59(48.4%) were resident medical officers. About 45% of the HCPs did not identify the appropriate pharmacovigilance (PV) definition. More than half of the HCPs (52.2%) distinguished the appropriate PV purpose. Nearly 80% HCPs did not know the acceptable reporting time frame, while 22.1% HCPs knew that regulatory body for ADRs does not exist in Pakistan. The majority (95.08%) of the HCPs either strongly agreed or agreed that reporting an ADRs is a professional obligation and all the HCPs were of the opinion that PV should be taught in detail to HCPs. Exploring the barriers, it was identified that the key barriers to ADRs reporting were "unavailability of professional environment to discuss ADRs," Relative Importance Index (RII) = 0.813, "lack of incentives for reporting" (RII = 0.774), "lack of knowledge regarding reporting" (RII = 0.693), and "insufficient knowledge of pharmacotherapy in detecting ADRs" (RII = 0.662). In addition to these, "complicated reporting forms" (RII = 0.616), "lack of motivation for reporting ADRs" (RII = 0.610), and "absence of professional confidence" were seen as major hindrances in effective reporting of ADRs (RII = 0.598). Conclusion: Concerning PV and ADR reporting poor knowledge was noted. However, the majority of the HCPs showed an explicit attitude regarding ADRs reporting. The majority of the HCPs disclosed unavailability of professional environment to discuss about ADRs, lack of incentives, and how to report the main factors hindering the ADRs reporting. It is emphasized that health authorities carve out a niche for a well purposeful PV center and pledge educational activities and trainings for increasing understanding and approaches regarding reporting of ADR.