A Recurrent Nonsense Mutation in NECTIN4 Underlying Ectodermal Dysplasia-Syndactyly Syndrome with a Novel Phenotype in a Consanguineous Kashmiri Family.

EDSS1, a syndrome characterized by ectodermal dysplasia-syndactyly, is inherited in an autosomal recessive manner due to mutations in the NECTIN4/PVRL4 gene. Clinical manifestations of the syndrome include defective nail plate, sparse to absent scalp and body hair, spaced teeth with enamel hypoplasia, and bilateral cutaneous syndactyly in the fingers and toes. Here, we report a consanguineous family of Kashmiri origin presenting features of EDSS1. Using whole exome sequencing, we found a recurrent nonsense mutation (NM_030916: c.181C > T, p.(Gln61 ∗)) in the NECTIN4 gene. The variant segregated perfectly with the disorder within the family. The candidate variant was absent in 50 in-house exomes pertaining to other disorders from the same population. In addition to the previously reported clinical phenotype, an upper lip cleft was found in one of the affected members as a novel phenotype that is not reported by previous studies in EDSS1 patients. Therefore, the study presented here, which was conducted on the Kashmiri population, is the first to document a NECTIN4 mutation associated with the upper lip cleft as a novel phenotype. This finding broadens the molecular and phenotypic spectrum of EDSS1.

Role of iron in the reduction of anemia among women of reproductive age in low-middle income countries: insights from systematic review and meta-analysis.

BACKGROUND: Iron deficiency anemia is a common public health issue among women of reproductive age (WRA) because it can result in adverse maternal and birth outcomes. Although studies are undertaken to assess iron efficacy, some gaps and limitations in the existing literature need to be addressed. To fill the gaps, we conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) assessing the role of iron in reducing anemia among WRA in low-middle-income countries (LMICs). METHODS: A comprehensive search strategy was used to search Medline through PubMed, Embase, and Science Direct for RCTs published between 2000 and 2020. The primary outcome was the mean change in hemoglobin level. We used standardized mean differences and their respective 95% CI to estimate the pooled effect. We used I2 statistics and Egger's test to assess heterogeneity and publication bias, respectively. This review was carried out in accordance with revised guidelines based on the Preferred Reporting Items for Systematic Review and Meta-analysis. RESULTS: The findings showed that iron therapy improved hemoglobin and ferritin levels, though the results varied across studies. An overall pooled effect estimate for the role of iron therapy in improving the hemoglobin levels among WRA was -0.71 (95% CI: -1.27 to -0.14) (p = 0.008). Likewise, the overall pooled effect estimate for the role of iron therapy in improving the ferritin levels among WRA was -0.76 (95% CI: -1.56 to 0.04) (p = 0.04). The heterogeneity (I2) across included studies was found to be statistically significant for studies assessing hemoglobin (Q = 746.93, I2 = 97.59%, p = 0.000) and ferritin level (Q = 659.95, I2 = 97.88%, p = 0.000). CONCLUSION: Iron therapy in any form may reduce anemia's burden and improve hemoglobin and ferritin levels, indicating improvement in iron-deficiency anemia. More evidence is required, however, to assess the morbidity associated with iron consumption, such as side effects, work performance, economic outcomes, mental health, and adherence to the intervention, with a particular focus on married but non-pregnant women planning a pregnancy in the near future. TRIAL REGISTRATION: Registered with PROSPERO and ID is CRD42020185033.

Outcomes in Lower Pole Kidney Stone Management Using Mini-Percutaneous Nephrolithotomy Compared With Retrograde Intra Renal Surgery: A Randomized Controlled Trial.

Background Because of the anatomical properties of the inferior calyx, lower pole stones are difficult to remove through the ureter, even if the stones are fragmented. Retrograde intra-renal surgery (RIRS) is typically employed to treat the smaller lower pole stones (1.0-2.0 cm) while percutaneous nephrolithotomy (PCNL) is primarily used to treat the larger diameter stones or when RIRS has failed to clear the stones. This study was conducted to compare mini-PCNL and RIRS for the management of lower pole kidney stones in terms of stone clearance. Material and methods This randomized control trial was conducted in the Department of Urology, Shaikh Zayed Hospital, Lahore from October 2020 to December 2022. A total of 150 patients between the ages of 18 and 80 years with a kidney stone size of 10-20 mm at the lower pole were included. Patients with positive urine culture, anatomical abnormalities, uncontrolled diabetes (hemoglobin{Hb}A1c >9%), and undergone previous renal surgery were excluded. Group A patients were treated with mini-PCNL, while group B patients were managed with RIRS. Follow-up visits were planned four weeks postoperatively with CT KUB (computed tomography of kidneys, ureters, and bladder) plain to assess stone clearance. Results The mean age in group A was 43.27 ± 13.86 years, while in group B was 45.32 ± 14.14 years. Out of 150 patients, 102 (68.0%) were males and 48 (32.0%) were females. Mean size of the stone was 15.30 ± 2.21 mm. Stone clearance after mini-PCNL was found in 69 (92.0%) patients and after RIRS in 59 (78.67%) patients (p-value = 0.021). Mean hospital stay after RIRS was 1.1 ± 0.09 days, while it was 2.3 ± 0.64 days after mini-PCNL (p-value < 0.001). Two (2.67%) patients in the mini-PCNL group developed bleeding postoperatively. The stone clearance rate in older patients (51 to 80 years) was significantly higher in the mini-PCNL group than RIRS group. Similarly, the stone clearance rate in female patients and in patients with larger stones (16 to 20 mm) was found to be higher in mini-PCNL group as compared to the RIRS group. Conclusion This study concluded that both mini-PCNL and RIRS are safe and efficient techniques for treating lower pole kidney stones with a size of 11-15 mm. However, mini-PCNL has a higher stone clearance rate compared to RIRS in the treatment of stones larger than 15 mm in size. This study further suggested that patients treated with mini-PCNL had a longer hospital stay compared to patients treated with RIRS.

Prevalence and Outcomes of Myocarditis in Dengue-Infected Patients Admitted to a Tertiary Care Hospital of Low-Middle Income Country.

Background: Myocarditis is a challenging diagnosis due to the heterogeneity of clinical presentations. Myocarditis can present with a mildly raised cardiac enzyme to severe myocarditis leading to congestive heart failure, arrhythmias, cardiogenic shock, and death. It is a predictor of morbidity and mortality in dengue-infected patients. The exact prevalence of dengue myocarditis and its outcomes are unknown in Pakistan. Objectives: We aim to study the prevalence and association of myocarditis with the length of stay in the hospital and mortality of dengue-infected patients. Methods: A retrospective observational study done at a tertiary care hospital. We reviewed hospital record files of 1008 consecutive patients with dengue viral infection admitted from November 2018 to November 2019. Results: Out of 1008 dengue-infected patients, 55.4% of patients were older than 35 years and 68.4% were males. Hypertension (HTN) was the most common comorbid condition. The prevalence of myocarditis in hospitalized dengue-infected patients was 4.2%. All (100%) of dengue myocarditis patients had raised cardiac troponin I (cTn-I), 59.5% of patients had at least one electrocardiography (ECG) change, and 24% had reduced ejection fraction (EF) (defined as EF < 55%). On multivariable analysis, patients with raised cTn-I levels (adjusted odds ratios = 5.29; [95% confidence interval (CI): 2.16-12.96]) and abnormal echocardiography (ECHO) [aOR = 4.38; 95% CI: 1.26-15.27)] had a prolonged hospital stay (>3 days). Raised cTn-I levels (aOR = 8.2; [95% CI: 1.83-36.84]) was significantly associated with in-hospital mortality. Conclusions: Raised cTn-I is the predictor of length of stay and in-hospital mortality in dengue-infected patients. Atrial fibrillation, diabetes mellitus, hypertension, low serum bicarbonate, high serum creatinine, and any abnormality on echocardiography were associated with adverse outcomes in dengue-infected patients.

Investigating The Role of Inflammatory Markers at Admission in Defining the Severity of Moderate-to-Critical COVID-19: A Cross-Sectional Analysis.

Background and aims: The spectrum of Coronavirus disease-2019 (COVID-19) has been clinically defined from asymptomatic carriers to critical illness. Different inflammatory markers have been used to account for the severity and outcomes of this disease in different settings. Our study aims to investigate the role of these inflammatory markers in defining COVID-19 severity. Methods: This cross-sectional study included 200 confirmed cases of COVID-19. Inflammatory markers including lymphocyte count, D-Dimers, Ferritin, CRP, LDH were noted at admission. The moderate-to-critical disease was defined according to the WHO criteria. Descriptive statistics were applied. Mann-Whitney U-test was applied to compare the difference of markers between moderate-severe and critical patients. ROC was plotted to determine the cut-off values of these markers. Binary logistics regression analysis was used to assess which markers significantly predict the severity of COVID-19. Results: A D-dimer value of >775 ng/ml and LDH >495 U/L had a sensitivity of 72.9% and 79.2% and specificity of 57.9% and 53.6% respectively for critical COVID-19 illness. CRP levels of >100.5 mg/dl has a sensitivity of 66.7%. All inflammatory markers were significantly higher in a critical group of patients (p < 0.05) except for lymphopenia. Binary logistics regression analysis shows that LDH levels and D-dimers were only significant predictors of severity in COVID-19 patients. Conclusion: Inflammatory markers at admission are very useful in defining the severity of COVID-19 in addition to the clinical criteria. This is also useful in predicting adverse outcomes.

Indirect effects of COVID-19 pandemic on reproductive, maternal, newborn and child health services in Pakistan.

Background: COVID-19 is having many impacts on health, economy and social life; some due to the indirect effects of closure of health facilities to curb the spread. Closures were implemented in Pakistan from March 2020, affecting provision of reproductive, maternal, newborn and child health (RMNCH) services. Aims: To appraise the effects of containment and lockdown policies on RMNCH service utilization in order to develop an early response to avoid the catastrophic impact of COVID-19 on RMNCH in Pakistan. Methods: Routine monitoring data were analysed for indicators utilization of RMNCH care. The analysis was based on Period 1 (January-May 2020, first wave of COVID-19); Period 2 (June-September 2020, declining number of cases of COVID-19); and Period 3 (October-December 2020, second wave of COVID-19). We also compared data from May and December 2020 with corresponding months in 2019, to ascertain whether changes were due to COVID-19. Results: Reduced utilization was noted for all RMNCH indicators during Periods 1 and 3. There was a greater decline in service utilization during the first wave, and the highest reduction (~82%) was among children aged < 5 years, who were treated for pneumonia. The number of caesarean sections dropped by 57%, followed by institutional deliveries and first postnatal visit (37% each). Service utilization increased from June to September, but the second wave of COVID-19 led to another decrease. Conclusion: To reinstate routine services, priority actions and key areas include continued provision of family planning services along with uninterrupted immunization campaigns and routine maternal and child services.

Design, Preparation and evaluation of various parameters of controlled release matrices of losartan potassium using polymers combination.

Controlled release formulations are administered once a day and reduce frequency of dose and ensuring patient's compliance. In the current research controlled release matrices of losartan potassium formulated with polymeric combinations of ethocel grade 7 with carbopol 934P NF using different concentrations of polymers. In some polymeric tablets, Co-excipients like CMC, Starch, HPMC was added by replacing of 10% of filler in formulations at 10:5. Tablets were prepared by direct compression method and evaluated for physicochemical characteristics. USP Method-1 (rotating basket method) was used to carry out dissolution study in phosphate buffer pH 6.8. Drug release kinetics determined and comparison of dissolution patterns was done with reference tablets. The polymeric combinations well retarded drug release and drug was released by anamolous non-fickian diffusion mechanism. Dissolution profiles of tested tablets and reference tablets were found not similar. Drug release rate was increased by co-excipients. It was concluded from this research work that this polymeric combination can be used efficiently in designing of controlled release martices.

Evaluation of Standard Loose Plastic Packaging for the Management of Rhyzopertha dominica (F.) (Coleoptera: Bostrichidae) and Tribolium castaneum (Herbst) (Coleoptera: Tenebriondiae).

Three standard foodstuff plastic packaging namely polyethylene (PE), polypropylene (PP), and polyvinylchloride (PVC) were evaluated for management of lesser grain borer Rhyzopertha dominica (F.) (Coleoptera: Bostrichidae) and red flour beetle Tribolium castaneum (Herbst) (Coleoptera: Tenebrionidae). Resistance parameters in packaging were recorded as punctures, holes, penetrations, sealing defects, and invasions with two thicknesses and tested for two lengths of time. Damages like punctures, holes and penetrations by both insects were more in PE packaging however R. dominica made more penetrations in PP than in PE. For both insects sealing defects and invasions were predominant in PVC than in others. Thickness did not affect significantly damage types but significantly more holes and penetrations by R. dominica were in less thickness. Punctures and holes by R. dominica were more after less time period but other damages in packaging were more after more time period. However for T. castaneum all sorts of damages were seen more after more time period. Overall categorization between two insects showed R. dominica made more penetrations and T. castaneum made more invasions compared with their counterparts. Pictures were taken under camera fitted microscope to magnify punctures and holes in different packaging and thicknesses. Insect mortality due to phosphine was more in PP and PE packaging and least in PVC packaging and thickness effect was marginal. T. castaneum mortality was significantly more after 48 h than after 24 h. Damages extent in packaging and fumigation results showed PP to be the best of three packaging materials to manage these insects.

Use of systematic surface roughing to enhance the spatial resolution of the dual-ended readout of axially-oriented 100 mm long LYSO crystals.

In this work we explored the effects of using systematic band patterns of surface roughing to modulate the light transport in a dual-ended readout detector for PET imaging that uses 100 mm long LYSO crystals oriented in the axial direction. The long surfaces of 3 × 2 × 100 mm³ LYSO crystals, initially polished on all sides, were systematically roughed in a band pattern with 0.8 mm bands of roughed surface spaced at 5 mm increments over the central 8 cm of the crystal length. Cases of one to four surfaces of the crystal roughed with this pattern were explored. Two configurations of bands were examined for the opposite surfaces of the crystals: (i) bands created in the same axial location (coinciding bands) and (ii) band locations interleaved (interleaving bands). Each crystal was then wrapped in Teflon and read out at both ends using position sensitive photomultiplier tubes (PSPMTs). An electronically collimated 511 keV photon beam was oriented perpendicular to the long direction of the crystal and data acquired at discrete locations along the crystal length. The ratio of the two PMT signals was used to find the axial position of interaction and axial-positioning resolution in the light sharing direction of the dual-ended readout detector while their sum was used to determine the light output and energy resolution. The axial-positioning resolution corrected for the beam width improved from an average of 8.7 mm FWHM with no surface treatment to 5.9, 3.9 or 3.4 mm FWHM for coinciding band patterns on one, two or four surfaces, respectively. The banding patterns resulted in degraded energy resolution, with a decrease from 11.1% FWHM for the untreated crystal to 12.0%, 13.5% and 13.6% for the patterns on one, two and four surfaces, respectively. When the axial-positioning resolution is corrected for the beam width, we estimated the best resolution for the case of four banded surfaces to be 3.4 mm FWHM in this study. The same axial-positioning resolution was obtained when interleaving bands were created on only two opposite surfaces with a better energy resolution of 12.2%.

A novel missense mutation in the ectodysplasin-A (EDA) gene underlies X-linked recessive nonsyndromic hypodontia.

BACKGROUND: Nonsyndromic hypodontia or congential absence of one or more permanent teeth is a common anomaly of dental development in humans. This condition may be inherited in an autosomal (dominant/recessive) or X-linked (dominant/recessive) mode. Mutations in three genes, PAX9, MSX1, and AXIN2, have been determined to be associated with autosomal dominant and recessive tooth agenesis. Recent studies in a few families showed that mutations in the ectodysplasin A (EDA) gene result in X-linked nonsyndromic hypodontia. METHODS: Genotyping of a five-generation Pakistani family with X-linked isolated hypodontia having three affected men was carried out using EDA-linked polymorphic microsatellite markers on chromosome Xq12-q13.1. To screen for a mutation in the EDA gene, all of its coding exons and splice junction sites were PCR amplified from genomic DNA of affected and unaffected individuals of the family and sequenced directly in an ABI Prism 310 automated DNA sequencer. RESULTS: We successfully mapped the affected locus to chromosome Xq12-q13.1, and found a novel missense mutation (c.993G>C) in the EDA gene in the affected men. The mutation causes substitution of glutamine with histidine (p.Q331H) in the tumor necrosis factor homology domain of EDA. CONCLUSIONS: A mutation identified in this study extends the body of evidence implicating the EDA gene in X-linked nonsyndromic hypodontia and supports the role of EDA-EDAR-EDARADD signaling in the morphogenesis of teeth.

A homozygous nonsense mutation in the human desmocollin-3 (DSC3) gene underlies hereditary hypotrichosis and recurrent skin vesicles.

Desmosomes are the major players in epidermis and cardiac muscles and contribute to intercellular binding and maintenance of tissue integrity. Two important constituents of desmosomes are transmembrane cadherins named desmogleins and desmocollins. The critical role of these desmosomal proteins in epithelial integrity has been illustrated by their disruption in mouse models and human diseases. In the present study, we have investigated a large family from Afghanistan in which four individuals are affected with hereditary hypotrichosis and the appearance of recurrent skin vesicle formation. All four affected individuals showed sparse and fragile hair on scalp, as well as absent eyebrows and eyelashes. Vesicles filled with thin, watery fluid were observed on the affected individuals' scalps and on most of the skin covering their bodies. A scalp-skin biopsy of an affected individual showed mild hair-follicle plugging. Candidate-gene-based homozygosity linkage mapping assigned the disease locus to 8.30 cM (8.51 Mbp) on chromosome 18q12.1. A maximum multipoint LOD score of 3.30 (theta = 0.00) was obtained at marker D18S877. Sequence analysis of four desmoglein and three desmocollin genes, contained within the linkage interval, revealed a homozygous nonsense mutation (c.2129T>G [p.Leu710X]) in exon-14 of the desmocollin-3 (DSC3) gene.