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Novel denovo variants of exome sequences are major cause of pathogenic neurodevelopmental disorders with a dominant genetic mechanism that emphasize their heterogeneity and complex phenotypes. White Sutton syndrome and Gabriele-de-Vries syndrome are congenital neuro-impairments with overlap of severe intellectual disability, microcephaly, convulsions, seizures, delayed development, dysmorphism of faces, retinal diseases, movement disorders and autistic traits. POGZ gene codes for pogo transposable element-derived zinc-finger protein and YY1 gene regulates transcription, chromatin, and RNA-binding proteins that have been associated with White Sutton and Gabriele-de-Vries syndromes, in recent data. We present probands of two unrelated consanguineous families with complicated, unexplained neurocognitive syndromic characteristics clinically undiagnosed. Objectives of the study were to identify altered genetics and protein characteristics underlying molecular pathological pathways in both the patients. Whole exome sequencing identifies novel, denovo missense variant NM_015100.4: c.776 C>T (p. Pro259Leu) in exons 19 of POGZ gene and non-frameshift variant NM_003403.5: c.141_143delGGA (p. Glu47del) in exon 1 of YY1 gene for White Sutton syndrome in eight years five-month-old girl and Gabriele-de-Vries syndrome in seven years eight months old boy residing in Rawalpindi and Chakwal districts of Punjab, Pakistan respectively. Protein modelling for identified variants predicts size and conformation modifications in mutated amino acid residues that lead to damaging effects in the conserved domains expressed as neurological pathophysiology. The present study widens the diversely ethnic and highly inbred gene pool of Punjab, Pakistan population for spontaneously originated deleterious mutations and contributes to the continuously expanding phenotypic canvas. Molecular genetic identification and personalized diagnosis for the patients suffering from complicated neurodevelopmental phenotypes, for better care, management of day-to-day activities and prolonged life span are the utmost hopes., Competing Interests: The authors declare that they have no competing financial interests or relationships that could influence the work presented in the study., (Copyright: This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.)

Background: Cleft lip and/or palate (CLP) is the most common orofacial congenital disability, presenting significant medical, psychological, and social challenges. In Pakistan, the incidence of CLP is high, estimated at one in 523 live births, but accurate data are lacking due to the absence of a birth registry. Early diagnosis and intervention are crucial for improving outcomes. This study evaluated the impact of CLP on patients' quality of life in Karachi, comparing pre- and post-surgical phases., Methods: A sequential exploratory quantitative-qualitative mixed-methods study was conducted at two tertiary care hospitals in Karachi. In the quantitative phase, 280 patients with CLP, either awaiting or post-surgery, completed the Oral Health Impact Profile (OHIP-14) questionnaire to assess oral health-related quality of life (OHRQoL). Based on questionnaire responses, 30 participants were purposively selected for in-depth, semi-structured interviews exploring their experiences. Quantitative data were analyzed using SPSS version 25; qualitative data were analyzed thematically., Results: Quantitative findings revealed significant gender disparities in cleft types and correction status; females had a higher prevalence of unilateral cleft lip, while males had more cleft palate cases. Dental and oral health issues significantly affected daily activities, with higher impacts in cleft palate patients. OHRQoL varied by gender, cleft type, and correction status, with those post-surgery reporting poorer OHRQoL. Qualitative analysis identified six themes: Diagnosis and Early Treatment, Challenges and Impact, Postsurgical Experiences, Support Systems, Healthcare Experiences, and Future Perspectives. Inconsistencies in psychological support, accessibility and financial burdens were presented as significant issues. Sentiment analysis highlighted varied emotions, from despair to hope and gratitude., Conclusions: CLP significantly affects patients' quality of life in Karachi across multiple dimensions. Early diagnosis and surgical intervention are essential but often hindered by financial and accessibility issues. Psychological effects, including low self-esteem and social isolation, highlight the need for integrated mental health support. Family and community support are critical for patient resilience. A comprehensive approach addressing medical, psychological, social, and systemic factors is necessary to improve outcomes for individuals with CLP., Competing Interests: Declarations. Ethics approval and consent to participate: The study received ethical approval from the Research and Ethics Committee of Hamdard University Dental Hospital (1245-03-24) dated 07.03.24. Informed consent was obtained from all subjects. For participants under 18, consent was also secured from parents/legal guardian/s. All experiments were performed in accordance with relevant guidelines and regulations (such as the Declaration of Helsinki). Consent for publication: Not applicable. Competing interests: The authors declare that there is potentially no conflict of interest related to the article., (© 2024. The Author(s).)

Background: Strabismus is a complex oculomotor condition characterized by a misalignment of the visual axis. The genetics of strabismus are poorly defined although a few candidate genes have been identified, among which is the WNT2 gene. Our study was designed to assess the association of single nucleotide polymorphisms (SNPs) of WNT2 in Pakistani strabismus patients., Methods: A total of six SNPs, three intronic and three in the 3́ untranslated region, were screened in the current study. Logistic regression was performed using a dominant, recessive and additive model to determine the association of SNPs with strabismus and its clinical subtypes: esotropia and exotropia. Furthermore, haplotype analysis was performed., Results: Regression analysis revealed an association of rs2896218, rs3779550, rs2285544 and rs4730775 with strabismus under the dominant model. When analyzed separately, rs2896218 and rs2285544 were found to be associated with both esotropia and exotropia, while rs4730775 was significantly associated only with exotropia under the dominant model. Based on clinical parameters, rs2896218, rs2285544 and rs4730775 were also found to be associated with the group of strabismus patients who were diagnosed at birth, but not in the group of patients who were diagnosed later in life. Haplotype analysis revealed that the haplotype A T T (corresponding to rs2896218, rs3779550 and rs2285544) was significantly more prevalent in the strabismus group., Conclusion: Overall, the results of the present study suggest an association of WNT2 polymorphisms with strabismus and its subtypes in the Pakistani population, though further studies are needed to elucidate their role in strabismus etiology., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background : The dopaminergic pathways control neural signals that modulate mood and behaviour along and have a vital role in the aetiology of major depression (MDD), schizophrenia (SHZ) and bipolar disorder (BD). Genome-wide association studies (GWAS) have reported several dopaminergic and cognitive pathway genes association with these disorders however, no such comprehensive data was available regarding the Pakistani population. Objective : The present study was conducted to analyse the 11 genetic variants of dopaminergic and cognitive system genes in MDD, SHZ, and BD in the Pakistani population. Methods : A total of 1237 subjects [MDD n  = 479; BD n  = 222; SHZ n  = 146; and controls n  = 390], were screened for 11 genetic variants through polymerase chain reaction (PCR) techniques. Univariant followed by multivariant logistic regression analysis was applied to determine the genetic association. Results : Significant risk associations were observed for rs4532 and rs1799732 with MDD; and rs1006737 and rs2238056 with BD. However, after applying multiple test corrections rs4532 and rs1799732 association did not remain significant for MDD. Moreover, a protective association was found for three variants; DRD4 -120bp, rs10033951 and rs2388334 in the current cohort. Conclusions : The present study revealed the risk association of single nucleotide polymorphisms (SNPs) rs1006737 and rs2238056 with BD and the protective effect of the DRD4 -120bp variant in MDD and BD, of rs2388334 in BD and of rs10033951 in MDD, BD, and SHZ in the current Pakistani cohort. Thus, the study is valuable in understanding the genetic basis of MDD, BD and SHZ in the Pakistani population, which may pave the way for future functional studies.

Introduction: Evidence shows that cancer treatment-related symptoms could be managed effectively in 8-18 years old children through Digital Health Interventions (DHIs), consequently improving their health-related quality of life (HRQOL). However, limited research is available about digitally mediated educative health interventions for children with cancer from lower-middle income countries like Pakistan. This study aims to develop a videogame intervention for children with cancer and test the clinical efficacy of the videogame concerning HRQOL and cancer treatment-related symptoms. Moreover, the following feasibility outcomes will be recorded: acceptability, appropriateness, cost, feasibility and intervention fidelity., Methods and Analysis: An exploratory sequential mixed methods design is used in this study. In the first phase of the study, we interviewed 28 participants (14 child-parent dyads) and assessed their symptom experiences affecting children's HRQOL. Moreover, their preferences for the development of the videogame were also elicited. Based on the findings from relevant literature and the interviews, we developed the videogame in collaboration with clinical and digital experts in the study's second phase. In the third phase of the study, a pilot randomised controlled trial will be conducted at a Tertiary Care Hospital in Karachi, Pakistan. There will be two groups: the intervention group and the control group. The intervention group children will receive the videogame application for 8 weeks, during which symptom management strategies will be taught to them. Children in the attention control group will receive weekly WhatsApp messages on healthy behaviours.The primary outcome will be the HRQOL of children, and the secondary outcome will be cancer symptoms frequency and distress. These outcomes will be assessed preintervention and 8 weeks post intervention. The feasibility outcomes will be assessed quantitatively and qualitatively through a questionnaire, videogame dashboard, interviews with a subset of intervention group child-parent dyads and a focus group discussion with nurses and doctors, post intervention, respectively., Ethics and Dissemination: The study has been approved by the Ethics Review Committee of the Aga Khan University (2022-6833-21251). Data are accessible only to the research team in a secure form. The findings will be disseminated through publications., Trial Registration Number: ClinicalTrials.gov Identifier NCT05796895, registered in April 2023., Competing Interests: Competing interests: No, there are no competing interests., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Environmental enteric dysfunction (EED) is characterized by reduced absorptive capacity and barrier function of the small intestine, leading to poor ponderal and linear childhood growth., Objectives: To further define gene expression patterns that are associated with EED to uncover new pathophysiology of this disorder., Methods: Duodenal biopsies from cohorts of children with EED from Bangladesh, Pakistan and Zambia were analyzed by immunohistochemistry (IHC) to interrogate gene products that distinguished differentiation and various biochemical pathways in immune and epithelial cells, some identified by prior bulk RNA sequence analyses. Immunohistochemical staining was digitally quantified from scanned images and compared to cohorts of North American children with celiac disease (gluten-sensitive enteropathy) or with no known enteric disease and no pathologic abnormality (NPA) detected in their clinical biopsies., Results: After multivariable statistical analysis, we identified statistically significant (P < 0.05, 2-tailed t-test) elevated signals representing cluster of differentiation 45 (80%; 95% confidence interval [CI]: 24%, 127%), lipocalin 2 (659%; 95% CI: 198%, 1838%), and regenerating family 1 beta (221%; 95% CI: 47%, 600%) and lower signals corresponding to granzyme B (-74%; 95% CI: -82%, -62%), and sucrase isomaltase (-58%; 95% CI: -75%, -29%) in EED biopsies compared with NPA biopsies. Computerized algorithms also detected statistically significant elevation in intraepithelial lymphocytes (49%; 95% CI: 9%, 105%) and proliferation of leukocytes (267%; 95% CI: 92%, 601%) in EED biopsies compared with NPA biopsies., Conclusions: Our results support a model of chronic epithelial stress that decreases epithelial differentiation and absorptive function. The close association of several IHC parameters with manual histologic scoring suggests that automated digital quantification of IHC panels complements traditional histomorphologic assessment in EED., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Environmental enteric dysfunction (EED) is an asymptomatic intestinal disorder associated with growth impairment, delayed neurocognitive development, and impaired oral vaccine responses., Objectives: We set out to develop and validate a histopathologic scoring system on duodenal biopsies from a cohort study of children with growth failure in Bangladesh, Pakistan, and Zambia ("EED") with reference to biopsies from United States children with no clinically reported histologic pathology (referred to hereafter as "normal") or celiac disease., Methods: Five gastrointestinal pathologists evaluated 745 hematoxylin and eosin slide images from 291 children with EED (mean age: 1.6 y) and 66 United States children (mean age: 6.8 y). Histomorphologic features (i.e., villus/crypt architecture, goblet cells, epithelial and lamina propria acute/chronic inflammation, Brunner's glands, Paneth cells, epithelial detachment, enterocyte injury, and foveolar metaplasia) were used to score each histopathologic slide. Generalized estimating equations were used to determine differences between EED, normal, and celiac disease, and receiver operating characteristic curves were used to assess predictive value., Results: Biopsies from the duodenal bulb showed higher intramucosal Brunner's gland scores and lower intraepithelial lymphocyte scores than from the second or third parts of the duodenum (D2/3), so only D2/3 were included in the final analysis. Although 7 parameters differed significantly between EED and normal biopsies in regression models, only 5 (blunted villus architecture, increased intraepithelial lymphocytosis, goblet cell depletion, Paneth cell depletion, and reduced intramucosal Brunner's glands) were required to create a total score percentage (TSP-5) that correctly identified EED against normal biopsies (AUC: 0.992; 95% CI: 0.983, 0.998). Geographic comparisons showed more severe goblet cell depletion in Bangladesh and more marked intraepithelial lymphocytosis in Pakistan., Conclusions: This scoring system involving 5 histologic parameters demonstrates very high discrimination between EED and normal biopsies, indicating that this scoring system can be applied with confidence to studies of intestinal biopsies in EED., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Environmental enteric dysfunction (EED) is a precursor of growth faltering in children living in impoverished conditions who are frequently exposed to environmental toxins and enteropathogens, leading to small bowel inflammatory, malabsorptive, and permeability derangements and low-grade chronic systemic inflammation., Objectives: We explored the association between anthropometrics and duodenal histologic features of EED among children from 3 lower middle-income country centers., Methods: In this cross-sectional study, Pakistani children (n = 63) with wasting, Bangladesh children (n = 116) with stunting or at risk for stunting (height-for-age Z score [HAZ] <-1 but ≥-2), and Zambian children (n = 108) with wasting or stunting received nutritional intervention. Children with anthropometric status refractory to intervention underwent endoscopy. Linear regression models included anthropometric around endoscopy, scores of histology parameters, and a global index score of EED-the total score percent-5 (TSP-5). Multivariable models were adjusted for center, age, sex, and histology slide quality., Results: Intersite variation was observed while exploring the association between anthropometrics and the TSP-5; for example, Pakistani children had the worst HAZ, yet their median TSP-5 score was lower than that of the other 2 centers. Even within each site, no overall pattern of higher TSP-5 score was observed with worsening HAZ. During univariate analysis, TSP-5 (coefficient: 0.01; 95% confidence interval [CI]: 0, 0.02), goblet cell depletion (coefficient: 0.22; 95% CI: 0.06, 0.37), and Paneth cell depletion (coefficient: 0.14; 95% CI: 0.01, 0.27) were associated with HAZ scores; however, they lost statistical significance in the multivariable models, with study center most strongly confounding the relationships seen in univariate models between anthropometry and histology., Conclusions: This study contributes a crucial negative finding that duodenal morphological features did not associate with anthropometric phenotypes; hence, anthropometric measurements may not be a suitable outcome measure for use in EED trials. Trial outcomes may need to be defined by combining the functional and structural elements of the gut to monitor EED., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Environmental enteric dysfunction (EED) is a subclinical syndrome of altered small intestinal function postulated to be an important contributor to childhood undernutrition. The role of small intestinal bacterial communities in the pathophysiology of EED is poorly defined due to a paucity of studies where there has been a direct collection of small intestinal samples from undernourished children. Sixty-three members of a Pakistani cohort identified as being acutely malnourished between 3 and 6 months of age and whose wasting (weight-for-length Z -score [WLZ]) failed to improve after a 2-month nutritional intervention underwent esophagogastroduodenoscopy (EGD). Paired duodenal luminal aspirates and duodenal mucosal biopsies were obtained from 43 children. Duodenal microbiota composition was characterized by sequencing bacterial 16S rRNA gene amplicons. Levels of bacterial taxa (amplicon sequence variants [ASVs]) were referenced to anthropometric indices, histopathologic severity in biopsies, expression of selected genes in the duodenal mucosa, and fecal levels of an immunoinflammatory biomarker (lipocalin-2). A "core" group of eight bacterial ASVs was present in the duodenal samples of 69% of participants. Streptococcus anginosus was the most prevalent, followed by Streptococcus sp., Gemella haemolysans , Streptococcus australis , Granulicatella elegans , Granulicatella adiacens, and Abiotrophia defectiva . At the time of EGD, none of the core taxa were significantly correlated with WLZ. Statistically significant correlations were documented between the abundances of Granulicatella elegans and Granulicatella adiacens and the expression of duodenal mucosal genes involved in immune responses (dual oxidase maturation factor 2, serum amyloid A, and granzyme H). These results suggest that a potential role for members of the oral microbiota in pathogenesis, notably Streptococcus , Gemella, and Granulicatella species, warrants further investigation.IMPORTANCEUndernutrition among women and children is a pressing global health problem. Environmental enteric dysfunction (EED) is a disease of the small intestine (SI) associated with impaired gut mucosal barrier function and reduced capacity for nutrient absorption. The cause of EED is ill-defined. One emerging hypothesis is that alterations in the SI microbiota contribute to EED. We performed a culture-independent analysis of the SI microbiota of a cohort of Pakistani children with undernutrition who had failed a standard nutritional intervention, underwent upper gastrointestinal tract endoscopy, and had histologic evidence of EED in their duodenal mucosal biopsies. The results revealed a shared group of bacterial taxa in their duodenums whose absolute abundances were correlated with levels of the expression of genes in the duodenal mucosa that are involved in inflammatory responses. A number of these bacterial taxa are more typically found in the oral microbiota, a finding that has potential physiologic and therapeutic implications., Competing Interests: The authors declare no conflict of interest.

Background: Hereditary sensory and autonomic neuropathies (HSANs) are rare heterogeneous group of neurological disorders caused by peripheral nerve deterioration. The HSANs sub-clinical classes have clinical and genetic overlap which often lead to misdiagnosis. In the present study a Pakistani family with five affected members suffering from severe neuropathy were genetically analyzed to identify the disease causative element in the family., Methods: Genome wide high-density single nucleotide polymorphism (SNP) microarray analysis was carried out followed by whole exome sequencing of the affected proband and another affected sibling. Shared homozygous regions in all severely affected members were identified through homozygosity mapping approach., Results: The largest homozygous region of 14.1 Mb shared by the five severely affected members of the family was identified on chromosome 2. Subsequent exome sequencing identified a novel single nucleotide deletion c.2658del; p.(Ser887Profs*64) in KIF1A . Segregation analysis revealed that this mutation was homozygous in all five affected individuals of the family with severe clinical manifestation, while members of the family that were heterozygous carriers shared abnormal skin features (scaly skin) only with the homozygous affected members., Conclusions: A novel frameshift mutation p.(Ser887Profs*64) in KIF1A is the potential cause of severe HSANIIC in a Pakistani family along with incomplete penetrance in mutation carriers. We demonstrate that using a combination of different techniques not only strengthens the gene finding approach but also helps in proper sub-clinical characterization along with identification of mutated alleles exhibiting incomplete penetrance leading to intrafamilial clinical variability in HSAN group of inherited diseases.

Background: Studies show that reducing the length of hospital stay (LOS) for surgical patients leads to cost savings. We hypothesize that LOS has a nonlinear relationship to cost of care and reduction may not have a meaningful impact on it. We have attempted to define the relationship of LOS to cost of care. We utilized the itemized bill, generated in real time, for hospital services., Materials: Adult patients admitted under General, Neuro, and Orthopedic surgery over a 3-month period, with an LOS between 4 and 14 days, were the study population. Itemized bill details were analyzed. Charges in Pakistani rupees were converted to US dollar. Ethical exemption for study was obtained., Results: Of the 853 patients, 38% were admitted to General Surgery, 27% to Neurosurgery, and 35% to Orthopedics. A total of 64% of the patients had an LOS between 4 and 6 days; 36% had an LOS between 7 and 14 days. Operated and conservatively managed constituted 82% and 18%, respectively. Mean total charge for operated patients was higher $3387 versus $1347 for non-operated ones. LOS was seen to have a nonlinear relationship to in-hospital cost of care. The bulk of cost was centered on the day of surgery. This was consistent across all services. The last day of stay contributed 2.4%-3.2% of total charge., Conclusions: For surgical patients, the cost implications rapidly taper in the postoperative period. The contribution of the last day of stay cost to total cost is small. For meaningful cost containment, focus needs to be on the immediate perioperative period., (© 2024 International Society of Surgery/Société Internationale de Chirurgie (ISS/SIC).)

Objectives: To highlight the clinical characteristics of paediatric patients presenting with non-Hodgkin's lymphoma, treatment toxicities, and outcome., Methods: The retrospective study was conducted at the Aga Khan University Hospital, Karachi, and comprised data of all paediatric patients aged 0-18 years diagnosed with non-Hodgkin's lymphoma from 2010 to 2020. Demographic characteristics, presentation, treatment provided, complications, if any, and treatment outcome were recorded. Data was analysed using SPSS 21., Results: Of the 92 patients, 69(75.0%) were males. The overall mean age was 14.35±5.80 years. The most common presenting complaint was pyrexia 42(45.7%), the most common diagnosis was Burkitt lymphoma 40(43.5%), the most common complication related to gastrointestinal issues 8(15.7%), and most toxicities were reported with the use of FAB-LMB96 (French American-British Mature B-Cell Lymphoma 96) for B-cell non-Hodgkin's lymphoma 23 (45.1%). Mortality was the outcome in 17(18.5%) cases, while 19(20.7%) patients were lost to follow-up. PFS and OS was 60.4%, and OS 81.3% respectively at 10 years follow-up, median PFS was 17.5 months ([IQR]: 4.5-43.5 months) (p=0.011) and median OS was 33.5 months (IQR: 19.5-84 months) (p=0.007)., Conclusions: Early recognition of symptoms, specialist care, and proper planning can decrease treatment-related complications that result in abandonment.

With an increasing incidence of psychiatric disorders worldwide, there is a need for a better understanding of the population-specific contributing risk factors that are associated with common psychiatric conditions. This study aimed to assess the correlation between socioeconomic, environmental and clinical features associated with major depression (MDD n = 479), bipolar disorder (BD n = 222) and schizophrenia (SHZ n = 146), in the Pakistani population. Multinomial logistic regression and Pearson's correlation were applied to assess the association and correlation between demographic, socioeconomic, environmental, and clinical features of MDD, BD and SHZ. In the present study, MDD was found to be more prevalent than BD and SHZ. The average age at onset (AAO), was observed to be earlier in females with BD and SHZ, in addition, females with a positive family history of MDD, BD and SHZ also had an earlier AAO. The fitted multinomial logistic regression model indicated a significant association of; aggression, tobacco use, drugs abuse, history of head injuries and family history with BD as compared to MDD, while insomnia and suicidality were significantly associated with MDD. Strong positive correlations were observed mainly between age/AAO, AAO/tobacco use and aggression/insomnia in all three cohorts. In conclusion, the present study identifies possible contributing socio-demographic, biological and environmental factors that are correlated and associated with the psychiatric conditions in the Pakistani population., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Objective:  To collect and analyse epidemiologic data of all malignancies by age group and gender for the Karachi population to estimate the cancer incidence of 5-years (2017-2021) and identify major risk factors for setting priorities towards cancer control programs., Study Design: Observational study. Place and Duration of the Study: Karachi Cancer Registry (KCR) Secretariat, Pakistan Health Research Council (PHRC), JPMC, Karachi, from 2017-2021., Methodology: Cancer data of seven tertiary care hospitals of Karachi submitted to KCR during the study period were analysed including age, gender, date of first contact, primary site and ICD coding. All the data was cleaned, merged, and analysed. All patients 0-14 years were classified as 'children', all aged 15-19 years were classified as 'adolescents', and those age 20-years and above as 'adults'. Age standardised incidence rates (ASIR) were determined for both genders., Results: During the last five years (2017-2021), a total of 65,886 malignant cases were received. The distributions seen amongst males and females were 33,510 (51%) and 32,376 (49%), respectively with 60,145 (91.3%) tumours found in adults (≥20 years), 4844 (7.3%) in children, and 897 (1.4%) in adolescents. The three most common tumour sites were oral, liver, and colorectal in males; breast, oral and ovary in females; bone, brain and connective tissue in adolescents; and leukaemia, brain and bone in children. The overall ASIR (%) in males was 89.20 for adults, 9.19 for children, and 1.61 for adolescents. The overall ASIR (%) in females was 93.44 for adults, 5.45 for children, and 1.11 for adolescents., Conclusion: Oral cancer, a largely preventable cancer is the leading cancer in males while breast cancer is the leading cancer in females followed by oral cancer. In adolescents and children, the incidence closely matches most of the world., Key Words: Karachi, Cancer registry, Oral cancer, Breast cancer, Age-standerdised ratio.

Background: Patient safety is a top priority for many healthcare organisations worldwide. However, most of the initiatives aimed at the measurement and improvement of patient safety culture have been undertaken in developed countries. The purpose of this study was to measure the patient safety culture at a tertiary care hospital in Pakistan using the Hospital Survey on Patient Safety Culture (HSOPSC)., Methods: The HSOPSC was used to measure the patient safety culture across 12 dimensions at Aga Khan University Hospital, Karachi. 2,959 individuals, who had been working at the hospital, were administered the HSOPSC in paper form between June and September 2019., Results: The response rate of the survey was 50%. In the past 12 months, 979 respondents (33.1%) had submitted at least one event report. Results showed that the personnel viewed the patient safety culture at their hospital favourably. Overall, respondents scored highest in the following dimensions: 'feedback and communication on error' (91%), 'organisational learning and continuous improvement' (85%), 'teamwork within units' (83%), 'teamwork across units' (76%). The dimensions with the lowest positive per cent scores included 'staffing' (40%) and 'non-punitive response to error' (41%). Only the reliability of the 'handoffs and transitions', 'frequency of events reported', 'organisational learning' and 'teamwork within units' was higher than Cronbach's alpha of 0.7. Upon regression analysis of positive responses, physicians and nurses were found to have responded less favourably than the remaining professional groups for most dimensions., Conclusion: The measurement of safety culture is both feasible and informative in developing countries and could be broadly implemented to inform patient safety efforts. Current data suggest that it compares favourably with benchmarks from hospitals in the USA. Like the USA, high staff workload is a significant safety concern among staff. This study lays the foundation for further context-specific research on patient safety culture in developing countries., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Meta-GWAS report numerous variants associated with type 2 diabetes (T2D), however, for diabetic retinopathy (DR) no loci achieved genome-wide significance. There are limited candidate gene analyses for T2D and/or DR reported from the Pakistani population. Therefore, the current study was designed to evaluate the genetic association of 10 loci with T2D, non-proliferative DR (NPDR), and proliferative DR (PDR). In total 375 T2D cases and 205 controls were collected. The T2D cases included diabetic no retinopathy (n = 196), NPDR (n = 95), and PDR (n = 84). Genomic DNA was isolated, and 19 SNPs were genotyped. To determine association of SNPs with T2D, logistic regression analyses were performed adjusting for age and sex. Moreover, for association of SNPs with NPDR and PDR logistic regression analyses adjusting for diabetes duration and age of T2D onset were performed. In multivariate analysis, the minor alleles of rs1043618 [G > C, odds ratio (OR) 95% confidence interval (CI) = 1.45 (1.13-1.87), p = 4.00E-3], rs3807987 [G > A, 1.87 (1.22-2.94), p = 0.01], rs12672038 [G > A, 1.53 (1.04-2.30), p = 0.03] and rs2055858 [G > C, 1.70 (1.20-2.43), p = 3.00E-3] were associated with higher risk while rs1801133 (C > T, 0.59 (0.42-0.83), p = 2.28E-3) was associated with a lower risk of T2D. Moreover, minor alleles of rs2055858 [G > C, 1.77 (1.17-2.68), p = 0.02], and rs3759890 [C > G, 2.17 (1.39-3.39), p = 4.00E-3] showed an association with PDR when compared with DNR. However, only the association of rs1801133 survived multiple test correction. Hence, we report that rs1801133 is associated with T2D in the Pakistani population. In addition, out of studied 10 genes 8 proteins had higher interactions among themselves that are predicted to be partially biologically connected, as a group., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022. Published by Elsevier B.V.)

Over the years, several developing countries have been suffering from high infant and child mortality rates, however, according to the recent statistics, Pakistan falls high on the list. Our narrative review of copious research on this topic highlights that several factors, such as complications associated with premature births, high prevalence of birth defects, lack of vaccination, unsafe deliveries, poor breastfeeding practices, complications during delivery, sudden infant death syndrome (SIDS), poor socioeconomic conditions, and a struggling healthcare system, have influenced these rates. Bearing in mind the urgency of addressing the increased infant and child mortality rate in Pakistan, multiple steps must be taken in order to prevent unnecessary deaths. An effective initiative could be spreading awareness and education among women, as a lack of education among women has been indirectly linked to increased child mortality in Pakistan across many researches conducted on the issue. Furthermore, the government should invest in healthcare by hiring more physicians and providing better supplies and improving infrastructure, especially in underdeveloped areas, to decrease child mortality due to lack of clean water and poor hygiene. Lastly, telemedicine should be made common in order to provide easy access to women who cannot visit the hospital.

Purpose: Strabismus (STBMS) is a multifactorial ocular disorder in children that leads to misalignment of the eyes. Insulin-like growth factor 1 ( IGF1 ) has been shown to be involved in the development of extraocular muscles and myopia; however, data are limited on the genetic associations of IGF1 with STBMS in Pakistan., Methods: Two hundred seventy-four STBMS cases and 272 unaffected controls were recruited, and their DNA was extracted. Two IGF1 single nucleotide polymorphisms, rs6214 and rs5742632, were genotyped using PCR-restriction fragment length polymorphism. Univariate logistic regression analysis was performed to determine the association of these single nucleotide polymorphisms with STBMS, and the results were adjusted for age and sex. In addition, 26 extraocular muscle tissues were collected from patients with STBMS undergoing squint correction surgery, along with 3 deceased control samples. IGF1 mRNA expression was measured by quantitative PCR; the Mann-Whitney U test was applied, and fold change was calculated. Logistic regression analysis was applied to determine the association of RNA expression and fold change with genotype., Results: Multivariate logistic regression analysis revealed that rs5742632 (odds ratio [95% confidence interval] = 1.05[1.01-1.06], p = 0.03) is associated with STBM. Moreover, rs6214 (1.03[1.01-1.05], p = 0.03) and rs5742632 (1.09[1.04-1.11], p = 0.04) were associated with exotropia. Statistically, no significant difference in IGF1 mRNA expression in the extraocular muscles between the STBMS cases and the controls was observed., Conclusions: IGF1 polymorphisms rs5742632 (A>G) and rs6214 (C>T) are plausible risk factors for the development of exotropia. However, the physiologic mechanism requires further evaluation., (Copyright © 2022 Molecular Vision.)

Objective: To identify the local patterns of manifestations, organ involvement other than lungs, diagnostic tools and treatment regimens related to patients of sarcoidosis., Methods: The retrospective study was conducted from November 1, 2019, to February 28, 2020, at the Aga Khan University Hospital, Karachi, and comprised data of sarcoidosis patients who needed hospitalisation between 2009 and 2019. The entire clinical spectrum was noted based on organ involvement. Data was analysed using SPSS 21., Results: Of the 80 patients, 53(66.3%) were women. The overall mean age at diagnosis was 52.0±13.5 years. Pulmonary sarcoidosis was found in 60(75%) patients, while 13(16.3%) had extrapulmonary manifestations, and 6(8.8%) had both pulmonary and extrapulmonary involvement. None of the patients had hypercalcaemia, while antinuclear antibodies were positive in 2 (18.2%) patients. In terms of treatment, 75(93.8%) patients received corticosteroids. Acute exacerbation of interstitial lung disease was the most common reason of hospitalisation 16(20%). Mortality was the outcome in 11(14.7%) cases., Conclusions: Sarcoidosis was found to be more prevalent in women aged 50 years and above. A quarter of patients had extrapulmonary manifestation, while interstitial lung disease was the most common complication.

Pakistan is endemic to a number of viral infections, owing to its humid climate, topographical variation, soaring population, and lack of education and awareness. These viruses may have several different modes of transmission, including respiratory or airborne transmission, sexual transmission, blood-borne, fecal-oral transmission, vector-borne transmission, and transmission following an organ transplant. Although several different microorganisms are responsible for causing these infections, a few viruses are found more commonly in Pakistan and are primarily responsible for causing infections. In this study, we present a review of the most recent studies on different viruses, transmitted through various transmission routes, found commonly in Pakistan, along with the prevalence of each, and recommend control measures required against these viruses., Competing Interests: No Conflict of Interest is declared, (Copyright (c) 2022 Zehra Naseem, Maaha Ayub, Sharaf Ali Shah, Syed Asad Ali, Syed Hani Abidi.)

Background: The underperformance of oral vaccines in children of low- and middle-income countries is partly attributable to underlying environmental enteric dysfunction (EED)., Methodology: We conducted a longitudinal, community-based study to evaluate the association of oral rotavirus vaccine (Rotarix®) seroconversion with growth anthropometrics, EED biomarkers and intestinal enteropathogens in Pakistani infants. Children were enrolled between three to six months of their age based on their nutritional status. We measured serum anti-rotavirus immunoglobulin A (IgA) at enrollment and nine months of age with EED biomarkers and intestinal enteropathogens., Results: A total of 391 infants received two doses of rotavirus (RV) vaccine. 331/391 provided paired blood samples. Of these 331 children, 45% seroconverted at 9 months of age, 35% did not seroconvert and 20% were seropositive at baseline. Non-seroconverted children were more likely to be stunted, wasted and underweight at enrollment. In univariate analysis, insulin-like growth factor (IGF) concentration at 6 months were higher in seroconverters, median (25th, 75th percentile): 26.3 (16.5, 43.5) ng/ml vs. 22.5 (13.6, 36.3) ng/ml for non-seroconverters, p-value = 0.024. At nine months, fecal myeloperoxidase (MPO) concentrations were significantly lower in seroconverters, 3050(1250, 7587) ng/ml vs. 4623.3 (2189, 11650) ng/ml in non-seroconverted children, p-value = 0.017. In multivariable logistic regression analysis, alpha-1 acid glycoprotein (AGP) and IGF-1 concentrations were positively associated with seroconversion at six months. The presence of sapovirus and rotavirus in fecal samples at the time of rotavirus administration, was associated with non-seroconversion and seroconversion, respectively., Conclusion: We detected high baseline RV seropositivity and impaired RV vaccine immunogenicity in this high-risk group of children. Healthy growth, serum IGF-1 and AGP, and fecal shedding of rotavirus were positively associated with RV IgA seroconversion following immunization, whereas the presence of sapovirus was more common in non-seroconverters., Trial Registration: Clinical Trials ID: NCT03588013., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Aims: Cataract formation is accelerated by hyperglycemia due to the excessive production of oxidative stress. This study aimed to examine the underlaying role of glutathione peroxidase 1 (GPX1) rs1800668, catalase (CAT) rs1001179 and superoxide dismutase 1 (SOD1) 50 bp Indel promotor region variants in the pathogenesis of cataract in patients with diabetes., Methods: A population-based case-control study of n=680 individuals was conducted which comprised of four respective groups: type 2 diabetes mellitus, diabetic cataract, senile cataract patients and controls. Screening of genotypes was performed by allele-specific (AS) and conventional polymerase chain reaction (PCR). Statistical testing was carried out using SPSS© 20.0, MedCal© and SNPStats© software's. Bioinformatics analysis of linkage disequilibrium was done by HaploView© software 7.0., Results: GPX1 (rs1800668) showed significant association with higher susceptibility of opacification in type 2 diabetes mellitus (χ 2 =23.0, Adjusted OR=1.63, 95% CI: 1.05-2.49, p<0.001). A protective role was anticipated by CAT variant (rs1001179) for the development of resistance against the pathogenicity of cataract with diabetes (χ 2 = 107, Adjusted OR=0.17, 95% CI: 0.10-0.29, p<0.001). Linkage disequilibrium (LD) plot of GPX1 and CAT variants revealed that CTC-CTT haplotypes demonstrated the presence of linkage (D'=1.0) and co-inheritance (LOD=13.84) in patients of diabetic cataract., Conclusions: GPX1 (rs1800668) variant may serve as an antioxidant biomarker for the assessment of risk for cataract in type 2 diabetes mellitus. GPX1 enzyme owed an antioxidant activity which can reduce the oxidative stress and hence could develop resistance in cataractogenesis. The findings could be beneficial as a potential target to the future pharmacogenomic studies of cataract prevention and eradication in diabetes mellitus., (© 2021. Springer-Verlag Italia S.r.l., part of Springer Nature.)

Environmental enteric dysfunction (EED) is a subclinical condition of intestinal inflammation, barrier dysfunction and malabsorption associated with growth faltering in children living in poverty. This study explores association of altered duodenal permeability (lactulose, rhamnose and their ratio) with higher burden of enteropathogen in the duodenal aspirate, altered histopathological findings and higher morbidity (diarrhea) that is collectively associated with linear growth faltering in children living in EED endemic setting. In a longitudinal birth cohort, 51 controls (WHZ > 0, HAZ > -1.0) and 63 cases (WHZ< -2.0, refractory to nutritional intervention) were recruited. Anthropometry and morbidity were recorded on monthly bases up to 24 months of age. Dual sugar assay of urine collected after oral administration of lactulose and rhamnose was assessed in 96 children from both the groups. Duodenal histopathology (n = 63) and enteropathogen analysis of aspirate via Taqman array card (n = 60) was assessed in only cases. Giardia was the most frequent pathogen and was associated with raised L:R ratio (p = 0.068). Gastric microscopy was more sensitive than duodenal aspirate in H. pylori detection. Microscopically confirmed H. pylori negatively correlated with HAZ at 24 months (r = -0.313, p = 0.013). Regarding histopathological parameters, goblet cell reduction significantly correlated with decline in dual sugar excretion (p< 0.05). Between cases and controls, there were no significant differences in the median (25th, 75th percentile) of urinary concentrations (μg/ml) of lactulose [27.0 (11.50, 59.50) for cases vs. 38.0 (12.0, 61.0) for controls], rhamnose [66.0 (28.0, 178.0) vs. 86.5 (29.5, 190.5)] and L:R ratio [0.47 (0.24, 0.90) vs. 0.51 (0.31, 0.71)] respectively. In multivariable regression model, 31% of variability in HAZ at 24 months of age among cases and controls was explained by final model including dual sugars. In conclusion, enteropathogen burden is associated with altered histopathological features and intestinal permeability. In cases and controls living in settings of endemic enteropathy, intestinal permeability test may predict linear growth. However, for adoption as a screening tool for EED, further validation is required due to its complex intestinal pathophysiology., Competing Interests: The authors have declared that no competing interests exist.

Schistosomiasis is rarely seen in Pakistan and is generally not very high on the list of differential diagnoses. However, it is an important cause of haematuria in certain endemic areas. It can affect multiple organs including the bladder, liver and lungs. We present a case of a young Pakistani male, travelling to and from Africa, who presented with complains of haematuria and suprapubic discomfort. Final pathologic diagnosis was urinary schistosomiasis (hematobium species). This case is particularly notable for the characteristic sago nodules identified on cystoscopy. It is important to consider schistosomiasis in the differential of haematuria in such scenarios as it confers significant morbidity if left untreated. Key Words: Schistosomiasis, Schistosoma hematobium, Haematuria, Urinary bladder.

Purpose: The aim of this study was to evaluate the feasibility and effectiveness of the Parent Empowerment Program (PEP) to help caretakers deliver a home program to promote developmental activities and gross motor function in their children with Down syndrome., Methods: Parents attended a 14-month program with training sessions 1-4 times a month. Outcomes were measured using a change in the Gross Motor Function Measure (GMFM-88) at baseline and assessment one., Results: Forty-eight families participated in the PEP. Children's mean age was 16.2 ± 10.8 months. There were significant changes in GMFM-88 scores between baseline and assessment one; t (30) =-9.158, p< 0.001; 95% CI -14.6 - -22.9. Previous hospitalization significantly affected GMFM scores., Conclusion: This study describes a clinically applied research that focuses on program design, development and evaluation. Findings indicate that the PEP is effective in improving gross motor function in children with Down's syndrome in Pakistan. Parents were satisfied with the program outcomes and were able to cope with the requirements at home. The PEP had favorable outcomes and may be an effective method to support PT services in resource poor countries.

Objective: Brain tumors are the second most common pediatric malignancy and the most common cause of cancer-related mortality and morbidities. Major advances in terms of surgery, radiation, and chemotherapy have led to better outcomes in developed countries. Delayed diagnosis, advanced disease at presentation, late referrals, nosocomial infections, delays to radiotherapy, and poor support services are the major reasons for poorer outcomes in developing countries. Little is known about the profile of brain tumors in Pakistan. This study aims to evaluate the epidemiology, management, and clinical outcomes of children with brain tumors in Pakistan in a single tertiary care center., Methods/materials: All children (0-16 years) with primary CNS tumors from 2004 to 2014 at Aga Khan University Hospital were reviewed retrospectively for clinical data, demographics, radiological findings, management, and outcome., Results: One hundred seventy-five children were included in the study. Male to female ratio was 1.4:1. Most of the patients were in 5-10 years age group (38.9%). Most common presenting complains were headache 115 (65.7%) and vomiting 100 (57.1%). Predominant site was infratentorial 93 (53%). Glial tumors were 105 (60%) followed by embryonal 40(22.9%), craniopharyngiomas 25 (14.3%), and germ cell 1 (0.6%). Astrocytomas (25.7%) were the most common glial tumors while medulloblastoma (15.4%) was the most common embryonal tumor. Majority of the patients underwent surgical resection (78.8%). Radiation was given to 47 (26.8%) patients. A half of the patients, 89 (50%), were lost to follow-up. Forty-two (24%) patients expired, 20 (11.4%) are alive with residual disease while 15 patients (8.5%) were cured with no evidence of recurrence and regular follow-ups., Conclusion: This is the only study from Pakistan showing demographics of the childhood brain tumors. Significant improvement needs to be made for timely diagnosis, early referrals, and collaborated team efforts with multidisciplinary tumor board to improve outcome.

Environmental Enteric Dysfunction (EED) is an acquired small intestinal inflammatory condition underlying high rates of stunting in children <5 years of age in low- and middle-income countries. Children with EED are known to have repeated exposures to enteropathogens and environmental toxins that leads to malabsorptive syndrome. We aimed to characterize association of linear growth faltering with enteropathogen burden and subsequent changes in EED biomarkers. In a longitudinal birth cohort (n = 272), monthly anthropometric measurements (Length for Age Z score- LAZ) of asymptomatic children were obtained up to 18 months. Biological samples were collected at 6 and 9 months for the assessment of biomarkers. A customized TaqMan array card was used to target 40 enteropathogens in fecal samples. Linear regression was applied to study the effect of specific enteropathogen infection on change in linear growth (ΔLAZ). Presence of any pathogen in fecal sample correlated with serum flagellin IgA (6 mo, r = 0.19, p = 0.002), fecal Reg 1b (6 mo, r = 0.16, p = 0.01; 9mo, r = 0.16, p = 0.008) and serum Reg 1b (6 mo, r = 0.26, p<0.0001; 9 mo, r = 0.15, p = 0.008). At 6 months, presence of Campylobacter [β (SE) 7751.2 (2608.5), p = 0.003] and ETEC LT [β (SE) 7089.2 (3015.04), p = 0.019] was associated with increase in MPO. Giardia was associated with increase in Reg1b [β (SE) 72.189 (26.394), p = 0.006] and anti-flic IgA[β (SE) 0.054 (0.021), p = 0.0091]. Multiple enteropathogen infections in early life negatively correlated with ΔLAZ, and simultaneous changes in gut inflammatory and permeability markers. A combination vaccine targeting enteropathogens in early life could help in the prevention of future stunting., Competing Interests: The authors have declared that no competing interests exist.

This study investigates the pharmacological potential of Adiantum incisum, Alternanthera pungens and Trichodesma indicum. Biological activities of plant extracts (aqueous, methanolic and n-hexane extracts of whole plants) were screened by antitumor potato disc assay (10000, 1000, 100, 10 ppm doses), antifungal tube dilution assay (50, 25, 12.5, 6.25mg/ml) and antioxidant DPPH/reducing power assays (250, 200, 150, 100, 50μg/ml). Significant amount of alkaloids (230.83±30.20mg/g) in Adiantum incisum with lowest amount of phenolics in Alternanthera pungens (43.45 ±14.22μg/mg) were detected. Significant antitumor potential (p<0.05) was revealed by Trichodesma indicum n-hexane extract (85% tumor inhibition; IC 50 <10ppm). Moderate to significant antifungal activity (50.73%-78.3%) was shown against Aspergillus niger by Adiantum incisum extracts. Hexane extract of Trichodesma indicum revealed significant antifungal activity (98.9% inhibition) against Mucor specie. Methanolic extracts of all plants displayed significant DPPH radical scavenging potential (96.72%-60.33%; IC 50 <50μg/ml) and Ferric power reducing ability with absorbance values (0.164-0.942) very close to standard ascorbic acid. Present study supports the extensive use of these plants in folk medicine and also promotes elaborative in-vivo investigations, isolation of pure therapeutic compounds and formulation of plant-based drugs.

Objective: To determine the various constituents of commercial, broiler chicken feed and the presence of these constituents in their meat., Methods: The experimental study was conducted at the Pakistan Council of Scientific and Industrial Research laboratory, Karachi. Samples of commercial broiler chicken feed and meat were collected in 2015 from a large poultry farm that supplies chicken meat to various suburban areas of the city. Another set of organic chickens were bred in an animal house. The samples of feed, meat and droppings were then analysed for the estimation of basic constituents and additives in the laboratory. Data was analysed using SPSS 20.0., Results: The constituents were measured in 26 samples of chicken meat from each group. Calories (p<0.01), amount of protein (p<0.01), total fats (p<0.05), cholesterol (p<0.01), saturated fats (p<0.01), monounsaturated (p<0.05) and polyunsaturated fats (p<0.01) were significantly increased in commercial broiler chicken compared to that of organic chicken meat. The commercial chicken feed was found to contain crude carbohydrate, crude protein, crude fat, crude fibre, vitamins, amino acids, premixes of vitamins and toxicities of roxarsone, melamine and pesticides. Additive constituents were also present in the commercial chicken meat. These components were absent in organic chicken meat and droppings which suggests that they were absent in their feeding contents., Conclusions: Organic chickens were found to be safer for consumption than commercial chickens.

Background: Acute lymphoblastic leukemia (ALL) is the most common cancer of childhood. Some evidence suggests differences in clinical and cytogenetic characteristics of ALL based on geographic and ethnic variations. However, data on ALL characteristics and early outcome of therapy from low/middle-income countries such as Pakistan are scanty., Procedure: A prospective, multi-institutional cohort study in Karachi enrolled 646 newly diagnosed children with ALL over 3 years. Standard forms were used to collect demographic, clinical, and laboratory data at presentation and at the end of induction., Results: Of the total, 66.1% (n = 427) were males. Median age was 6 (mean ± SE 6.87 ± 0.16; range 0.16-18) years. The most common clinical presentation was fever (88.7%). BPC-ALL was diagnosed in 78.5%, while 17.5% had T-ALL; 28.8% had a WBC >50 × 10(9) /L. With 316 patients karyotyped, hypodiploidy and hyperdiploidy were seen in 5.1% and 10.7%, respectively. Of those tested, ETV6-RUNX1 translocation was detected in 13.2%, while BCR-ABL1 translocation and MLL gene rearrangements were seen in 7.3% and 4.6%, respectively. The cumulative loss to follow up before and during induction was 12.8% (n = 83) and 11.5% (n = 74) died before or during this phase. Induction was successfully completed by only 75.6% (n = 489) of the entire cohort and 69.6% (n = 450) achieved remission., Conclusion: These patients had ALL with higher risk features than that reported from developed countries. One quarter failed to complete induction chemotherapy. This suboptimal result requires further study and development of innovative interventions, particularly focusing on the causes and solutions for late referral, abandonment, and infections., (© 2015 Wiley Periodicals, Inc.)

Objective: To assess the morbidity and mortality associated with complicated diverticulitis in Pakistan., Methods: The retrospective case series was conducted at an urban tertiary care university hospital of Karachi, Pakistan, comprising data from December 1989 to November 2010. International Classification of Diseases codes for diverticular disease and diverticulitis with abscess, fistula, stricture, bowel obstruction and perforation were obtained from the medical record department. SPSS 19 was used for statistical analysis., Results: A total of 60 (1.9%) cases with complicated diverticulitis were located from among 3170 records reviewed. Mean age was 62.7 +/- 13 years with male-to-female ratio being 36:24. In 37 (62%) patients, the diagnosis was established on computed tomography scan of the abdomen, followed by barium enema in 12 (20%) and colonoscopy in 11 (18%). Post-operative morbidity was observed in 24 (40%) and 7 (16%) expired within 28 days of surgery. Post-operative intra-abdominal sepsis, wound dehiscence and incisional hernia were significantly associated with generalised peritonitis (p < 0.05), while admission to intensive care unit was associated with age over 60 years and faecal peritonitis. Post-operative mortality was significantly associated with high American Society of Anaesthesiologists-score III and IV and age above 60 years., Conclusion: Complicated diverticulitis carries significant morbidity and mortality in Pakistani population. Since the trend is on the rise, therefore we propose a prospective multi-centre cohort study to understand the spectrum of disease, management and identification of risk factors to achieve the best possible outcomes in patients with complicated diverticulitis.

Introduction: Varicella zoster infection (VZI) is well recognized as a potential cause of morbidity and mortality in immunocompromised pediatric oncology patients (POP). The purpose of this study was to describe the clinical profile and risk factors for complications and outcomes of VZI in POP treated with acyclovir., Methodology: Medical records of all POP with a discharge diagnosis of VZI over a period of seven years (2005-2011) were reviewed. The demographic features, underlying malignancy, risk factors for VZI, complications, and outcomes were recorded., Results: Thirty-six POP with VZI were identified. Leukemia was the most common underlying malignancy (n = 20, 58.8%), followed by lymphoma (n = 7, 20.6%) and solid organ tumors (n = 7, 20.6%). Most of the cases (41%) were observed in children under five. All patients were treated with acyclovir. Varicella-related complications developed in 10 (29%) patients. The most frequent complication was bloodstream infection (n = 3, 8.8%), followed by pneumonia (n = 2, 5.9%), skin infection (n = 2, 5.9%), hepatitis, renal failure, and encephalitis. Independent risk factors associated with complications were age < five years, weight for age < fifth percentile, delay in seeking care (> seven days after onset of symptoms) and severe neutropenia (ANC < 500/cm). One child died secondary to varicella encephalitis., Conclusion: Our data suggests that young age, poor health-seeking behavior, severe neutropenia, and being underweight are the major risk factors for the development of varicella-related complications in POP in developing countries. These complications could be favorably modified through active immunization of immunocompetent children.

Background: Cytogenetic abnormalities have important implications in diagnosis and prognosis of acute leukemia and are now considered an important part of the diagnostic workup at presentation. Karyotype, if known at the time of diagnosis, guides physicians to plan appropriate management strategies for their patients., Aim and Objectives: To determine the cytogenetic profile of acute lymphoblastic leukemia (ALL) in Pakistani children in order to have insights regarding behavior of the disease., Materials and Methods: A retrospective analysis of all the cases of ALL (<15years old) diagnosed at Aga Khan University from January 2006 to June 2011 was performed. Cytogenetic analysis was made for all cases using the trypsin-Giemsa banding technique. Karyotypes were interpreted using the International System for Human Cytogenetic Nomenclature (ISCN) criteria., Results: A total of 153 patients were diagnosed as ALL during the study period, of which 127 samples successfully yielded metaphase chromosomes. The male to female ratio was 1.8:1. A normal karyotype was present in 51.2% (n=65) of the cases whereas 48.8% (n=62) had an abnormal karyotype. Most of the abnormal cases showed hyperdiploidy(13.4%) followed by t(9;22)(q34;q11.2) (7.08%)., Conclusions: This study revealed a relative lack of good prognostic cytogenetic aberrations in Pakistani children with ALL.

Objective: To evaluate the demographic features, outcome and prognostic factors seen in children with acute lymphoplastic leukaemia at a tertiary care hospital., Methods: The retrospective descriptive study was conducted at Aga Khan University Hospital, Karachi, comprising data related to children below 15 years of age and treated between January 1997 and December 2006. Kaplan Meir survival curves were used to describe overall and event-free survival rates. Cox Proportional Hazards model was used to describe factors associated with death and relapse. SPSS 16 was the main statistical tool., Results: Of the total 121 children diagnosed with the condition, 79 (65.3%) were males; 86 (71.1%) patients were between 1-9 years of age; Immunophenotyping was done in 99 (81.81%) patients: 86 (87%) cases had precursor B and 13 (13.13%) had precursor T. Of the total, 106 (87.6%) patients opted for treatment, while 15 (11.6%) were lost to follow-up. Besides, 26 (21.7%) patients had at least one relapse; the most common site being bone marrow in 13 (50%) followed by central nervous system in 9 (36.6%). There were 20 (16.5%) deaths in the sample. Infection was the most frequent cause of death. The event-free survival and overall survival was 63% (n = 76) and 65% (n = 79) respectively., Conclusion: Through the clinical characteristics of children with acute lymphoblastic leukamia were similar to those reported in literature, the outcomes were inferior. The high rate of infections and relapse warrant better supportive care and risk-based approach.

Objective: In this study, we aimed to investigate the genetic background of thyroid dyshormonogenesis (TDH)., Context: Thyroid dyshormonogenesis comprises 10-15% of all cases of congenital hypothyroidism (CH), which is the most common neonatal endocrine disorder, and might result from disruptions at any stage of thyroid hormone biosynthesis. Currently seven genes (NIS, TPO, PDS, TG, IYD, DUOX2 and DUOXA2) have been implicated in the aetiology of the disease., Design: As TDH is mostly inherited in an autosomal recessive manner, we planned to conduct the study in consanguineous/multi-case families., Patients: One hundred and four patients with congenital TDH all coming from consanguineous and/or multi-case families., Measurements: Initially, we performed potential linkage analysis of cases to all seven causative-TDH loci as well as direct sequencing of the TPO gene in cases we could not exclude linkage to this locus. In addition, in silico analyses of novel missense mutations were carried out., Results: TPO had the highest potential for linkage and we identified 21 TPO mutations in 28 TDH cases showing potential linkage to this locus. Four of 10 distinct TPO mutations detected in this study were novel (A5T, Y55X, E596X, D633N)., Conclusions: This study underlines the importance of molecular genetic studies in diagnosis, classification and prognosis of CH and proposes a comprehensive mutation screening by new sequencing technology in all newly diagnosed primary CH cases., (© 2012 John Wiley & Sons Ltd.)

Bardet-Biedl Syndrome is a multisystem autosomal recessive disorder characterized by central obesity, polydactyly, hypogonadism, learning difficulties, rod-cone dystrophy and renal dysplasia. Bardet-Biedl Syndrome has a prevalence rate ranging from 1 in 100,000 to 1 in 160,000 births although there are communities where Bardet-Biedl Syndrome is found at a higher frequency due to consanguinity. We report here a Pakistani consanguineous family with two affected sons with typical clinical features of Bardet-Biedl Syndrome, in addition to abnormal liver functioning and bilateral basal ganglia calcification, the latter feature being typical of Fahr's disease. Homozygous regions obtained from SNP array depicted three known genes BBS10, BBS14 and BBS2. Bidirectional sequencing of all coding exons by traditional sequencing of all these three genes showed a homozygous deletion of 10 nucleotides (c.1958&#95;1967del), in BBS10 in both affected brothers. The segregation analysis revealed that the parents, paternal grandfather, maternal grandmother and an unaffected sister were heterozygous for the deletion. Such a large deletion in BBS10 has not been reported previously in any population and is likely to be contributing to the phenotype of Bardet-Biedl Syndrome in this family., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Introduction: Pediatric oncology patients are at increased risk of contracting healthcare-associated infections (HAIs), which are responsible for increased morbidity and mortality rates as well as treatment costs.  This study aimed to identify the frequency of HAIs among pediatric oncology patients and their outcome., Methodology: Pediatric oncology patients admitted between January 2009 and June 2010 in a pediatric ward at Aga Khan University Hospital, Karachi, Pakistan, who developed HAIs, were analyzed., Results: A total of 90 HAIs were identified in 32 patients in 70 admissions. The HAI rate among pediatric oncology patients was 3.1/100 admission episodes. Bloodstream infections (63 episodes, 90.0%) were the most common, followed by urinary tract infection (two episodes, 2.9%). Gram-positive infections were seen in 54 (60%) patients, followed by Gram-negative infection in 34 (37.8%), and fungi in 2 (2.8%) cases. Coagulase negative staphylococci was the most common Gram-positive and Escherichia coli and Pseudomonas aeruginosa were most common Gram-negative infections. Mortality rate among pediatric oncology patients who developed HAIs was 12.5% (4/32). Total parental nutrition use and length of stay longer than 30 days were the identified risk factors associated with increased mortality among pediatric oncology patients who developed HAIs., Conclusion: We report an HAI rate among pediatric oncology patients of 3.1/100 admission episodes with a mortality rate of 12.5% in Pakistan. Further studies should be done, especially in the developing world, to identify the risk factors associated with increased mortality among pediatric oncology patients so that adequate measures can be taken to reduce the mortality among these patients.

Objective: To document the demographics and outcome of children with Acute Myeloid Leukemia (AML) treated at a tertiary care facility of Pakistan., Methods: A retrospective study was conducted at Aga Khan University on children (less than 15 years) diagnosed to have AML between January 2000 to May 2007.Total 40 cases were diagnosed out of which 37 charts were available for review., Results: The average age of presentation was 8.5 +/- 4.5 years and 75% were males. The most common presenting feature was fever in 83% followed by bleeding in 41% and pallor in 39%. Initial WBC of > 100,000 was seen in 19% of patients. The most common FAB subtype was M4 39%. Twenty three patients underwent treatment out of which 12 patients are alive and in remission. Majority were followed up around 2 years and 6 months. Out of the 11 patients who died three had resistant disease, four relapsed and rest died due to sepsis mostly during induction., Conclusions: The most common sub type in our study is AML M4 although AML M2 is reported as predominant subtype. About a third of the patients could not start or complete therapy due to financial constraints. The overall survival for our patients who completed therapy was 52%.

Objective: To evaluate the outcome and prognostic factors for oncology patients in the PICU of a tertiary care centre in a developing country., Methods: A retrospective chart review was done to assess the outcome of children with cancer in the pediatric intensive care unit (PICU) of a developing country from January 2000 through December 2009. 74 medical records were reviewed for data regarding demographics, admitting diagnosis, Pediatric Risk of Mortality (PRISM) III score and the therapeutic modalities used., Results: Of the 74 children admitted with mean age of 6.3 years (range 1-14); 53 were boys (71.6%) and 21 were girls (28.4%). Majority of the patients (37%) had hematological malignancy. The major indication for PICU admission was post-operative care (32%) followed by acute respiratory failure (24.3%), neurological complications (20.3%). The median PRISM III score was 7.0 (range 0-30). The overall mortality was 32.4% (24/74). The mean length of PICU stay was 6.3 days (ranging from 0-28 days). Seventy percent (52/74) of the children had multi organ failure (MOF). Mortality was significantly related to presence of multi-organ dysfunction syndrome and high PRISM III scores on admission and use of inotropic support with mechanical ventilation., Conclusions: The mortality in children with cancer in PICU in the present study is comparable to previous reports and is related to higher PRISM III score, presence of multiorgan dysfunction syndrome and use of ICU therapies.

Background: With advancing age the chances of benign prostatic hyperplasia (BPH) and carcinoma prostate (CaP) increases. Although previous studies on physical parameters and personal data parameters have shown the positive associations between BMI, family history, and marital status but they have not seen the effect of occupation and socioeconomic status on BPH and CaP. The objective of the present study was to see the effects of anthropometric measurements and personal history parameters on BPH and CaP in our community., Methods: Ninety-three willing subjects from the outpatient department of Sindh Institute of Urology and Transplant (SIUT) were selected for the study. Height and weight were measured, BMI calculated and personal data information, i.e., occupation, marital status, smoking history, family history and socioeconomic history were recorded. Data were analysed for association of various parameters with BPH and CaP., Results: Significant association between weight, BMI and skilled labourers was found when normal were compared with BPH cases., Conclusion: No significant association between other parameters and BPH, CaP cases was found, except weight, BMI and skilled labour. Body weight should be managed well as it can lead to both cardiovascular as well as prostatic diseases.

Objective: To examine variants at the 9p21 locus in a case-control study of acute myocardial infarction (MI) in Pakistanis and to perform an updated meta-analysis of published studies in people of European ancestry., Methods and Results: A total of 1851 patients with first-ever confirmed MI and 1903 controls were genotyped for 89 tagging single-nucleotide polymorphisms at locus 9p21, including the lead variant (rs1333049) identified by the Wellcome Trust Case Control Consortium. Minor allele frequencies and extent of linkage disequilibrium observed in Pakistanis were broadly similar to those seen in Europeans. In the Pakistani study, 6 variants were associated with MI (P<10(-2)) in the initial sample set, and in an additional 741 cases and 674 controls in whom further genotyping was performed for these variants. For Pakistanis, the odds ratio for MI was 1.13 (95% CI, 1.05 to 1.22; P=2 x 10(-3)) for each copy of the C allele at rs1333049. In comparison, a meta-analysis of studies in Europeans yielded an odds ratio of 1.31 (95% CI, 1.26 to 1.37) for the same variant (P=1 x 10(-3) for heterogeneity). Meta-analyses of 23 variants, in up to 38,250 cases and 84,820 controls generally yielded higher values in Europeans than in Pakistanis., Conclusions: To our knowledge, this study provides the first demonstration that variants at the 9p21 locus are significantly associated with MI risk in Pakistanis. However, association signals at this locus were weaker in Pakistanis than those in European studies.

Summary: Lymphoma is the third most common childhood malignancy. Less information is available on this disease and its outcome from our country. We present here a single institute experience. A retrospective study was carried out at Aga Khan University Hospital, Karachi on children (<15 y) diagnosed with lymphoma from 1998 to 2007. Sixty-eight patients were identified. Fifty-one children were diagnosed as non-Hodgkin lymphoma (NHL). Mean age of presentation was 8.4 years with male-to-female ratio of 5.8 : 1. Most common histopathologic subtype of NHL was Burkitt lymphoma (55%). Abdominal mass was the main presenting feature of Burkitt and diffuse large B cell lymphoma. T-lymphoblastic lymphoma presented mainly as mediastinal mass. Ten children died, 4 secondary to tumor lysis syndrome, 5 because of disease progression, and 1 with chemotherapy-induced toxicity. One-third of the patients left without treatment. Seventeen children were diagnosed as Hodgkin lymphoma with mixed cellularity as the commonest subtype (65%). Overall survival of children with NHL and Hodgkin lymphoma was 62% and 94%, respectively. A greater proportion of NHL, advanced stage, and profound male preponderance were observed. Improvement in survival can only be achieved with increasing awareness, identifying and tackling causes of abandonment, early referral, and better supportive care.

Phlebitis and cellulitis are commonly encountered problems in oncology patients receiving chemotherapy through peripherally inserted intravenous catheters. Use of central venous access devices (CVAD) is desirable. We have seen a steady increase in the use of CVADs in our oncology service with frequent use of indwelling ports, particularly during the last 2 years. In this study we have attempted to elucidate advantages of CVAD and compared them to peripheral catheters. This is a retrospective study with chart review of all oncology patients admitted in our oncology service at the Aga Khan University Hospital from March 2003 to March 2005. A survey was also conducted from a randomly selected sample of parents of children with cancer to elicit parental views regarding their choice of a particular catheter. Catheter-related infections were quite common (over 50%) in patients with peripheral lines, resulting in increased costs and prolonged hospitalization. Externalized CVADs were found difficult to care for, carried a risk of being accidentally pulled out or punctured, and were deemed undesirable for older female patients for cosmetic reasons. We found that the internalized CVADs (portacath) were superior to the externalized or peripheral lines and resulted in better patient and family satisfaction. Use of peripheral lines must be gradually phased out of pediatric oncology practice in Pakistan. Indwelling CVADs have become the standard of care internationally and should be considered for most patients in developing countries whenever resources are available.