A novel nonsense variant in EXOC8 underlies a neurodevelopmental disorder.

Human exocyst complex is an evolutionary conserved multimeric complex composed of proteins encoded by eight genes EXOC1-EXOC8. It is known that the exocyst complex plays a role in ciliogenesis, cytokinesis, cell migration, autophagy, and fusion of secretory vesicles. Recently, loss of function variants in EXOC7 and EXOC8 has been associated with abnormalities of cerebral cortical development leading to a neurodevelopmental phenotype. Neurodevelopmental disorders are a huge group of clinically and genetically heterogeneous disorders. In the present study, we recruited a large consanguineous family segregating a neurodevelopmental disorder in an autosomal recessive form. We performed clinical phenotyping by imaging the patient's brain followed by whole exome sequencing examining DNA from two affected individuals. The clinical phenotypes of the disease were suggestive of brain atrophy. Clinical examination revealed intellectual impairment with hypertonia and brisk reflexes. WES followed by Sanger sequencing revealed a novel homozygous nonsense mutation [EXOC8; NM_175876.5; c.1714G > T; p.(Glu572Ter)] in the DNA of affected individuals. Both parents of the patients were heterozygous for the identified mutation. All the pathogenicity prediction softwares predicted the identified variant as disease causing. This study reports a second protein-truncating variant in EXOC8. The findings confirm that loss of function variants in EXOC8 underlies a neurodevelopmental disorder. The identification of a protein-truncating variant in EXOC8 in the current study can be helpful in establishing genotype-phenotype correlations. Our results also provide new insights into genetic counseling and clinical management for the affected individuals.

Successful Outpatient Management of Children at a Secondary Care Hospital in Pakistan in a Dengue Fever Epidemic and Their Clinical Outcomes.

BACKGROUND: There is limited published literature on the feasibility of WHO 2009 guidelines for the management of dengue fever (DF) in Pakistani children. This study aimed to assess the outcome of children with DF who received outpatient treatment according to these guidelines during a DF epidemic. METHOD: This was a prospective cohort study conducted at Federal General Hospital, a secondary care hospital, Islamabad, Pakistan, from 1st August to 31st October 2019. Using WHO DF 2009 guidelines, children ≤13 years, diagnosed as confirmed DF (NS1 Ag +), were classified into the outpatient (DF) or the inpatient group (DF with warning signs or severe dengue (SD)). The inpatient group was admitted to the Pakistan Institute of Medical Sciences, a tertiary care hospital, and discharged on recovery. These children were followed for the primary outcome, i.e., recovery or hospitalization by day 14 of enrollment. Additionally, clinical and laboratory features (Hb, HCT, TLC, PLT, and ALT) of the patients in the outpatient who remained stable with those who progressed to inpatient care during follow-up were compared; also, time of recovery of blood counts was assessed. RESULTS: Of 93 children with DF, 87 (93.5%) received outpatient care at enrollment. Of these, 6 (7.8%) deteriorated by day 7 and were admitted to inpatient care. SD was present in 6/93 (6.4%) patients at presentation and were admitted. All children showed signs of recovery until day 14. Male gender (p=0.049), lower normal mean platelet (p=0.02), and high mean hematocrit (p=0.001) were associated with disease progression. CONCLUSION: The majority of children with confirmed DF who received outpatient treatment according to WHO 2009 guidelines were successfully managed. Additionally, confirmed DF with warning signs or SD were admitted and recovered. Regular follow-ups according to the guidelines are pertinent. Thrombocytopenia and high HCT were associated with disease progression.

Risk factors for mortality among admitted children with complications of measles in Pakistan: An observational study.

OBJECTIVE: To identify the vaccination status and risk factors for mortality in children admitted with complications of measles. METHODS: The retrospective study was conducted at Children Hospital, Pakistan Institute of Medical Sciences, Islamabad, Pakistan, and comprised data of children admitted with complications of measles between 2013 and 2017. Information on vaccination history, complications of measles, anthropometry, hospital stay and outcome within 15 days of admission was retrieved from hospital records. Data was analysed using Stata 14. RESULTS: Of the 307 children admitted, 79(26%) were aged <9 months and were excluded. Of the remaining 228 subjects, 109(47.8) were unvaccinated. Risk factors significantly associated with mortality were an unvaccinated state of measles vaccine, being stunted, and encephalitis in comparison with pneumonia (p<0.05). A total of 39(17%) children died within 15 days of admission. CONCLUSIONS: Encephalitis, non-vaccination and under-nutrition were significantly associated with mortality in children with complications of measles.

Qualitative exploration of facilitating factors and barriers to use of antenatal care services by pregnant women in urban and rural settings in Pakistan.

BACKGROUND: World Health Organisation recommends that pregnant women with no complications should visit a healthcare provider at least four times to receive sufficient antenatal care services. In Pakistan only 37% of women reported to have had four or more antenatal care visits during their last pregnancy. This study aimed to explore facilitators and barriers to use of antenatal care services in rural and urban communities of two selected districts in Pakistan. METHODS: Qualitative explorative study using in-depth interviews with currently pregnant women, lady health workers and doctors providing antenatal care services, and focus group discussion with women who had a child aged 5 years or younger, was conducted in a rural community in the district Swabi and in a tertiary care hospital in urban Islamabad in Pakistan. The audio-recorded interviews and discussions were transcribed verbatim in Urdu (the language spoken by the respondents). A list of topical codes for all topics related to the research questions was developed. Subsequently the text pertaining to each topical code was discussed and summarised in a document that presented the findings for each topic using quotes and tables. RESULTS: We conducted in-depth interviews with six lady health workers, four doctors, and ten currently pregnant women, and facilitated ten focus group discussions with women who had a child aged 5 years or younger. Currently pregnant women, and women who had a child aged 5 years or younger, were not aware of the recommended minimum number of antenatal care visits to be made during pregnancy. Facilitating factors to visit a particular health care facility were: availability of qualified healthcare providers (private facility); trust in healthcare providers; recommendation from a family member, friend or lady health worker (in rural areas); availability of good quality services including medical equipment and laboratory facilities; low cost (public facility); and easy access to the health facility (private facility). Common barriers to visiting a health facility for antenatal care services were: financial limitations; perceived absence of any major health problems during pregnancy; difficulties in reaching the health facility; restriction from husband or mother-in-law; busy performing household chores; no previous experience of antenatal care visits; and perceived unavailability of healthcare providers and/or services. CONCLUSIONS: The current study identified several policy-relevant facilitating factors and barriers to visiting a health facility for antenatal care services as reported by urban and rural women, and healthcare providers. There is a need to formulate and implement intervention packages based on these findings to increase the coverage of the recommended four antenatal care visits in Pakistan.

Perceptions of antenatal iron-folic acid supplements in urban and rural Pakistan: a qualitative study.

BACKGROUND: In Pakistan, 51% of women are anaemic in pregnancy yet only 44% of women use antenatal iron-folic acid (IFA) supplements. Little information exits on the perception and barriers to the use of IFA supplements during pregnancy in Pakistan. The aim of the study was to understand women and healthcare providers' perceptions, and to investigate the cultural and behavioural factors influencing the use of antenatal IFA supplements in rural and urban settings of Pakistan. METHODS: We conducted 10 focus group discussions with mothers, 10 in-depth interviews with currently pregnant women, 6 in-depth interviews with Lady Health Workers and 4 in-depth interviews with doctors providing antenatal care services. The study was conducted in two districts of Pakistan--district Swabi and Islamabad for rural and urban samples, respectively. Data was collected between August and November 2012. RESULTS: The majority of women were aware of the perceived benefits of antenatal IFA supplements. However, the rural women had more limited information about the benefits of IFA supplements than the urban women. The facilitating factors for the women's use of supplements were: they had knowledge of benefits; they had trust in the healthcare providers; the supplements were available; they had the financial capacity to buy them; they felt better after taking these supplements; and they received support from family members. The barriers to the women's use of supplements were: they forgot to take them; the non-availability of supplements; their limited financial capacity to buy them; the lack of antenatal care services; family members not allowing use of the supplements; not knowing about the benefits or no education; fear or experience of side effects; considering them as contraceptives; and felt better thus stopped. CONCLUSION: The coverage of antenatal IFA supplementation can be improved by reducing the barriers related to the use of antenatal IFA supplementation in Pakistan. Interventions focused on providing adequate awareness, good quality counselling, reminder messages, availability of free supplements throughout pregnancy and reducing the side effects should be developed and implemented.

Assessment of nutritional status and serum leptin in children with inflammatory bowel disease.

OBJECTIVES: Children with inflammatory bowel disease (IBD) commonly have altered nutrition and growth. Measurement of serum leptin may enhance other modalities to assess the nutritional state of children with IBD. The aim of the present study was to define the nutritional status of children with newly diagnosed IBD by measuring anthropometry and serum leptin levels. PATIENTS AND METHODS: Twenty-eight children newly diagnosed with IBD and 56 age- and sex-matched controls were enrolled prospectively. Anthropometry (weight, height, and body mass index [BMI] expressed as z scores) and serum leptin levels were measured. RESULTS: The children with IBD had lower mean BMI z scores and weight-for-age percentiles than controls (P = 0.05 and P = 0.01, respectively). The mean (standard deviation) serum leptin levels of the children with IBD were 2.4 (± 1.9) pg/mL, compared with 5.2 (± 4.6) pg/mL for controls (P = 0.01). The BMI percentile correlated positively with leptin levels in both groups. Following adjustment for BMI percentiles, serum leptin levels were lower in children with IBD than in controls (P = 0.02). Leptin levels did not correlate with serum markers of inflammation or disease activity scores. CONCLUSIONS: Detailed and focused nutritional assessment should be an integral part of the management of all children with IBD. Children at the time of diagnosis of IBD have significant undernutrition and have lower serum leptin levels than controls. The inflammatory state in IBD appears not to alter leptin metabolism. Further study of the effect of leptin in IBD is required.

Coeliac disease screening in children: assessment of a novel anti-gliadin antibody assay.

Coeliac disease (CD) screening has progressed rapidly with tissue transglutaminase (TTG), the screening tool of choice. However, TTG may be unreliable in young children and advances in CD etiology understanding have seen improvements in anti-gliadin (AGA) assay technology. The aim of this study was to investigate the utility of an updated and refined AGA (Neogliadin) assay for CD screening in children with gastrointestinal symptoms. Children attending the Sydney Children's Hospital, Randwick, with gastrointestinal symptoms had sera collected and assayed by Neogliadin and commercial TTG assays in addition to the usual clinical work-up. One hundred and fifteen children were recruited in which 32 were diagnosed with CD. AGA-IgA screening by Neogliadin showed improved sensitivity (83%) and specificity (91%) but did not eclipse the sensitivity (93%) and specificity (90%) of TTG-IgA screening. In the children diagnosed with CD, 7 were identified as younger than 5 years of age with 4/7 AGA-IgA positive, 5/7 AGA-IgG positive, and 6/7 TTG-IgA positive. The updated Neogliadin IgA assay does not improve on the accuracy achieved by TTG screening. TTG appears to be a suitable screening tool for children younger than 5 years of age although this preliminary finding requires confirmation.

Clinical outcome in children hospitalized with complicated measles.

OBJECTIVE: To determine the association of clinical outcome of measles in children with demographic profile and complications. DESIGN: A cross-sectional analytical study. PLACE AND DURATION OF STUDY: Isolation ward, The Children's Hospital, Pakistan Institute of Medical Sciences (PIMS), from January 2003 to August 2004. PATIENTS AND METHODS: Detailed history and physical examination of all the hospitalized patients with complications of measles was filled in case report form. Immunization cards were assessed for measles vaccination status. Data was analyzed by using SPSS version 10 software. The clinical outcome of measles was compared with demographic profile and complications by using Chi-square test and p-values were obtained. RESULTS: Two hundred and five hospitalized patients with complications of measles were studied. There were 61.5% males. Mean age was 46.1 months and 57% patients were vaccinated against measles. Malnourished patients were 71.2% and had a longer hospital stay (p=0.010). Pneumonia (40.0%) and diarrhoea (38.5%) were the commonest complications. Seven children died. Mortality was significantly associated with younger age (p=0.04), unvaccinated status (p=0.04) and presence of encephalitis (p=0.00001). CONCLUSION: The most common complications of measles are pneumonia and diarrhoea with dehydration requiring hospitalization. Malnourished children experience more complications and have longer hospital stay. Mortality is significantly associated with infancy, unvaccinated status and encephalitis. A second dose of measles should be introduced at 15 months of age.

Comparative efficacy of amoxicillin, cefuroxime and clarithromycin in the treatment of community -acquired pneumonia in children.

OBJECTIVE: To compare the clinical response to amoxicillin, cefuroxime and clarithromycin in the treatment of community-acquired pneumonia in children and to see the cost effectiveness of each treatment. DESIGN: Randomized clinical control trial. PLACE AND DURATION OF STUDY: Department of Pediatrics, Khyber teaching hospital, Peshawar, from October 2001 to February 2002. SUBJECTS AND METHODS: Patients between 3 to 72 months of age, admitted in the hospital with community acquired pneumonia, were randomly divided into three groups,1,2,3. They were started on amoxicillin, cefuroxime and clarithromycin respectively. The patients were assessed daily. If there was no clinical improvement at 48 hours the antibiotic was changed. ANOVA statistical test was applied to see the clinical response to the treatment in the three groups. Cost effectiveness of the treatment was compared. RESULTS: There was no statistical difference in the clinical response at 48 hours of initiating treatment and at discharge (p > 0.01 each). The mean hospital stay in group 1 and 2 was 3.3 days and group 3 was 3.2 days respectively (p > 0.01). Ninety-seven percent patients in group 1 and 3, and 95% patients in group 2 showed clinical improvement. The cost of treatment of community acquired pneumonia for 8 days was Rs 496/-, 730/-, 1018/- for amoxicillin, clarithromycin and cefuroxime respectively. CONCLUSION: Amoxicillin was found the most cost effective followed by clarithromycin and cefuroxime respectively in the treatment of non-severe and severe community-acquired pneumonia.

Neonatal sepsis in hospital-born babies: bacterial isolates and antibiotic susceptibility patterns.

OBJECTIVE: To determine the frequency of bacterial isolates from neonatal blood cultures and their susceptibility patterns in hospital-born babies having sepsis. DESIGN: An observational study. PLACE AND DURATION OF STUDY: Obstetrics Unit and Special Care Baby Unit of Khyber Teaching Hospital, Peshawar from 1st January to 31st December 2001. SUBJECTS AND METHODS: This study was carried out on the neonates born and admitted in hospital with positive blood culture reports. Early onset neonatal sepsis (EONNS) and late onset neonatal sepsis (LONNS) were defined as illness appearing from birth to seven days and from eight to twenty-eight days postnatal age respectively. The blood culture reports were analyzed by SPSS package and cross tabulation was done. RESULTS: One hundred and twelve hospital-born babies presented with sepsis. Sixty-seven neonates had positive cultures. Escherichia coli (E. coli) was the commonest organism causing EONNS (35; 77.1%) followed by Pseudomonas (4; 8.9%), Klebsiella (4; 8.9%) and Staphylococcus aureus (2; 4.4%) respectively. In the LONNS E. coli (19; 77.3%) was the commonest followed by Staphylococcus and Pseudomonas (2; 9% each) and Klebsiella (1; 4.5%). The gram-negative organisms showed high degree of resistance to commonly used antibiotics, ampicillin (79.3%), amoxicillin (74.6%) and ceftazidime (71.6%), cefotaxime (55.2%) and comparatively low resistance to gentamicin (43.2%), tobramycin (34.3%), imipinem (23.6%), amikacin (22.3%), ofloxacin and ciprofloxacin (11.9%) respectively. Staphylococcus aureus showed almost the same resistance to ampicillin, 75%, and comparatively low resistance to the rest of the antibiotics as compared to the gram-negative organisms. CONCLUSION: Neonatal sepsis is mainly caused by gram-negative organisms, which are developing resistance to commonly used antibiotics.