PHENOTYPIC AND GENOTYPIC CHARACTERISTICS OF PROGRESSIVE FAMILIAL INTRAHEPATIC CHOLESTASIS TYPE 3 IN PEDIATRIC POPULATION IN PAKISTAN

OBJECTIVE: To determine the phenotypic and genotypic characteristics of progressive familial intrahepatic cholestasis (PFIC) type 3 in Pakistani children in a hospital setting. METHODS: This cross-sectional observational study was conducted at department of Pediatrics Gastroenterology & Hepatology, The Children’s Hospital Lahore, Pakistan from October 2020 to March 2021. Patients of either sex under 16 years of age presenting with jaundice, pruritus, neonatal cholestasis or with chronic liver and gamma glutamyl transferase >100 IU/ml were included in the study after taking informed consent by parents. For Molecular genetics 2ml blood in EDTA was sent to an international laboratory free of cost on research basis. Reports were assessed and levels were noted and genetic coding was also recorded. Data was entered and analyzed in SPSS version 22. Molecular data was interpreted with the help of clinical geneticist. RESULTS: Out of 34 children, 14 (41.2%) were males and 20 (58.8%) were females. Mean age of children was 6.71±3.10 years. Consanguinity was noted in 32 (94.1%) parents having positive family history in 24 (70.6%) cases. The most common mutation was c. 1783C>T p.(Arg595*),  noted in 12 (35.3%) cases, followed by c. 2861G>T p.(Gly954 ASP) [8 (23.5%) cases], c. 153G>A p.(Trp51) [3 (8.8%) cases], c. 1714 C>T p.(Gln572*) c. 1906C>T p. (Gln636), c. 3220G>A p.(Gly1074Arg, c. 3433del p. (val1145Leufsx7)  in 2 (5.9%) cases each, c. 3859 C>T p.(1287Argext*) c. 88-91del p.(Lys30gly fsx7) and c. 1429c>T p. (Gln477) in one (2.9%) case each. CONCLUSION: Children with PFIC type 3 have variable phenotypic and genotypic presentation

Bi-allelic MYMX variants cause a syndromic congenital myopathy with recognizable facial palsy, growth restriction, and dysmorphism

Myogenic fusion, primarily regulated by the Myomaker and Myomixer proteins, is essential for skeletal muscle development, yet its mechanisms remain poorly understood. This study presents the clinical and molecular details of the third and fourth reported patients with biallelic variants in MYMX, the gene that encodes Myomixer. We identified a homozygous truncating variant [c.107 T > A (p.Leu36Ter)] and a homozygous stop-codon loss variant [c.255 A > G (p.Ter85TrpextTer41)] in MYMX, both associated with a complex neuromuscular syndrome characterized by generalized hypotonia, congenital myopathy, facial nerve palsy, growth restriction and facial dysmorphism. Additional variable features include hearing loss (confirmed in one patient, suspected in the other), scoliosis, joint contractures, cleft palate, hypoglossia, potentially contributing to Pierre Robin sequence, and abnormalities on neuroimaging studies including cerebellar atrophy and Chiari 1 deformity. Comparative analysis of patients with pathogenic variants in MYMK and MYMX, including our cases, reveals largely overlapping phenotypes, underscoring their synergistic role in myofiber formation and implicating their involvement in the etiology of neuromuscular conditions

Clinical and genetic characterization of a progressive RBL2-associated neurodevelopmental disorder

Retinoblastoma (RB) proteins are highly conserved transcriptional regulators that play important roles during development by regulating cell-cycle gene expression. RBL2 dysfunction has been linked to a severe neurodevelopmental disorder. However, to date, clinical features have only been described in six individuals carrying five biallelic predicted loss of function (pLOF) variants. To define the phenotypic effects of RBL2 mutations in detail, we identified and clinically characterized a cohort of 35 patients from 20 families carrying pLOF variants in RBL2, including fifteen new variants that substantially broaden the molecular spectrum. The clinical presentation of affected individuals is characterized by a range of neurological and developmental abnormalities. Global developmental delay and intellectual disability were uniformly observed, ranging from moderate to profound and involving lack of acquisition of key motor and speech milestones in most patients. Disrupted sleep was also evident in some patients. Frequent features included postnatal microcephaly, infantile hypotonia, aggressive behaviour, stereotypic movements, seizures, and non-specific dysmorphic features. Neuroimaging features included cerebral atrophy, white matter volume loss, corpus callosum hypoplasia and cerebellar atrophy. In parallel, we used the fruit fly, Drosophila melanogaster, to investigate how disruption of the conserved RBL2 orthologue Rbf impacts nervous system function and development. We found that Drosophila Rbf LOF mutants recapitulate several features of patients harbouring RBL2 variants, including developmental delay, alterations in head and brain morphology, locomotor defects, and perturbed sleep. Surprisingly, in addition to its known role in controlling tissue growth during development, we found that continued Rbf expression is also required in fully differentiated post-mitotic neurons for normal locomotion in Drosophila, and that adult-stage neuronal re-expression of Rbf is sufficient to rescue Rbf mutant locomotor defects. Taken together, our study provides a clinical and experimental basis to understand genotype-phenotype correlations in an RBL2-linked neurodevelopmental disorder, and suggests that restoring RBL2 expression through gene therapy approaches may ameliorate some symptoms caused by RBL2 pLOF

Clinical and genetic delineation of autosomal recessive and dominant ACTL6B-related developmental brain disorders

Purpose: This study aims to comprehensively delineate the phenotypic spectrum of ACTL6B-related disorders, previously associated with both autosomal recessive and autosomal dominant neurodevelopmental disorders. Molecularly, the role of the nucleolar protein ACTL6B in contributing to the disease has remained unclear. Methods: We identified 105 affected individuals, including 39 previously reported cases, and systematically analyzed detailed clinical and genetic data for all individuals. Additionally, we conducted knockdown experiments in neuronal cells to investigate the role of ACTL6B in ribosome biogenesis. Results: Biallelic variants in ACTL6B are associated with severe-to-profound global developmental delay/intellectual disability, infantile intractable seizures, absent speech, autistic features, dystonia, and increased lethality. De novo monoallelic variants result in moderate-to-severe global developmental delay/intellectual disability, absent speech, and autistic features, whereas seizures and dystonia were less frequently observed. Dysmorphic facial features and brain abnormalities, including hypoplastic corpus callosum, and parenchymal volume loss/atrophy, are common findings in both groups. We reveal that in the nucleolus, ACTL6B plays a crucial role in ribosome biogenesis, particularly in pre-rRNA processing. Conclusion: This study provides a comprehensive characterization of the clinical spectrum of both autosomal recessive and dominant forms of ACTL6B-associated disorders. It offers a comparative analysis of their respective phenotypes provides a plausible molecular explanation and suggests their inclusion within the expanding category of “ribosomopathies.”<p/

Evaluation of prognostic risk models for postoperative pulmonary complications in adult patients undergoing major abdominal surgery: a systematic review and international external validation cohort study

Background Stratifying risk of postoperative pulmonary complications after major abdominal surgery allows clinicians to modify risk through targeted interventions and enhanced monitoring. In this study, we aimed to identify and validate prognostic models against a new consensus definition of postoperative pulmonary complications. Methods We did a systematic review and international external validation cohort study. The systematic review was done in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. We searched MEDLINE and Embase on March 1, 2020, for articles published in English that reported on risk prediction models for postoperative pulmonary complications following abdominal surgery. External validation of existing models was done within a prospective international cohort study of adult patients (≥18 years) undergoing major abdominal surgery. Data were collected between Jan 1, 2019, and April 30, 2019, in the UK, Ireland, and Australia. Discriminative ability and prognostic accuracy summary statistics were compared between models for the 30-day postoperative pulmonary complication rate as defined by the Standardised Endpoints in Perioperative Medicine Core Outcome Measures in Perioperative and Anaesthetic Care (StEP-COMPAC). Model performance was compared using the area under the receiver operating characteristic curve (AUROCC). Findings In total, we identified 2903 records from our literature search; of which, 2514 (86·6%) unique records were screened, 121 (4·8%) of 2514 full texts were assessed for eligibility, and 29 unique prognostic models were identified. Nine (31·0%) of 29 models had score development reported only, 19 (65·5%) had undergone internal validation, and only four (13·8%) had been externally validated. Data to validate six eligible models were collected in the international external validation cohort study. Data from 11 591 patients were available, with an overall postoperative pulmonary complication rate of 7·8% (n=903). None of the six models showed good discrimination (defined as AUROCC ≥0·70) for identifying postoperative pulmonary complications, with the Assess Respiratory Risk in Surgical Patients in Catalonia score showing the best discrimination (AUROCC 0·700 [95% CI 0·683–0·717]). Interpretation In the pre-COVID-19 pandemic data, variability in the risk of pulmonary complications (StEP-COMPAC definition) following major abdominal surgery was poorly described by existing prognostication tools. To improve surgical safety during the COVID-19 pandemic recovery and beyond, novel risk stratification tools are required. Funding British Journal of Surgery Society

Misses &amp; near misses: Drug administration errors

Background: Mistakes made during administration of drugs to patients can be lethal. In order to analyse these mishaps we need to study the particular circumstances of each accident and define the reasons behind the mistake or lapse. This paper reports the findings of a confidential pilot study designed to highlight the frequency of such unfortunate incidences and formulate recommendations applicable in our society to prevent some of these tragic outcomes. Methods: Sixty doctors and nurses from different hospitals were randomly enquired about the personal knowledge of pharmacological mistakes with which they were either closely associated or they had first hand information of the incident. All data was collected in confidence on condition of anonymity. Results: We discovered 21 instances of drug administration errors. Dispensation of wrong drug to a patient was the commonest mistake discovered. Nurses gave majority of these injections during the night. Half the victims of these mishaps lost their lives. Conclusions: From this confidential inquiry, we have found that tragedies with loss of life are not infrequent in our set up: Typical scenario involved muscle relaxant given instead of narcotic analgesic by a student nurse during the night. When the mistake was not detected in time it frequently ended in tragic loss of life. It is disturbing to note that minimum basic facilities of proper cardiopulmonary resuscitation were not available in some hospitals. Recommendations: Only senior nurses / doctors should give IV injections. Conscious effort should be made to minimise the use of IV medication, drugs should be used only with proper indications when suitable oral alternatives are not feasible. The nurses` training as well as nurse patient ratio needs to be improved. Muscle relaxants should not be available outside operating rooms and critical care units. We need to set up a central confidential data-reporting centre for voluntary (anonymous?) reporting of such mistakes or mishaps so that they could be analysed and concrete preventive measures recommended.</jats:p

BIABHIG PATIENTS;

Objective: Diabetics develop complications as a result ofinfection, microangiopathic and neuropathic changes. All these complication can be anticipated andprevented with good glycemic control and maintaining good podiatric care. This study was conducted todetermine the presentation and out come of diabetics in general surgical ward. Design: Observational crosssectional study Setting: Emergency and out patient department of South Surgical Ward, Mayo HospitalLahore. Period: Six months (1st June to 30th November 2004), Material and methods: 51 patients withdiabetes mellitus presenting, it included all the patients with diagnosed diabetes mellitus presenting withsurgical complications relating to their diabetes. All other patients who were normoglycemic or knowndiabetics without any surgical complications were excluded. Patients presenting with ulcerations on foot andlegs were classified on the basis of Wegners classification. Results: Out of 51 patients, 43.1%( 22) had adiagnosis of diabetic foot, 33.3%( 17) had an abscess and 23.5%( 12) had an abscess. According to theWagener's classification*. Class 2 was most common at presentation 34.8% and 23.5% of the patientspresenting with diabetic foot had to undergo an amputation thus suffering from a permanent disability.Conclusion: Good surgical debridement and proper use of antibiotics is required as well as good glycemiccontrol for early and safe recovery.</jats:p

Role of Laparoscopy - A Diagnostic Aid, its Indications &amp; Benefits

Patients with an obscure and unrelievable abdominal condition may be forced to receive open laparotomy for diagnosis. Diagnostic Laparoscopy has been suggested as an alternative to diagnostic laparotomy in selected cases. It is a prospective descriptive study in which, thirty one patients under-going diagnostic Laparoscopy using conventional pneumoperitoneal techniques from January 2000 to June 2002 were included in this study. The correlation between preoperative diagnosis. laparoscopic diagnosis and pathologic diagnosis as well as the outcome of laparoscopic diagnosis and treatment have been assessed. Major indications for diagnostic Laparoscopy included acute abdominal pain (n=9). chronic abdominal pain (n=13), different intraabdominal tumor (n=7). All patients with acute abdominal conditions. 8 of the 13 patients with chronic abdominal pain and 4 of the 7 patients with abdominal tumors had no reasons for a further exploratory procedure, thus preventing the morbidity or mortality which might occur after unnecessary laparotomy. Diagnostic Laparoscopy benefits patients by avoiding unnecessary surgery. avoiding unnecessary delay in diagnosis and treatment and shortening the operative and hospitalized period. However. it provides only an alternative not a substitute for traditional diagnostic procedures and will never lessen the importance of conventional laparotomy.</jats:p

Xeroderma Pigmentosum

Xeroderma pigmentosum comprises of a heterogeneous group of autosomal recessive hereditary diseases, which are characterized by a number of clinical characteristics and abnormal DNA repair mechanism. These patients are prone to multiple cutaneous malignancies at an early stage in life. We present 2 cases of xeoderma pigmentosum with malignant melanoma and conclude that such cases must be identified at an early stage and properly educated to protect themselves from malignancies.</jats:p