Inhibiting membrane rupture with NINJ1 antibodies limits tissue injury.

Plasma membrane rupture (PMR) in dying cells undergoing pyroptosis or apoptosis requires the cell-surface protein NINJ11. PMR releases pro-inflammatory cytoplasmic molecules, collectively called damage-associated molecular patterns (DAMPs), that activate immune cells. Therefore, inhibiting NINJ1 and PMR may limit the inflammation that is associated with excessive cell death. Here we describe an anti-NINJ1 monoclonal antibody that specifically targets mouse NINJ1 and blocks oligomerization of NINJ1, preventing PMR. Electron microscopy studies showed that this antibody prevents NINJ1 from forming oligomeric filaments. In mice, inhibition of NINJ1 or Ninj1 deficiency ameliorated hepatocellular PMR induced with TNF plus D-galactosamine, concanavalin A, Jo2 anti-Fas agonist antibody or ischaemia-reperfusion injury. Accordingly, serum levels of lactate dehydrogenase, the liver enzymes alanine aminotransaminase and aspartate aminotransferase, and the DAMPs interleukin 18 and HMGB1 were reduced. Moreover, in the liver ischaemia-reperfusion injury model, there was an attendant reduction in neutrophil infiltration. These data indicate that NINJ1 mediates PMR and inflammation in diseases driven by aberrant hepatocellular death.

HFIP-Mediated Multicomponent Reactions: Synthesis of Pyrazole-Linked Thiazole Derivatives.

The development of one-pot, atom, and step-economic new methods avoiding metal, harsh reaction conditions, and toxic reagents for the synthesis of medicinally important hybrid molecules bearing more than one bioactive moieties is currently one of the hot topics in organic synthesis. Herein, we report a green and efficient room temperature multicomponent reaction for the synthesis of novel pyrazole-linked thiazoles involving a one-pot C-C, C-N, and C-S bond-forming process from the reaction of aryl glyoxal, aryl thioamide, and pyrazolones in 1,1,1,3,3,3-hexafluoroisopropanol, a hydrogen bond donating reaction medium. A set of diverse hybrid molecules bearing thiazole and pyrazole moieties were prepared in good to excellent yields by using this method. This methodology can also be extended to prepare thiazole-linked barbiturates as well as imidazole-linked pyrazoles. All the products were fully characterized by spectroscopic techniques. The notable features of this protocol are room temperature, metal as well as additive-free reaction conditions, use of recyclable solvent, water as the byproduct, wide substrate scope, operational simplicity, easy purification, applicability for gram-scale synthesis, high atom economy, and the presence of two bioactive pyrazole and thiazole moieties in the products.

Association of omental pedicled flap with anastomotic leak following low anterior resection for rectal cancer.

BACKGROUND AND OBJECTIVES: Anastomotic leak following colorectal anastomosis adversely impacts short-term, oncologic, and quality-of-life outcomes. This study aimed to assess the impact of omental pedicled flap (OPF) on anastomotic leak among patients undergoing low anastomotic resection (LAR) for rectal cancer using a multi-institutional database. METHODS: Adult rectal cancer patients in the US Rectal Cancer Consortium, who underwent a LAR for stage I-III rectal cancer with or without an OPF were included. Patients with missing data for surgery type and OPF use were excluded from the analysis. The primary outcome was the development of anastomotic leaks. Multivariable logistic regression was used to determine the association. RESULTS: A total of 853 patients met the inclusion criteria and OPF was used in 106 (12.4%) patients. There was no difference in age, sex, or tumor stage of patients who underwent OPF versus those who did not. OPF use was not associated with an anastomotic leak (p = 0.82), or operative blood loss (p = 0.54) but was associated with an increase in the operative duration [ß = 21.42 (95% confidence interval = 1.16, 41.67) p = 0.04]. CONCLUSIONS: Among patients undergoing LAR for rectal cancer, OPF use was associated with an increase in operative duration without any impact on the rate of anastomotic leak.

Outcomes of oncoplastic breast surgery compared to breast-conserving surgery in breast cancer patients in a developing country: a retrospective cohort study.

Background and Objective: Breast-conserving surgery (BCS) with adjuvant radiotherapy remains the standard of care for early breast cancers in Pakistan. We sought to compare the outcomes of BCS with oncoplastic surgery (OPS), a relatively infrequent approach to breast cancer treatment in the country. Methods: This retrospective cohort study was conducted at Aga Khan University Hospital and Ziauddin Hospital in Karachi. Patients who had biopsy-proven Stage-I to III breast cancer and underwent either OPS or BCS between August 1, 2016, and December 31, 2021, were identified and followed for 30 days. Data were collected by reviewing patient files and electronic records. Results: A total of 481 patients were included in the study, where 204 (42.4%) underwent BCS and 277 (57.6%) underwent OPS. Mean tumor volume (146.8 vs. 90.4 cm3), and postoperative complications (2.2 % vs. 0%) were higher in OPS while the frequency of positive margins was greater in the BCS group (15.7 % vs. 2.2 %). There were no significant differences in the histologic type of tumor between the two groups. Conclusion: OPS is a valid alternative approach to breast cancer treatment that can be offered to women with early stage, locally advanced, multifocal or tumors at complex locations owing to the reduced occurrence of positive margins and thus lowered re-excision rates.

Development of stem cell ethics and legislation in the world and in Pakistan; a narrative review.

Stem cells can transform into specialized types of cells, and their capability of self-renewal is limitless. The advancements in stem cell therapy have encountered various hurdles. Considering the massive scope of stem cells applications in health, an effective regulation and monitoring system should be implemented. It is important to ensure that stem cell research projects in Pakistan work closely with the ethics committees as respecting human rights are of paramount importance. It is also necessary that the ethics and legislation guidelines are reviewed, updated, and monitored effectively at every evolving step.

The impact of community medical camps on medical students and graduates' education.

Objectives: To investigate the impact of volunteering at community medical camps on medical students' and graduates' clinical and soft skills, knowledge of community health, and future career goals. METHODS: The cross-sectional pilot study was conducted at the Aga Khan University Hospital, Karachi from July to October 2020, and comprised medical students or trainees who had attended at least one medical camp in a community-based setting organised by any of the two non-governmental organisations who collaborated in the study. Responses were obtained through a self-reported online survey from the participants. Data was analyzed using SPSS 25. RESULTS: Of the 52 subjects, there were 25(48.9%) males and 27(51.9%) females with overall mean age 25.4±3.8 years. Majority of the participants 35(67.3%) had attended a private first-tier medical school while 17(32.7%) had attended other local medical schools. Overall, 40(76.9%) subjects reported improved community knowledge, , 44(84.6%) had experiential learning and confidence in outpatient management, and 49(94%) had improved soft skills. Besides, 21(40.4%) participants agreed to have been influenced to pursue a career in primary care, and 25(48.1%) reported a direct impact on their choice of career specialty. Compared to males, females reported improved awareness and alertness (p=0.016), increased confidence approaching communities (p=0.032), and increased compassion towards patient care (p=0.047). CONCLUSIONS: Community-based medical camps had an overall positive impact on volunteering medical students.

An Easy-To-Use Prehospital Severity Scoring Tool To Triage COVID-19 Positive Adults In A Resource-Limited Setting.

Objectives: To develop an easy-to-use severity scoring tool for prehospital triage of patients infected by the coronavirus disease-2019 in resource-limited settings. METHODS: The cohort study was conducted at a tertiary care hospital in Karachi, from August to September 2020, and comprised adult patients of either gender who tested positive for coronavirus disease-2019 on real-time polymerase chain reaction. The scoring system and categorisation were based on validated scales for the detection of pneumonia and opinions from pulmonologists. Data was analysed using SPSS 19. RESULTS: Of the 206 participants, 100(48.5%) were in-patients and 106(51.5%) were out-patients. There were 144(69.9%) males and 62(30.1%) females with an overall mean age of 48.4±16.2 years. After categorisation based on severity, significantly higher number of in-patients were found to be in categories III and IV (p<0.05). CONCLUSIONS: The severity scoring tool could effectively help classify coronavirus disease-2019 patients into mild, moderate and severe cases.

An initial experience of using dual energy contrast enhanced mammography at a tertiary care hospital in Pakistan.

Objective: Contrast enhanced mammography (CEM), a relatively new and promising modality, combines mammography (MMG) with an iodinated contrast material to illuminate neovascularity within the breast; analogous to magnetic resonance imaging (MRI). CEM improves the overall sensitivity of MMG; reduces the need for unnecessary biopsies and follow-up imaging and can be considered a reasonable substitute for MRI. In Pakistan, CEM was recently introduced and to assess its usability a study was conducted on five patients before making it available as a regular investigation. Case presentations: Four out of the five patients had a clinical suspicion of malignancy with two patients having heterogeneously dense breasts and two with dense breasts. All enhancing lesions were concordant on biopsy and had similar corresponding findings on additional imaging such as ultrasound (US) and/or MRI. CEM in all four cases of biopsy proven malignancy facilitated surgical planning. The fifth patient underwent CEM for screening and was found to have no enhancing lesion. Conclusion: In low-middle-income countries (LMICs) where breast MRI is not readily available and expensive for the populace, CEM can be a reliable alternative. The initial experience with CEM at our hospital shows better visualization of malignant lesions in dense and heterogeneously dense breasts with an easy-to-perform technique and a shorter imaging time while facilitating surgical decision-making in terms of breast conservation.

Visible Light-Mediated C(sp2)-H Selenylation of Amino Pyrazole and Amino Uracils in the Presence of Rose Bengal as an Organophotocatalyst.

Herein, we report an efficient methodology for the synthesis of alkyl, benzyl, and phenyl selenoethers of aminopyrazoles and aminouracils by C(sp2)-H functionalization in the presence of visible light and Rose Bengal as an organophotocatalyst. The reaction of amino pyrazole/iosothiazole/isoxazole or amino uracils with 0.5 equivalent of diphenyl/dibenzyl/diethyl diselenides in the presence of visible light in acetonitrile medium and a catalytic amount of Rose Bengal provided the corresponding phenyl, benzyl, or ethyl selenoethers in good to very good yields. We have also utilized some of the selenylated aminopyrazoles for the preparation of pyrazole-fused dihydropyrimidines tethered with arylselenoethers by a catalyst-free one-pot three-component reaction. The notable features of this methodology are metal-free reaction conditions, good to very good yields, use of an organic photocatalyst, and wide substrate scope; it is also applicable to gram-scale synthesis and provides selenoethers of medicinally important heterocycles such amio-pyrazole, isoxazole, isothiazole, and uracils.

Sc(OTf)3-Mediated One-Pot Synthesis of Coumarin-Fused Furans: A Thiol-Dependent Reaction for the Easy Access of 2-Phenyl-4H-furo[3,2-c]chromen-4-ones.

Herein, we report a simple and efficient method for the preparation of novel thioether-linked coumarin-fused furans from the one-pot three-component reaction of arylglyoxal, 4-hydroxycoumarin, and various aromatic thiols in the presence of Sc(OTf)3 as a catalyst. This methodology is also applicable to cyclic 1,3-dicarbonyls such as cyclohexane-1,3-dione and dimedone. Depending upon the thiols, this methodology can either give a three-component thioether-linked coumarin-fused furan (4) or a two-component furocoumarin product (5). Wide substrate scope, good to excellent yields, and products having more than one pharmaceutically important motif are the salient features of this methodology.

Current perspectives of oncoplastic breast surgery in Pakistan.

Oncoplastic breast surgery is based on the concept of tumour-specific immediate reconstruction. It combines both local and distant techniques to maintain breast texture, symmetry and cosmesis without compromising oncological outcome. The current narrative review was planned to highlight the current state and future of oncoplastic breast surgery in low- and middle-income countries where its utilisation in surgical practice remains insubstantial because majority of the surgeons who are treating breast cancer are either general surgeons or breast surgeons who do not have expertise in oncoplastic breast surgery or reconstructive surgery. Moreover, scarcity of financial resources, ignorance about oncoplastic breast surgery techniques, disfigurement distress and cultural taboos coerce women to hide in the shadows with their breast disease. Oncoplastic breast surgery needs more exposure in a developing country like Pakistan. There is a need to establish dedicated oncoplastic breast surgery training centres, fellowship programmes, workshops, and webinars to incorporate such techniques in the practice of breast surgeons.

Breast surgery super-specialization: Impact on advanced surgical training and research.

The earliest records of breast cancer (BC) date back to 3,000 - 2,500 B.C., ever since multiple curative options have been explored. First known wide margin excision was performed around 1st Century AD and a prototype of the modern-day BC surgery, Halsted radical mastectomy, was performed in the 20th Century. BC is the most common cancer in Pakistan accounting for up to 14.5% of the total cancer incidences. Accredited breast surgery fellowships were established in the UK and USA in 2002 and 2003, respectively. In Pakistan, the movement was delayed and the two-year College of Physicians and Surgeons Pakistan (CPSP) accredited breast surgery fellowship program started in 2019. The increasing annual incidence and changes in demands have led to an increased percentage of General Surgery graduates taking up specialty training. PubMed search from 1990 to 2021 showed a rising trend in the number of breast cancer publications from Pakistan; from almost no papers before 1990 to 615 between 2012 to 2021. This remarkable surge in BC-related research can be explained by the commencement of fellowship programs in breast surgery and related fields. An increase in specialist training will yield better results in the management of patients, improve clinical trials and help produce more meaningful publications from the country.

Outcome of purse-string versus linear skin closure after ileostomy stoma reversal in terms of stoma sites infection and cosmesis.

OBJECTIVE: To evaluate the incidence of infection and patient satisfaction in terms of cosmesis between purse-string closure and the usual linear closure of stoma wound. METHODS: The experimental randomised clinical trial was conducted from December 2017 to December 2018 at the Surgical Unit 1, Lahore General Hospital, Lahore, Pakistan, and comprised patients undergoing ileostomy stoma reversal. The patients were randomised into 2 groups using computer-generated random numbers. Group A underwent purse-string closure, while group B received linear closure. Both groups were followed post-operatively at 1 and 3 months for wound infection. Patient satisfaction was ascertained using standard tools. Data was analysed using SPSS version 20. RESULTS: Of the 72 patients, there were 37(51.4%) in group A and 35(48.6%) in group B. Overall, there were 50(69.4%) males and 22(30.5%) females. Infection occurred in 2(5.4%) group A patients and in 8(22.8%) group B patients (p=0.023). Patients in group A were more satisfied at 3 months post-surgery than patients in group B (p=0.001). CONCLUSIONS: Purse-string closure was found to be associated with a lower incidence of wound infection and higher patient satisfaction compared to linear closure.

Giant lipoma of submandibular region; an unusual presentation.

Lipomas in the submandibular region are very uncommon. Large submandibular neck mass (greater than 10 cm) with a rapid growth rate, may raise concern about possible malignancy of salivary glands. Failure to distinguish salivary gland tumour and liposarcoma from a lipoma may represent a medico-legal pitfall. It is very important for the surgeon to rule out liposarcomas when dealing with giant lipomas in such regions. We report a case of a 65-year-old male who presented in the OPD with complains of pain and a 15x12 cm, giant submandibular solitary lipoma of anterior neck which had rapidly increased in size. The diagnosis of lipoma was confirmed on physical examination, radiological investigations and Fine Needle Aspiration Cytology (FNAC). The Patient underwent surgical excision. The surgery produced excellent cosmetic results and no functional impairment. This study illustrates the literature regarding aetiology, epidemiology, followed by diagnostic and treatment modalities of submandibular lipomas.

Neuroendocrine tumour of the ampulla of Vater: A rare neoplasm at an atypical site.

The periampullary neuroendocrine tumour is an infrequently occurring tumour. Its prevalence among gastrointestinal neuroendocrine neoplasms is less than 0.3%, and less than 2% out of periampullary tumours. These neoplasms have relatively poor prognosis. Jaundice and pain in the abdomen are the early and most commonly occurring symptoms with weight loss being a late event. The carcinoid syndrome presents infrequently in periampullary neuroendocrine tumour and happens only if hepatic metastasis occurs. In this scenario, histopathology plays a paramount role in the diagnosis. Specific immunohistochemical staining is used for diagnosis while the treatment options are local excision, endoscopic excision and pancreaticoduodenectomy. Here is a case report of a 42-year-old patient who presented with complaint of obstructive jaundice for one month. Periampullary carcinoid tumour was diagnosed on biopsy, and she underwent Pancreaticoduodenectomy as treatment. Literature shows that there is poor precision of preoperative and intraoperative lymph node metastatic involvement regardless of the size of the tumour. Hence, radical resection must be considered the standard approach.

An atypical presentation of small bowel adenocarcinoma; a case report.

Small bowel malignancy (SBM) is a rare malignancy in the gastrointestinal tract. Duodenum is the most commonly involved segment and the most common histological subtype is adenocarcinoma (40%). Due to a lack of screening tools and vague symptoms, its clinical detection is very challenging. A 27-year-old man presented at the surgical emergency of Lahore General Hospital in February 2019 with non-specific gastrointestinal symptoms (vomiting, abdominal pain), for which he had previously visited the hospital multiple times. Later, on further workup, he had been diagnosed as a case of intussusception on CT scan. On exploration, he had an impassable stricture in the jejunum. Resection anastomosis of the jejunum was done, but later, on histopathology it turned out to be adenocarcinoma. Adenocarcinoma of the small bowel is a rare entity, and, particularly in Pakistan, the available literature is limited. SBM should be included in the differentials of patients with vague abdominal symptoms. Future studies for the evaluation of new investigations and treatment modalities should be encouraged to improve the overall outcome of the patients.

Covert nail injury to the back: A case report.

Occupational trauma in carpentry is common in our society due to lack of awareness on occupational safety and poor availability and adherence towards protective equipment. Given below is an unusual case of a young carpenter who presented in the orthopaedic outpatient department with complaint of difficulty in walking for the last four days. On examination, restricted movement of the hip joint on extension was observed. On further work up in the form of radiological investigations, a long iron nail was discovered as incidental finding in the back in close proximity to the ascending colon and duodenum in the retroperitoneum. Elective laparotomy was performed to remove the nail, after which the patient improved clinically and his presenting complaints were completely resolved on further follow up. This demonstrates the unusual way in which such a case can present in the outpatient department instead of the emergency department and with symptoms that may prompt one to think of anything but foreign body trauma, emphasising the need for proper history and meticulous relevant clinical examination, as covert foreign body injury can occur to the back, especially in patients involved in such occupations.

Fodder cutter (Tokka) injuries: A preventable morbidity.

Pakistan is an agricultural country where fodder cutter (Tokka) is a commonly used machine on the farms. While using it, farmers often meet with accidents causing injuries which are disastrous, and mainly involve the young generation often causing lifelong disability. This is a hospital-based case series, conducted from June 2018 to January 2019 in the Department of Surgery, Lahore General Hospital, Lahore. For this study the patient's demographic data, site of injury, procedure performed and post-operative outcome were recorded. The study includes a total of 30 cases of tokka injury, (23 males and 07 females) with median age of 25 years. Most commonly injured part of the body was the upper limb, in 26 patients, while the lower limb was involved in 2 patients. There were 18 amputations, 8 stumps formation and 4 debridements. Out of the 18, 9 had to be amputated at the wrist, and 9 amputations were performed higher than the wrist. Post-op recovery was uneventful in all cases. Measures such as safer machine design and education of farmers about the safety procedures can significantly avoid these tragedies.

Hydrogen Peroxide-Mediated Rapid Room Temperature Metal-Free C(sp2)-H Thiocyanation of Amino Pyrazoles, Amino Uracils, and Enamines.

A rapid metal- and additive-free room temperature method for C(sp2)-H thiocyanation of aminopyrazoles, aminoisoxazole, aminoisothiazole, amino uracils, and aliphatic enamines has been developed in an aqueous medium using hydrogen peroxide as a benign oxidant and ammonium thiocyanate as a thiocyanating agent. On the other hand, the reaction of hydrogen peroxide and ammonium thiocyanate followed by one-pot addition of NaOH provides the corresponding disulfides in the case of amino azoles, and pyrimidine-fused 2-amino thiazoles were observed in the case of aminouracils. The salient features of this method are the use of an eco-friendly oxidant, reaction tunability to access different products, wide substrate scope, and good to very good yields.

One-pot synthesis of pyrimidine linked naphthoquinone-fused pyrroles by iodine-mediated multicomponent reactions.

Herein we report iodine-mediated multicomponent reactions for the synthesis of naphthoquinone-fused pyrroles tethered with a pyrimidine moiety. The reaction of aryl methyl ketones (3) or terminal aryl alkynes (5) in the presence of molecular iodine in DMSO medium followed by sequential addition of barbituric acids (2) and 2-amino-1,4-naphthoquinone (1) provides the corresponding three-component hybrid molecules 4 having naphthoquinone-fused pyrroles tethered with a barbituric acid moiety. This three-component reaction proceeds via metal-free C-H oxidation followed by multi-component cyclization forming three new bonds (2 C-C, 1 C-N) in one pot. Alternatively, the same molecules can also be prepared from the reaction of arylglyoxals, 2-aminonaphthoquinone, and barbituric acids in the presence of a catalytic amount of iodine in methanol medium under reflux conditions. The salient features of these methodologies are: one-pot metal-free method, good yields, wide substrate scope, easy purification of products, and the presence of medicinally important naphthoquinone, pyrrole and pyrimidine moieties in the products.