SARS-CoV-2 Mac1 is required for IFN antagonism and efficient virus replication in cell culture and in mice.

Several coronavirus (CoV) encoded proteins are being evaluated as targets for antiviral therapies for COVID-19. Included in these drug targets is the conserved macrodomain, or Mac1, an ADP-ribosylhydrolase and ADP-ribose binding protein encoded as a small domain at the N terminus of nonstructural protein 3. Utilizing point mutant recombinant viruses, Mac1 was shown to be critical for both murine hepatitis virus (MHV) and severe acute respiratory syndrome (SARS)-CoV virulence. However, as a potential drug target, it is imperative to understand how a complete Mac1 deletion impacts the replication and pathogenesis of different CoVs. To this end, we created recombinant bacterial artificial chromosomes (BACs) containing complete Mac1 deletions (ΔMac1) in MHV, MERS-CoV, and SARS-CoV-2. While we were unable to recover infectious virus from MHV or MERS-CoV ΔMac1 BACs, SARS-CoV-2 ΔMac1 was readily recovered from BAC transfection, indicating a stark difference in the requirement for Mac1 between different CoVs. Furthermore, SARS-CoV-2 ΔMac1 replicated at or near wild-type levels in multiple cell lines susceptible to infection. However, in a mouse model of severe infection, ΔMac1 was quickly cleared causing minimal pathology without any morbidity. ΔMac1 SARS-CoV-2 induced increased levels of interferon (IFN) and IFN-stimulated gene expression in cell culture and mice, indicating that Mac1 blocks IFN responses which may contribute to its attenuation. ΔMac1 infection also led to a stark reduction in inflammatory monocytes and neutrophils. These results demonstrate that Mac1 only minimally impacts SARS-CoV-2 replication, unlike MHV and MERS-CoV, but is required for SARS-CoV-2 pathogenesis and is a unique antiviral drug target.

Effective Interferon Lambda Treatment Regimen To Control Lethal MERS-CoV Infection in Mice.

Effective broad-spectrum antivirals are critical to prevent and control emerging human coronavirus (hCoV) infections. Despite considerable progress made toward identifying and evaluating several synthetic broad-spectrum antivirals against hCoV infections, a narrow therapeutic window has limited their success. Enhancing the endogenous interferon (IFN) and IFN-stimulated gene (ISG) response is another antiviral strategy that has been known for decades. However, the side effects of pegylated type-I IFNs (IFN-Is) and the proinflammatory response detected after delayed IFN-I therapy have discouraged their clinical use. In contrast to IFN-Is, IFN-λ, a dominant IFN at the epithelial surface, has been shown to be less proinflammatory. Consequently, we evaluated the prophylactic and therapeutic efficacy of IFN-λ in hCoV-infected airway epithelial cells and mice. Human primary airway epithelial cells treated with a single dose of IFN-I (IFN-α) and IFN-λ showed similar ISG expression, whereas cells treated with two doses of IFN-λ expressed elevated levels of ISG compared to that of IFN-α-treated cells. Similarly, mice treated with two doses of IFN-λ were better protected than mice that received a single dose, and a combination of prophylactic and delayed therapeutic regimens completely protected mice from a lethal Middle East respiratory syndrome CoV (MERS-CoV) infection. A two-dose IFN-λ regimen significantly reduced lung viral titers and inflammatory cytokine levels with marked improvement in lung inflammation. Collectively, we identified an effective regimen for IFN-λ use and demonstrated the protective efficacy of IFN-λ in MERS-CoV-infected mice. IMPORTANCE Effective antiviral agents are urgently required to prevent and treat individuals infected with SARS-CoV-2 and other emerging viral infections. The COVID-19 pandemic has catapulted our efforts to identify, develop, and evaluate several antiviral agents. However, a narrow therapeutic window has limited the protective efficacy of several broad-spectrum and CoV-specific antivirals. IFN-λ is an antiviral agent of interest due to its ability to induce a robust endogenous antiviral state and low levels of inflammation. Here, we evaluated the protective efficacy and effective treatment regimen of IFN-λ in mice infected with a lethal dose of MERS-CoV. We show that while prophylactic and early therapeutic IFN-λ administration is protective, delayed treatment is detrimental. Notably, a combination of prophylactic and delayed therapeutic administration of IFN-λ protected mice from severe MERS. Our results highlight the prophylactic and therapeutic use of IFN-λ against lethal hCoV and likely other viral lung infections.

Differential TLR-ERK1/2 activity promotes viral ssRNA and dsRNA mimic-induced dysregulated immunity in macrophages.

RNA virus induced excessive inflammation and impaired antiviral interferon (IFN-I) responses are associated with severe disease. This innate immune response, also referred to as 'dysregulated immunity,' is caused by viral single-stranded RNA (ssRNA) and double-stranded-RNA (dsRNA) mediated exuberant inflammation and viral protein-induced IFN antagonism. However, key host factors and the underlying mechanism driving viral RNA-mediated dysregulated immunity are poorly defined. Here, using viral ssRNA and dsRNA mimics, which activate toll-like receptor 7 (TLR7) and TLR3, respectively, we evaluated the role of viral RNAs in causing dysregulated immunity. We show that murine bone marrow-derived macrophages (BMDMs) stimulated with TLR3 and TLR7 agonists induce differential inflammatory and antiviral cytokine response. TLR7 activation triggered a robust inflammatory cytokine/chemokine induction compared to TLR3 activation, whereas TLR3 stimulation induced significantly increased IFN/IFN stimulated gene (ISG) response relative to TLR7 activation. To define the mechanistic basis for dysregulated immunity, we examined cell-surface and endosomal TLR levels and downstream mitogen-activated protein kinase (MAPK) and nuclear factor kappa B (NF-kB) activation. We identified a significantly higher cell-surface and endosomal TLR7 expression compared to TLR3, which further correlated with early and robust MAPK (pERK1/2 and p-P38) and NF-kB activation in TLR7-stimulated macrophages. Furthermore, blocking EKR1/2, p38, and NF-kB activity reduced TLR3/7-induced inflammatory cytokine/chemokine levels, whereas only ERK1/2 inhibition enhanced viral RNA-mimic-induced IFN/ISG responses. Collectively, our results illustrate that high cell surface and endosomal TLR7 expression and robust ERK1/2 activation drive viral ssRNA mimic-induced excessive inflammatory and reduced IFN/ISG responses, and blocking ERK1/2 activity would mitigate viral-RNA/TLR-induced dysregulated immunity.

Acellular Human Amniotic Fluid-Derived Extracellular Vesicles as Novel Anti-Inflammatory Therapeutics against SARS-CoV-2 Infection.

The ongoing COVID-19 pandemic caused by SARS-CoV-2 is associated with acute respiratory distress syndrome (ARDS) and fatal pneumonia. Excessive inflammation caused by SARS-CoV-2 is the key driver of ARDS and lethal disease. Several FDA-approved drugs that suppress virus replication are in clinical use. However, despite strong evidence for the role of virus-induced inflammation in severe COVID-19, no effective anti-inflammatory drug is available to control fatal inflammation as well as efficiently clear the virus. Therefore, there is an urgent need to identify biologically derived immunomodulators that suppress inflammation and promote antiviral immunity. In this study, we evaluated acellular human amniotic fluid (acAF) containing extracellular vesicles (hAF-EVs) as a potential non-toxic and safe biologic for immunomodulation during COVID-19. Our in vitro results showed that acAF significantly reduced inflammatory cytokine production in TLR2/4/7 and SARS-CoV-2 structural protein-stimulated mouse macrophages. Importantly, an intraperitoneal administration of acAF reduced morbidity and mortality in SARS-CoV-2-infected mice. A detailed examination of SARS-CoV-2-infected lungs revealed that the increased protection in acAF-treated mice was associated with reduced viral titers and levels of inflammatory myeloid cell infiltration. Collectively, our results identify a novel biologic that has potential to suppress excessive inflammation and enhance survival following SARS-CoV-2 infection, highlighting the translational potential of acAF against COVID-19.

Correlation of the Nutritional Risk Screening 2002 Score With Post-operative Complications in Gastrointestinal and Hepatopancreatobiliary Oncosurgeries.

Introduction The Nutritional Risk Screening 2002 (NRS 2002) is a reliable tool for assessing patients' nutritional status and for identifying those who may benefit from nutritional support before undergoing surgery. However, its application and correlation with post-operative outcomes for Nepalese patients undergoing gastrointestinal and hepatopancreatobiliary oncosurgeries remain unexplored. The objective of this study was to correlate the NRS 2002's nutritional risk with post-operative complications classified by the Clavien-Dindo Classification. Methods A prospective analytical study was conducted at Kathmandu Medical College and Teaching Hospital, with 74 adults who underwent gastrointestinal and hepatopancreatobiliary oncosurgeries between 1st March 2021 and 30th August 2022. The study was conducted following ethical clearance from the Institutional Review Committee of the Hospital. A convenience sampling method was used. Data were analyzed using IBM SPSS Statistics for Windows, Version 20 (Released 2011; IBM Corp., Armonk, New York, United States). Results Among the 122 patients admitted during the study period, 74 met the inclusion criteria. Using the NRS-2002, 37.8% were found to be at nutritional risk. Such patients had a higher risk of complications and extended hospital stays, supported by an odds ratio of 1.647 (95% confidence interval: 1.223 -2.219) and a p-value of <0.001. Nutritional risk emerged as an independent predictor of post-operative complications. Conclusion The study suggests the potential of NRS-2002 as a significant predictor of outcomes after surgeries for gastrointestinal and hepatopancreatobiliary malignancies in the South Asian context, particularly in Nepal. Tools such as NRS 2002 play a pivotal role in early risk identification, which could subsequently influence both pre-operative and post-operative care strategies, ultimately enhancing patient outcomes.

Mutation of highly conserved residues in loop 2 of the coronavirus macrodomain demonstrates that enhanced ADP-ribose binding is detrimental to infection.

All coronaviruses (CoVs) encode for a conserved macrodomain (Mac1) located in nonstructural protein 3 (nsp3). Mac1 is an ADP-ribosylhydrolase that binds and hydrolyzes mono-ADP-ribose from target proteins. Previous work has shown that Mac1 is important for virus replication and pathogenesis. Within Mac1, there are several regions that are highly conserved across CoVs, including the GIF (glycine-isoleucine-phenylalanine) motif. To determine how the biochemical activities of these residues impact CoV replication, the isoleucine and the phenylalanine residues were mutated to alanine (I-A/F-A) in both recombinant Mac1 proteins and recombinant CoVs, including murine hepatitis virus (MHV), Middle East respiratory syndrome coronavirus (MERS-CoV), and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The F-A mutant proteins had ADP-ribose binding and/or hydrolysis defects that led to attenuated replication and pathogenesis in cell culture and mice. In contrast, the I-A mutations had normal enzyme activity and enhanced ADP-ribose binding. Despite increased ADP-ribose binding, I-A mutant MERS-CoV and SARS-CoV-2 were highly attenuated in both cell culture and mice, indicating that this isoleucine residue acts as a gate that controls ADP-ribose binding for efficient virus replication. These results highlight the function of this highly conserved residue and provide unique insight into how macrodomains control ADP-ribose binding and hydrolysis to promote viral replication and pathogenesis.

Previous Abdominal Scars among Patients Undergoing Laparoscopic Cholecystectomy in a Tertiary Care Centre.

Introduction: Abdominal scars result from various open abdominal surgeries. Laparoscopic surgery in previous open abdominal surgery possesses various challenges to the surgeon like gaining access to the abdominal cavity, and difficulty in dissection due to dense adhesions from previous surgeries for various intraabdominal pathologies. This study aimed to find out the prevalence of previous abdominal scars among patients undergoing laparoscopic cholecystectomy in a tertiary care centre. Methods: A descriptive cross-sectional study was conducted among patients undergoing laparoscopic cholecystectomy in a tertiary care centre from 1 May 2022 to 30 April 2023 after taking ethical approval from the Institutional Review Committee. Palmer's point approach via Hassen open technique or direct optical entry was used for cases with previous abdominal scars to gain access to the abdominal cavity. Patients with symptomatic gallstone diseases were included in the study whereas patients with cholecystitis, pancreatitis, and previous cesarean scar were excluded. Convenience sampling method was used. The point estimate was calculated at a 95% Confidence Interval. Results: Among 160 patients undergoing laparoscopic cholecystectomy, previous abdominal scars was found in 40 (25%) patients. Conclusions: The prevalence of previous abdominal scars contributing to intraoperative and post-operative difficulties among patients undergoing laparoscopic cholecystectomy was found to be higher than in studies done in similar settings. Keywords: laparoscopic cholecystectomy; open surgery; prevalence.

Laparoscopic anatomical segmentectomy: A paradigm shift towards minimally invasive liver surgery in Nepal: A cohort study.

Laparoscopic liver resection is taking stride in slowly replacing open surgeries for various hepatic pathologies in many developed countries. However, due to high cost and lack of expertise, there are only a handful of centres in the low-medium income countries who perform advanced laparoscopic liver resections regularly. In this study, a prospective analysis was carried out to assess and report the outcomes of laparoscopic anatomical segmentectomy (LAS) from a single centre in Nepal. Methods: The clinical data of all patients who underwent LAS between 1 October 2021 to 30 September 2022 were prospectively recorded. Demographics, pathological diagnoses, types of resections performed, perioperative parameters, postoperative length of stay, postoperative complications data and IWATE score were collected and analyzed. All operations were performed using the extrahepatic Glissonean technique with the use of indocyanine green dye as an adjunct during the intraoperative period. Results: In the study period, a total of 16 LAS were performed in our centre for various indications. The mean age of the patients in the series was 41.6 years, and seven of 16 patients were male. The majority of the cases were segment 2/3 resection indicated for various pathologies and segment 4b/5 indicated for carcinoma gallbladder. The median hospital stay was 6 days and only two cases developed major complication. There were no mortalities in our series. Conclusions: Taking into account the results produced from a single centre in a low-medium income country, laparoscopic anatomical segmentectomy is technically feasible with an acceptable safety profile.

Blunt Abdominal Trauma among Patients Admitted to the Department of Surgery at a Tertiary Care Centre: A Descriptive Cross-sectional Study.

Introduction: Blunt abdominal trauma bears significant morbidity and mortality worldwide and needs careful evaluation and management for a better outcome, where the resources are limited and the impact of the financial burden is very important. Previously, many cases used to be managed with operative procedures, and now the trend has been shifting to non-operative management. This study aimed to determine the prevalence of blunt abdominal trauma among patients admitted to the Department of Surgery of a tertiary care centre. Methods: This was descriptive cross-sectional study done between 1 February 2022 to 31 January 2023 after taking ethical approval from the Institutional Review Committee (Reference number: 2312202103). The decision of non-operative versus operative treatment was decided with dynamic clinical evaluation and severity of intraabdominal injuries. Demographic data, the mechanism of injury, and both conservative and operative management were studied. All the patients who were more than 18 years of age, and admitted to the Department of Surgery were included in the study. Convenience sampling method was used. Point estimate and 95% Confidence Interval were calculated. Results: Among a total of 1450 patients, the prevalence of blunt abdominal trauma was 140 (9.65%) (8.13-11.17, 95% Confidence Interval). A total of 61 (43.57%) were young within the age group of 18-30 with a male-female ratio of 4:1. Road traffic accidents 79 (56.43%) were the most common mechanism followed by falls from heights 51 (36.43%). Conclusions: The prevalence of blunt abdominal trauma among patients admitted to the Department of Surgery was found to be higher than in other studies done in similar settings. Keywords: blunt injuries; conservative management; operative surgical procedure.

Klebsiella pneumoniae C o-infection Leads to Fatal Pneumonia in SARS-CoV-2-infected Mice.

SARS-CoV-2 patients have been reported to have high rates of secondary Klebsiella pneumoniae infections. Klebsiella pneumoniae is a commensal that is typically found in the respiratory and gastrointestinal tracts. However, it can cause severe disease when a person's immune system is compromised. Despite a high number of K. pneumoniae cases reported in SARS-CoV-2 patients, a co-infection animal model evaluating the pathogenesis is not available. We describe a mouse model to study disease pathogenesis of SARS-CoV-2 and K. pneumoniae co-infection. BALB/cJ mice were inoculated with mouse-adapted SARS-CoV-2 followed by a challenge with K. pneumoniae . Mice were monitored for body weight change, clinical signs, and survival during infection. The bacterial load, viral titers, immune cell accumulation and phenotype, and histopathology were evaluated in the lungs. The co-infected mice showed severe clinical disease and a higher mortality rate within 48 h of K. pneumoniae infection. The co-infected mice had significantly elevated bacterial load in the lungs, however, viral loads were similar between co-infected and single-infected mice. Histopathology of co-infected mice showed severe bronchointerstitial pneumonia with copious intralesional bacteria. Flow cytometry analysis showed significantly higher numbers of neutrophils and macrophages in the lungs. Collectively, our results demonstrated that co-infection of SARS-CoV-2 with K. pneumoniae causes severe disease with increased mortality in mice.

Toll-like receptor 7 (TLR7)-mediated antiviral response protects mice from lethal SARS-CoV-2 infection.

SARS-CoV-2-induced impaired antiviral and excessive inflammatory responses cause fatal pneumonia. However, the key pattern recognition receptors that elicit effective antiviral and lethal inflammatory responses in-vivo are not well defined. CoVs possess single-stranded RNA (ssRNA) genome that is abundantly produced during infection and stimulates both antiviral interferon (IFN) and inflammatory cytokine/ chemokine responses. Therefore, in this study, using wild-type control and TLR7 deficient BALB/c mice infected with a mouse-adapted SARS-COV-2 (MA-CoV-2), we evaluated the role of TLR7 signaling in MA-CoV-2-induced antiviral and inflammatory responses and disease outcome. We show that TLR7-deficient mice are more susceptible to MA-CoV-2 infection as compared to infected control mice. Further evaluation of MA-CoV-2 infected lungs showed significantly reduced mRNA levels of antiviral type I (IFNα/ß) and type III (IFNλ) IFNs, IFN stimulated genes (ISGs, ISG15 and CXCL10), and several pro-inflammatory cytokines/chemokines in TLR7 deficient compared to control mice. Reduced lung IFN/ISG levels and increased morbidity/mortality in TLR7 deficient mice correlated with high lung viral titer. Detailed examination of total cells from MA-CoV-2 infected lungs showed high neutrophil count in TLR7 deficient mice compared to control mice. Additionally, blocking TLR7 activity post-MA-CoV-2 infection using a specific inhibitor also enhanced disease severity. In summary, our results conclusively establish that TLR7 signaling is protective during SARS-CoV-2 infection, and despite robust inflammatory response, TLR7-mediated IFN/ISG responses likely protect the host from lethal disease. Given similar outcomes in control and TLR7 deficient humans and mice, these results show that MA-CoV-2 infected mice serve as excellent model to study COVID-19.

SARS-CoV-2 Mac1 is required for IFN antagonism and efficient virus replication in mice.

Several coronavirus (CoV) encoded proteins are being evaluated as targets for antiviral therapies for COVID-19. Included in this set of proteins is the conserved macrodomain, or Mac1, an ADP-ribosylhydrolase and ADP-ribose binding protein. Utilizing point mutant recombinant viruses, Mac1 was shown to be critical for both murine hepatitis virus (MHV) and severe acute respiratory syndrome (SARS)-CoV virulence. However, as a potential drug target, it is imperative to understand how a complete Mac1 deletion impacts the replication and pathogenesis of different CoVs. To this end, we created recombinant bacterial artificial chromosomes (BACs) containing complete Mac1 deletions (ΔMac1) in MHV, MERS-CoV, and SARS-CoV-2. While we were unable to recover infectious virus from MHV or MERS-CoV ΔMac1 BACs, SARS-CoV-2 ΔMac1 was readily recovered from BAC transfection, indicating a stark difference in the requirement for Mac1 between different CoVs. Furthermore, SARS-CoV-2 ΔMac1 replicated at or near wild-type levels in multiple cell lines susceptible to infection. However, in a mouse model of severe infection, ΔMac1 was quickly cleared causing minimal pathology without any morbidity. ΔMac1 SARS-CoV-2 induced increased levels of interferon (IFN) and interferon-stimulated gene (ISG) expression in cell culture and mice, indicating that Mac1 blocks IFN responses which may contribute to its attenuation. ΔMac1 infection also led to a stark reduction in inflammatory monocytes and neutrophils. These results demonstrate that Mac1 only minimally impacts SARS-CoV-2 replication, unlike MHV and MERS-CoV, but is required for SARS-CoV-2 pathogenesis and is a unique antiviral drug target. SIGNIFICANCE: All CoVs, including SARS-CoV-2, encode for a conserved macrodomain (Mac1) that counters host ADP-ribosylation. Prior studies with SARS-CoV-1 and MHV found that Mac1 blocks IFN production and promotes CoV pathogenesis, which has prompted the development of SARS-CoV-2 Mac1 inhibitors. However, development of these compounds into antivirals requires that we understand how SARS-CoV-2 lacking Mac1 replicates and causes disease in vitro and in vivo . Here we found that SARS-CoV-2 containing a complete Mac1 deletion replicates normally in cell culture but induces an elevated IFN response, has reduced viral loads in vivo , and does not cause significant disease in mice. These results will provide a roadmap for testing Mac1 inhibitors, help identify Mac1 functions, and open additional avenues for coronavirus therapies.

An unusual case of subacute small bowel obstruction - Gallstone ileus.

INTRODUCTION AND IMPORTANCE: Gallstone ileus is caused by an impaction of one or more gallstones within the gastrointestinal tract, leading to mechanical intestinal obstruction. It is a rare complication of cholelithiasis leading to the formation of a cholecystoenteric fistula and is associated with high mortality rates. We report a case of atypical subacute small bowel obstruction due to gallstone ileus. PRESENTATION OF CASE: An 82-year-old man, with previously diagnosed cholelithiasis, presented with abdominal pain and vomiting for nine days. The contracted gallbladder with distended bowel loops was visualized on abdominal ultrasound. Computed tomography of the abdomen and pelvis revealed dilated loops of the small intestine with a gallstone in the proximal ileum, causing intestinal obstruction with pneumobilia, suggesting gallstone ileus with cholecystoduodenal fistula. The patient underwent an emergency laparotomy and enterolithotomy to remove the impacting gallstone. The cholecystoduodenal fistula was left undisturbed due to the significant risk of duodenal injury. The patient had an uneventful postoperative recovery. CONCLUSION: Gallstone ileus almost always requires surgical management. However, performing an interval biliary surgery is based on the clinical judgment of the surgeon. In our case, the patient's clinical status determined the treatment in which an enterotomy with stone extraction alone was largely sufficient, and has supported the literature. Gallstone ileus is an important differential diagnosis in elderly patients with gallstone disease, untreated or undiagnosed, presenting with features of small bowel obstruction.

Primary Grynfeltt Lumbar Hernia: A Case Report.

A weakening or defect in posterolateral abdominal wall can lead to development of lumbar hernia. These defects are particularly common in Petit's inferior triangle or Grynfeltt-Lesshaft superior triangle. There are very few cases of primary lumbar hernias that have been described in literature till date. As it is a rare entity, it is often misdiagnosed, leading to delay in management. We present a case of a 66-year-old male with no previous surgery who presented with a mass in left lumbar region for last ten years. The mass gradually increased in size and caused vague dragging pain. On Computed tomography, the diagnosis of Grynfeltt hernia was made. The patient underwent a laparoscopic mesh repair and had an uneventful postoperative hospital stay. Although a rare entity, there should be a high degree of suspicion of a lumbar hernia when evaluating a case of a lumbar mass. Early diagnosis by computed tomography and management with open or minimally invasive techniques can prevent complications.

Early Oral Feeding with Vascular Resection among Patients Undergoing Pancreatoduodenectomy in a Tertiary Care Hospital: A Descriptive Cross-sectional Study.

INTRODUCTION: Pancreatoduodenectomy with vascular resection is performed in locally advanced periampullary malignancies. In our practice, early oral feeding is initiated in patients undergoing pancreatoduodenectomy. This study aims to find the prevalence of early oral feeding with vascular resection among patients undergoing pancreatoduodenectomy. METHODS: This was a descriptive cross-sectional study conducted among hospital records of 152 patients who underwent pancreatoduodenectomy in the department of surgery of a tertiary care hospital from 2016 to 2020. Ethical approval was taken from the Institutional Review Committee (Reference number: 0812202102). Convenience sampling was done. Patients clinical and sociodemographic data were collected and analyzed using Statistical Package for the Social Sciences version 20. Point estimate at 95% Confidence Interval was calculated along with frequency, percentage, mean, and median. RESULTS: Among 152 patients undergoing pancreatoduodenectomy, early oral feeding with vascular resection was done in 17 (11.18%) (6.17-16.19 at 95% Confidence Interval). Portal vein and superior mesenteric artery were resected in one (5.88%) and hepatic artery in one (5.88%) patient. Type I, III and IV reconstruction was done in nine (52.9%), five (29.41%) and one (5.88%) respectively. Clinically relevant delayed gastric emptying and postoperative pancreatic fistula were seen in two (11.7%). Complication of Clavien-Dindo Grade III or higher was seen in one (5.88%) patient. One (5.88%) mortality was noted. CONCLUSIONS: The prevalence of early oral feeding with vascular resection among patients undergoing pancreatoduodenectomy was similar to other studies done in similar settings. Early enteral feeding is well tolerated in patients undergoing pancreatoduodenectomy with vascular resection.

A study of Clinical Profile and in Hospital Outcomes of patients undergoing Percutaneous Transvenous Mitral Commissurotomy at a Tertiary Care Center of Nepal.

Introduction: Rheumatic heart disease (RHD), is a common cause of mitral stenosis (MS) in developing nations. As per current recommendation, Percutaneous Transvenous Mitral Commissurotomy (PTMC) is advised as a Class IA (I-Class Of Recommendation, COR; A-Level Of Evidence, LOE) indication in patients with symptomatic severe mitral stenosis. We aim to examine the clinical profile and in-hospital results of PTMC for mitral stenosis. Methods: A cross-sectional retrospective study was conducted at Manmohan Cardiothoracic Vascular and Transplant Center from April 2020 to May 2022. A structured questionnaire was used to collect the data and ethical approval for conducting the study was taken from the Institutional Review Committee (IRC) of Institute of Medicine (IOM). The data was collected in Microsoft Excel (Ver. 2013). For statistical analysis, SPSS 21 (IBM Corp. Released 2012. IBM SPSS Statistics for Windows, Version 21.0. Armonk, NY: IBM Corp.) Association was measured using a parametric and non-parametric test (depending upon the distribution of data) and p value < 0.05 was considered significant. Results: A total of 104 patients who met the inclusion criteria underwent PTMC during the study period. The mean age group of the patient was 41.7 ± 12.5 years, of which 23 (22.1%) were males and 81 (78.9%) were females. Mean mitral valve area prior to PTMC was 0.98 ± 0.19 mm2 that increased to 1.69 ± 0.19 mm2 after the procedure and it was statistically significant (p=<0.001). The post PTMC MVA varied with PTMC Wilkin's score with less than or equal to 8 having favorable outcomes. Conclusion: Successful PTMC is highly influenced by the patients' increasing age, valve morphology (calcification, thickness, mobility), Left atrial dimensions, Pre PTMC mitral valve area, Degree of Baseline mitral regurgitation. Post procedure development of MR is usually well tolerated but rarely be severe enough requiring surgical valve replacement.

Strategies in the Management of Pancreatic Ductal Adenocarcinoma Involving Aberrant Right Hepatic Artery Arising From the Superior Mesenteric Artery.

Introduction The prevailing guidelines do not include the involvement of an aberrant right hepatic artery (aRHA) arising from the superior mesenteric artery in classifying borderline resectable pancreatic ductal adenocarcinoma (BR PDAC). Our novel classification aims to distinguish different entities depending on the location and degree of tumor involvement of aRHA and propose a strategy to manage tumor involvement of aRHA in PDAC. Material and methods The patients who underwent pancreaticoduodenectomy (PD) from September 1, 2018, to August 31, 2022 were analyzed retrospectively, and patients with aRHA were included in the study. Depending on the radiological data, arterial involvement of the aRHA was classified into group I with proximal involvement of the aRHA up to 2 cm from its origin in the superior mesenteric artery (SMA) and group II with distal involvement of aRHA beyond 2 cm from its origin in SMA. In addition, the resection margin status was correlated with the technique employed for managing the tumor-involved artery. Results A total of 122 patients underwent PD during the study period. Eight patients were identified to have tumor involvement of the aRHA arising from the SMA. Among the five patients in group I, three patients who had upfront surgery showed R1 resection regardless of periarterial divestment or resection/reconstruction of the involved artery, whereas R0 resection was achieved in the two patients who had neoadjuvant therapy. All patients in group II had R0 resection regardless of receiving neoadjuvant therapy. There were no significant morbidity and mortality in our series. Conclusion The aRHA should be considered in the classification of BR PDAC. Management strategies should be tailored based on the location and the degree of tumor involvement in the aRHA. We advocate neoadjuvant therapy for proximal involvement and upfront surgery for distal involvement of aRHA to achieve good oncological clearance.

Do Natural Portosystemic Shunts Need to Be Compulsorily Ligated in Living Donor Liver Transplantation?

BACKGROUND: Natural portosystemic shunt ligation practices in liver transplant vary widely across transplant centres and are frequently undertaken to prevent the serious consequence of portal steal phenomenon. No concrete indications have so far been convincingly identified for their management in living donor liver transplant. METHODS: We retrospectively studied the outcome of 89 cirrhotic patients who either did (n = 63) or did not (n = 25) undergo shunt ligation during living donor liver transplantation between 2017 and 2020. RESULTS: The incidence of early allograft dysfunction/nonfunction (P = 1.0) and portal venous complications (P = 0.555) were similar between the two groups. Although overall complications, biliary complications, and the composite of Grade III and IV complications were significantly higher in the nonligated group (P = 0.015, 0.052 and 0.035), 1- year graft and patient survival were comparable between them (P = 0.524). CONCLUSION: We conclude that shunt ligation in living donor liver transplantation may not always be necessary if adequate portal flow, good vascular reconstruction, and good graft quality have been ensured.

Successful Outcome of Uterocutaneous Fistula: A Case Report.

Uterocutaneous fistula is a rare complication that occurs after cesarean section and other pelvic operations. Here we report a case of a 27 years woman presented to our department with a mass and pus-like discharge coming from her previous Pfannenstiel incision for 1 month. The definitive treatment of such cases is hysterectomy but the case was managed by fistulectomy along with gonadotropin-releasing hormone agonist.

Approaches and Postoperative Complications of Artery-First Pancreaticoduodenectomy in a Tertiary Care Hospital in Nepal: A Descriptive Cross-sectional Study.

INTRODUCTION: Superior mesenteric artery first pancreaticoduodenectomy is being increasingly used for pancreatic head and peri-ampullary tumors. The aim of our study was to determine the frequency of various approaches of superior mesenteric artery pancreaticoduodenectomy along with its postoperative complications in a tertiary care center. METHODS: This is a descriptive cross-sectional study of patients undergoing superior mesenteric artery first pancreaticoduodenectomy with different approaches conducted at Kathmandu Medical College Teaching Hospital, Sinamangal, Kathmandu, Nepal, from May 2018 to April 2020. Ethical approval was taken from the Institutional Review Committee (reference no: 310520193). The whole sampling method was adopted. Thirty-four patients undergoing a superior mesenteric artery first pancreaticoduodenectomy at our center with different approaches were included in the study. The data analysis was done in the Statistical Package for the Social Sciences version 20. RESULTS: For 34 patients chosen for the study, the male: female ratio was 1.6:1, with a mean age of 53.7 years. The medial uncinate approach was done in the majority of the cases, 26 (76.4%), whereas the inferior infracolic (mesenteric) approach was done in 1 (2.9%) case. Regarding postoperative complications, Clavien Dindo grade 3 and grade 4 were present in 11 (32.3%) patients, pancreatic fistula (Grade B and C) was observed in 6 (17.6%) patients, and mortality occurred in 2 (5.8%). The mean hospital stay was 16±9 days. CONCLUSIONS: Superior mesenteric artery first pancreaticoduodenectomy with a different approach can be performed with acceptable morbidity and mortality. Early determination of resectibility is achieved in selected cases.