Adverse Events of SARS-CoV-2 Therapy: A Pharmacovigilance Study of the FAERS Database.

BACKGROUND: Over the past 2 years of the several strategies recommended to help fight COVID-19, nirmatrelvir/ritonavir is a novel drug shown in the EPIC-HR phase 2 to 3 clinical trial to lower COVID-19-related death or hospitalization at day 28 when compared with placebo. OBJECTIVE: Our study's aim was to explore the reported adverse events (AEs) associated with nirmatrelvir/ritonavir use for COVID-19. METHOD: We conducted a retrospective analysis using the FDA Adverse Event Reporting System (FAERS) database for AEs, listing nirmatrelvir/ritonavir as the primary drug between January and June 2022. The primary outcome was the incidence of reported AEs associated with nirmatrelvir/ritonavir. The OpenFDA database was queried using Python 3.10 to collect the AEs and Stata 17 was used to analyze the database. Adverse events were analyzed by associated medication, with "Covid-19" excluded. RESULTS: A total of 8098 reports were identified between January and June 2022. Most reported complaints in the AE system were COVID-19 and disease recurrence. The most common symptomatic AEs were dysgeusia, diarrhea, cough, fatigue, and headache. Event rates significantly rose between April and May. Disease recurrence and dysgeusia were the most commonly reported complaints for the top 8 concomitant drugs identified. Cardiac arrest, tremor, akathisia, and death were reported in 1, 3, 67, and 5 cases, respectively. CONCLUSIONS AND RELEVANCE: This is the first retrospective study done on reported AEs associated with nirmatrelvir/ritonavir use for COVID-19. COVID-19 and disease recurrence were the most reported AEs. Further monitoring of the FAERS database is warranted to periodically reassess the safety profile of this medication.

Rate of Multidrug-resistance to Antimicrobial Drugs in Patients in Pediatric Neurointensive Care.

Background: Multidrug-resistant (MDR) organisms in the critical care unit are a worldwide concern. The vulnerability to MDR infection in pediatric patients admitted in neurocritical care are due to altered mental status, immature immune system, higher risk of aspiration, and more frequent use of invasive devices. We aimed to measure the burden of MDR infection in pediatric neurosurgical intensive care unit (NSICU) patients. Methods: All pediatric patients between 1 and 18 years for intracranial and spine surgeries admitted for more than 48 hours in NSICU were enrolled in the study. If patients showed a clinical picture of pneumonia, bloodstream infection (BSI), or urinary tract infection (UTI) after receiving mechanical ventilation or an indwelling device for at least 48 hours, samples of tracheal aspirates, urine, blood, and cerebrospinal fluid (CSF) were sent for microbiological culture. We noted the type of organism, MDR infection rate, and associated risk factors. Pearson Chi-squared test and Fisher's test were used for statistical analysis; p < 0.05 was considered statistically significant. Results: A total of 274 pediatric patients were studied. In 1 year, there was a total of 1,790 patient days. The inclusive MDR infection rate was 17.3/1,000 patient days. Also, Klebsiella pneumoniae (38.7%) was the commonest MDR pathogen. The commonest source of infection was BSI (32.3%). The risk factors associated with MDR infections were the length of stay in NSICU, mechanical ventilation of more than 5 days, emergency surgery, respiratory and cardiac comorbidities, and poor nutrition status (p < 0.05). Conclusion: The MDR infection rate in our study was 17.3/1,000 patient days in pediatric patients. Also, K. pneumonia e was found to be the commonest MDR pathogen. Bloodstream was the commonest source of infection. How to cite this article: Patel S, Prabhakar H, Kapoor I. Rate of Multidrug-resistance to Antimicrobial Drugs in Patients in Pediatric Neurointensive Care. Indian J Crit Care Med 2023;27(1):67-72.

Parenchymal preserving liver resection for centrally located liver tumors: how I do it?

Central liver tumors often require extended hepatectomy or a central hepatectomy with complex biliary reconstructions. Extended resections are prone to higher chances of post-operative liver failure, while the resections mandating reconstructions run a risk of biliary leaks. Non-anatomical liver resections for these centrally located tumors provide a benefit of functional parenchymal preservation but a higher perceived risk of oncological inadequacy. This manuscript is an attempt to showcase author's technique of parenchymal sparing liver resection for central located liver tumor without the need for any biliary reconstruction while ensuring oncological adequacy during the conduct of the procedure.

Outcomes of rectal cancer patients with a positive pathological circumferential resection margin.

PURPOSE: Evidence-based management of positive pathological circumferential resection margin (pCRM) following preoperative radiation and an adequate rectal resection for rectal cancers is lacking. METHODS: Retrospective analysis of prospectively maintained single-centre institutional database was done to study the patterns of failure and management strategies after a rectal cancer surgery with a positive pCRM. RESULTS: A total of 86 patients with rectal adenocarcinoma with a positive pCRM were identified over 8 years (2011-2018). Majority had low-lying rectal cancers (90.7%) and were operated after preoperative radiotherapy (95.3%). Operative procedures included abdomino-perineal resections, inter-sphincteric resections, low anterior resections and pelvic exenteration in 61 (70.9%), 9 (10.5%), 11(12.8%) and 5 (5.8%) patients respectively. A total of 83 (96.5%) received chemotherapy as the sole adjuvant treatment modality while 2 patients (2.3%) were given post-operative radiotherapy and 1 patient underwent revision surgery. A total of 53 patients (61.6%) had recurrence, with 16 (18.6%), 20 (23.2%), 8(9.3%) and 9 (10.5%) patients having locoregional, systemic, peritoneal and simultaneous local-systemic relapse. Systemic recurrences were more often detected either by surveillance in an asymptomatic patient (20.1%) while local (13.1%) and peritoneal (13.2%) recurrences were more often symptomatic (p = 0.000). The 2-year overall survival (OS) and disease-free survival (DFS) of the cohort was 82.4% and 74.0%. Median local recurrence-free survival (LRFS) was 10.3 months. CONCLUSIONS: Patients with a positive pCRM have high local and distal relapse rates. Systemic relapses are more often asymptomatic as compared to peritoneal or locoregional relapse and detected on follow-up surveillance. Hence, identification of such recurrences while still salvageable via an intensive surveillance protocol is desirable.

Human Urine Alters Methicillin-Resistant Staphylococcus aureus Virulence and Transcriptome.

Gram-positive methicillin-resistant Staphylococcus aureus (MRSA) is an emerging cause of hospital-associated urinary tract infections (UTI), especially in catheterized individuals. Despite being rare, MRSA UTI are prone to potentially life-threatening exacerbations such as bacteremia that can be refractory to routine antibiotic therapy. To delineate the molecular mechanisms governing MRSA urinary pathogenesis, we exposed three S. aureus clinical isolates, including two MRSA strains, to human urine for 2 h and analyzed virulence characteristics and changes in gene expression. The in vitro virulence assays showed that human urine rapidly alters adherence to human bladder epithelial cells and fibronectin, hemolysis of sheep red blood cells (RBCs), and surface hydrophobicity in a staphylococcal strain-specific manner. In addition, transcriptome sequencing (RNA-Seq) analysis of uropathogenic strain MRSA-1369 revealed that 2-h-long exposure to human urine alters MRSA transcriptome by modifying expression of genes encoding enzymes catalyzing metabolic pathways, virulence factors, and transcriptional regulators. In summary, our results provide important insights into how human urine specifically and rapidly alters MRSA physiology and facilitates MRSA survival in the nutrient-limiting and hostile urinary microenvironment. IMPORTANCE Methicillin-resistant Staphylococcus aureus (MRSA) is an uncommon cause of urinary tract infections (UTI) in the general population. However, it is important to understand MRSA pathophysiology in the urinary tract because isolation of MRSA in urine samples often precedes potentially life-threatening MRSA bacteremia. In this report, we describe how exposure to human urine alters MRSA global gene expression and virulence. We hypothesize that these alterations may aid MRSA in acclimating to the nutrient-limiting, immunologically hostile conditions within the urinary tract leading to MRSA UTI.

ASO Author Reflections: Revision Surgery or Timely Chemotherapy for Incidental Gallbladder Cancers: What is Actually Helping?

Revision surgery with or without chemotherapy in the neoadjuvant or adjuvant setting remains the standard treatment for incidental gallbladder cancers (iGBCs). Over the years, researchers have retrospectively analyzed the surgical audits and tried to establish the perceived benefit and optimal timing for revision surgery. Patkar and colleagues have analyzed the outcomes for 517 patients with iGBC, concluding that there is no optimal timing for performing a revision surgery after initial cholecystectomy. Revision surgery is essentially the most accurate staging procedure and should be offered to patients at any time of presentation if they remain non-metastatic. Timely initiation of chemotherapy is the key to improving the outcomes for patients with this otherwise inherently aggressive disease.

Revision Surgery for Incidental Gallbladder Cancer-Challenging the Dogma: Ideal Timing and Real-World Applicability.

BACKGROUND: There is a lack of consensus on the ideal time interval and therapeutic value of revision surgery in patients with incidental gallbladder cancer (iGBC) in the context of multimodality management. PATIENTS AND METHODS: Retrospective analysis of an institutional database of patients with iGBC who underwent surgery from January 2010 to December 2019 was performed. Patients who underwent upfront surgery were divided into four time interval groups: A, B, C, and D (< 6 weeks, 6-10 weeks, 10-14 weeks, and > 14 weeks, respectively). RESULTS: A cohort of 517 patients planned for revision surgery was analyzed. Overall, 382 (73.9%) patients underwent upfront surgery while 135 (26.1%) were given neoadjuvant treatment. With median follow-up of 18 months, 2-year overall survival (OS) was 66% and disease-free survival (DFS) was 52.6%, with inferior survival outcomes observed with advancing stage and presence of residual disease on final histopathology. Propensity score-matched analysis after matching for pT stage of cholecystectomy specimen suggested a survival benefit for patients operated between 10 and 14 weeks in terms of OS (p = 0.049) and DFS (p = 0.006). Patients with locally advanced iGBC at presentation had superior OS when operated after neoadjuvant therapy [3-year estimated OS of 59.9% vs 32.3%, respectively (p = 0.001)]. CONCLUSIONS: Revision surgery is at best the most accurate staging procedure guiding timely initiation of systemic therapy. Patients with iGBC operated between 10 and 14 weeks after initial cholecystectomy tend to have favorable survival outcomes, although this depends on final disease stage. Revision surgery should also be offered to all patients presenting at any later point of time, if deemed operable.

Long-term oncological outcomes of the sphincter preserving total mesorectal excision with varying distal resection margins.

INTRODUCTION: A subcentimeter distal resection margin (DRM) appears to be acceptable for most patients, however, long-term follow up and specific subsets where DRM would influence recurrences have not been adequately investigated. METHODS: A retrospective analysis of all sphincter-preserving resections for mid and low rectal cancers between July 2011 and May 2015 was performed. Extended total mesorectal excisions (TME) and patients with positive pathologic circumferential margins (CRM) were excluded. RESULTS: Two hundred and thirty-six patients fit the inclusion criteria. DRM > 20 mm was obtained in 117 patients (49.6%), between 10 and 20 mm in 78 (33%) and <10 mm in 41 (17.4%) patients. Pathological DRM was positive in 4 patients (1.7%). Sixty-five recurrences occurred at a median follow up of 78.5 months. DRM did not influence any of the oncological outcomes. In a subset analysis of patients with poor pathological response to neoadjuvant radiation, that is, tumor regression grade > 3, DRM influenced disease-free survival (DFS) but not overall survival with a hazard ratio of 4.4 (p = 0.02). This was confirmed on multivariate regression analysis in this subgroup as well where pathological nodal status and DRM < 10 mm were independent predictors of DFS. CONCLUSIONS: A subcentimeter DRM may be acceptable in most patients except those who have an inadequate response to neoadjuvant radiation.

Clinical characteristics and outcomes of patients admitted to hospitals for posterior reversible encephalopathy syndrome: a retrospective cohort study.

BACKGROUND: Posterior reversible encephalopathy syndrome (PRES) is usually a benign, yet underdiagnosed clinical condition associated with subacute to acute neurological manifestations primarily affecting white matter. PRES is reversible when recognized promptly and treated early by removal of the insulting factor; however, can lead to irreversible and life-threatening complications such as cerebral hemorrhage, cerebellar herniation, and refractory status epilepticus. METHODS: We utilized the National Inpatient Sample database provided by the Healthcare Cost and Utilization Project (HCUP-NIS) 2017 to investigate the demographic variables (age, sex, and race) for patients with PRES, concomitant comorbidities and conditions, inpatient complications, inpatient mortality, length of stay (LOS), and disposition. RESULTS: A total of 635 admissions for patients aged 18 years or older with PRES were identified. The mean age was 57.2 ± 0.6 years old with most encounters for female patients (71.7%, n = 455) and white as the most prevalent race. Half the patients in our study presented with seizures (50.1%, n = 318), sixty-three patients (9.9%) presented with vision loss, and sixty-four patients (10.1%) had speech difficulty. In addition, 45.5% of patients had hypertensive crisis (n = 289). 2.2% of hospitalizations had death as the outcome (n = 14). The mean LOS was 8.2 (±0.3) days, and the mean total charges were $92,503 (±$5758). Inpatient mortality differed between males and females (1.7% vs. 2.4%) and by race (3.6% in black vs. 1.8% in white) but was ultimately determined to be not statistically significant. Most patients who present with vision disturbance have a high risk of intracranial hemorrhage. Furthermore, end-stage renal disease, atrial fibrillation, and malignancy seemed to be linked with a very high risk of mortality. CONCLUSION: PRES, formerly known as reversible posterior leukoencephalopathy, is a neurological disorder with variable presenting symptoms. Although it is generally a reversible condition, some patients suffer significant morbidity and even mortality. To the best of our knowledge, this is the largest retrospective cohort of PRES admissions that raises clinician awareness of clinical characteristics and outcomes of this syndrome.

Psoriasis as risk factor for non-ischemic dilated cardiomyopathy: a population-based cross-sectional study.

BACKGROUND: Psoriasis is a chronic inflammatory skin condition commonly associated with psoriatic arthritis, malignancy, diabetes, inflammatory bowel disease, and cardiovascular disease. Several reports and studies have reported an association between psoriasis and non-ischemic dilated cardiomyopathy (NIDCM). We aim to study the relationship between psoriasis and non-ischemic dilated cardiomyopathy in a large population-based study. METHODS: We utilized the Healthcare Cost and Utilization Project National Inpatient Sample 2017 database, which represents a 20% sample of all payer hospitalizations in the United States. We investigated hospitalizations for patients aged 18 years old or older with diagnoses of any type of psoriasis and non-ischemic dilated cardiomyopathy. Psoriasis, cardiomyopathy, and other comorbidities were identified through their international classification of diseases, 10th revision codes recorded in the discharge record for each hospitalization. RESULTS: Of a total of 6,084,184 all-cause admissions, 0.5% were admissions for patients with psoriasis (n = 32,807). Of the patients with and without psoriasis who had non-ischemic dilated cardiomyopathy, after adjusting for age, sex, race, diabetes mellitus, hypertension, alcohol abuse, cocaine abuse, arrhythmias, and obesity in a multivariate analysis, the presence of psoriasis was not significantly associated with non-ischemic dilated cardiomyopathy. CONCLUSION: Psoriasis is a chronic autoimmune disorder which carries a higher cardiovascular events and more prevalent traditional atherosclerotic risk factors in comparison to the general population. However, association with non-ischemic cardiomyopathy or NIDCM in particular has not been studied sufficiently. Our study, being one of the first larger studies to assess this correlation, indicated no relationship between psoriasis and non-ischemic dilated cardiomyopathy.