HPV-positive clinically advanced squamous cell carcinoma of the urinary bladder (aBSCC): A comprehensive genomic profiling (CGP) study.

BACKGROUND: Advanced bladder squamous cell carcinoma (aBSCC) is an uncommon form of urinary bladder malignancy when compared with the much higher urothelial carcinoma incidence. We studied the genomic alteration (GA) landscape in a series of aBSCC based on the association with human papilloma virus (HPV) to determine if differences in GA would be observed between the positive and negative groups. METHODS: Using a hybrid capture-based FDA-approved CGP assay, a series of 171 aBSCC were sequenced to evaluate all classes of GA. Tumor mutational burden (TMB) was determined on up to 1.1 Mbp of sequenced DNA and microsatellite instability (MSI) was determined on up to 114 loci. Programmed cell death ligand -1 (PD-L1) expression was determined by IHC (Dako 22C3) with negative expression when PD-L1 was 0, lower expression of positivity set at 1 to 49%, and higher expression set at ≥50% expression. RESULTS: Overall, 11 (6.4%) of the aBSCC were found to harbor HPV sequences (10 HPV16 and 1 HPV 11). HPV+ status was identified slightly more often in women (NS) and in younger patients (P = 0.04); 2 female patients with aBSCC had a prior history of SCC including 1 anal SCC and 1 vaginal SCC. HPV+ aBSCC had fewer GA/tumor (P < 0.0001), more inactivating mutations in RB1 (P = 0.032), and fewer inactivating GA in CDKN2A (P < 0.0001), CDKN2B (P = 0.05), TERT promoter (P = 0.0004) and TP53 (P < 0.0001). GA in genes associated with urothelial carcinoma including FGFR2 and FGFR3 were similar in both HPV+ and HPV- aBSCC groups. MTAP loss (homozygous deletion) which has emerged as a biomarker for PRMT5 inhibitor-based clinical trials was not identified in any of the 11 HPV+ aBSCC cases, which was significantly lower than the 28% positive frequency of MTAP loss in the HPV- aBSCC group (P < 0.0001). MTOR and PIK3CA pathway GA were not significantly different in the 2 groups. Putative biomarkers associated with immunotherapy (IO) response, including MSI and TMB status, were also similar in the 2 groups. PD-L1 expression data was available for a subset of both HPV+ and HPV- cases and showed high frequencies of positive staining which was not different in the 2 groups. CONCLUSIONS: HPV+ aBSCC tends to occur more often in younger patients. As reported in other HPV-associated squamous cell carcinomas, HPV+ aBSCC demonstrates significantly reduced frequencies of inactivating mutations in cell cycle regulatory genes with similar GA in MTOR and PIK3CA pathways. The implication of HPV in the pathogenesis of bladder cancer remains unknown but warrants further exploration and clinical validation.

First-Generation SARS-CoV-2 Vaccines: A Comparative Analysis between Vaccinated and Unvaccinated Hospitalized Patients Infected with SARS-CoV-2.

Background Severe acute respiratory syndrome corona virus-2 (SARS-CoV-2) variants, which have emerged due to several mutations in spike protein, have a potential to escape immune protection provided by the first-generation vaccines, thereby resulting in breakthrough infections. Objective To identify the socio-demographic factors, clinical features, and outcomes in both vaccinated and unvaccinated hospitalized patients infected with SARS-CoV-2. Method Socio-demographic details, clinical features, and the outcomes among fully vaccinated (double for Covishield/AstraZeneca and BBIBP-CorV and single for Janssen), partially vaccinated, and unvaccinated hospitalized patients with coronavirus disease of 2019 (COVID-19) were collected and analyzed using SPSS version 17. Result Among the hospitalized COVID-19 patients (n=299), 175 (58.5%) patients received a single-dose, 82 (27.4%) double-dose, and 124 (41.5%) did not receive any dose of the COVID-19 vaccines. The risk of SARS-CoV-2 infection when compared between vaccinated and unvaccinated patients was found to be associated among professional degree holders (23.4% versus 9.7%) (p<0.05), professional workers (43.4% vs. 25.0%) (p<0.05), hospitalization to general ward (76.6% vs. 72.6%) (p<0.05), and presence of multiple symptoms (> or equel 3) (86.8% vs. 75.0%) (p>0.05) and comorbidities (> or equal 2) (15.5% vs. 13.7%) (p>0.05). Despite such approximate incidences, the risk of in-hospital mortality among the vaccinated patients was reduced (0.6% vs. 3.2%) (p>0.05), when compared to the unvaccinated patients. The risk of in-hospital mortality was associated with the older age and the presence of multiple comorbidities including bronchial asthma, diabetes, and hypertension. Conclusion Full or partial vaccination against the SARS-CoV-2 variants of concerns might be effective in preventing in-hospital mortality among COVID-19 patients.

Risk factors and outcome analysis of patients with intraoperative rupture (IOR) of ruptured cerebral aneurysm during microsurgical clipping.

PURPOSE: To analyse baseline characteristics of patients with intraoperative rupture (IOR) or non-IOR who underwent microsurgical clipping for ruptured intracranial aneurysms. Additionally, to asses functional outcome in terms of Glasgow Outcome Scale (GOS) at 6 and 12 months. METHODS: A retrospective analysis of 471 patients who underwent microsurgical clipping for ruptured intracranial aneurysms from 2007 to 2018 in Nepal Mediciti Hospital, Nepal. Patients who underwent surgery for unruptured aneurysm were excluded from the study. The association of the base line characteristic in IOR and non-IOR were analysed. Variables analysed were the Hunt and Hess Scale (HHS) dichotomized as (1-3) and (4-5), Modified Fisher Scale dichotomized as (0-2) and (3-4), type of rupture, use of brain retractor, timing of IOR during surgery, aneurysmal factors (size of the neck, location, lobulation) and time of surgery. Outcome, GOS dichotomized into favourable (4-5) and unfavourable (1-3), assessed at 6 months and 12 months. RESULTS: Out of 471 patients treated for ruptured intracranial aneurysm, IOR occurred in 57 (12.10%) with mean age 49.47 (SD ±12.9), occurred more in smoker than non-smoker (45.6% vs. 18.6%; p=.000) and regular alcohol consumers (36.8% vs. 17.9%; p=.004). Favourable outcome with GOS (4-5) at 6 months was observed among patients with lower HHS (1-3), p=.025 and lower MFS (0-2), p=.04. However, outcome at 12 months was better associated with MFS (p=.013) and aneurysm size (p=.038), with more favourable outcome associated with aneurysm less than 10 mm. CONCLUSIONS: Alcohol consumption and smoking are associated risk factors that may contribute to IOR. HHS and MFS are strong predictors of outcome for IOR patients at 6 months. However, at 12 months, MFS is more predictive of outcome. Aneurysms greater than 10 mm had a strong association with outcome at 12 months than 6 months.

Deep Learning-Based Methods for Sentiment Analysis on Nepali COVID-19-Related Tweets.

COVID-19 has claimed several human lives to this date. People are dying not only because of physical infection of the virus but also because of mental illness, which is linked to people's sentiments and psychologies. People's written texts/posts scattered on the web could help understand their psychology and the state they are in during this pandemic. In this paper, we analyze people's sentiment based on the classification of tweets collected from the social media platform, Twitter, in Nepal. For this, we, first, propose to use three different feature extraction methods-fastText-based (ft), domain-specific (ds), and domain-agnostic (da)-for the representation of tweets. Among these three methods, two methods ("ds" and "da") are the novel methods used in this study. Second, we propose three different convolution neural networks (CNNs) to implement the proposed features. Last, we ensemble such three CNNs models using ensemble CNN, which works in an end-to-end manner, to achieve the end results. For the evaluation of the proposed feature extraction methods and CNN models, we prepare a Nepali Twitter sentiment dataset, called NepCOV19Tweets, with 3 classes (positive, neutral, and negative). The experimental results on such dataset show that our proposed feature extraction methods possess the discriminating characteristics for the sentiment classification. Moreover, the proposed CNN models impart robust and stable performance on the proposed features. Also, our dataset can be used as a benchmark to study the COVID-19-related sentiment analysis in the Nepali language.

Disabled women's attendance at community women's groups in rural Nepal.

There is strong evidence that participatory approaches to health and participatory women's groups hold great potential to improve the health of women and children in resource poor settings. It is important to consider if interventions are reaching the most marginalized, and therefore we examined disabled women's participation in women's groups and other community groups in rural Nepal. People with disabilities constitute 15% of the world's population and face high levels of poverty, stigma, social marginalization and unequal access to health resources, and therefore their access to women's groups is particularly important. We used a mixed methods approach to describe attendance in groups among disabled and non-disabled women, considering different types and severities of disability. We found no significant differences in the percentage of women that had ever attended at least one of our women's groups, between non-disabled and disabled women. This was true for women with all severities and types of disability, except physically disabled women who were slightly less likely to have attended. Barriers such as poverty, lack of family support, lack of self-confidence and attendance in many groups prevented women from attending groups. Our findings are particularly significant because disabled people's participation in broader community groups, not focused on disability, has been little studied. We conclude that women's groups are an important way to reach disabled women in resource poor communities. We recommend that disabled persons organizations help to increase awareness of disability issues among organizations running community groups to further increase their effectiveness in reaching disabled women.

Donepezil provides positive effects to patients treated with gabapentin for neuropathic pain: an exploratory study.

BACKGROUND: The first-line medication gabapentin and the acetylcholinesterase inhibitor donepezil represent a new promising combination to improve treatment outcomes for patients with severe neuropathic pain. The drugs have previously shown synergism following co-administration in nerve-injured rats. METHODS: The clinical relevance of adding donepezil to existing gabapentin treatment in patients with post-traumatic neuropathic pain was explored in this open-label study. The study comprised two consecutive periods of minimum 6 weeks: (1) titration of gabapentin to the highest tolerable dose or maximum 2400 mg daily, and (2) addition of donepezil 5 mg once daily to the fixed gabapentin dose. Efficacy and tolerability were assessed by ratings of pain intensity, questionnaires for pain and health-related quality of life, and reporting of adverse events. Pain scores were also analysed using mixed-effects analysis with the software NONMEM to account for intersubject variability. RESULTS: Eight patients commenced treatment with donepezil, of which two withdrew because of adverse events. Addition of donepezil resulted in clinically relevant reductions of pain (> 11 units on a 0-100 scale) and improved mental wellness in three of six patients. The remaining three patients had no obvious supplemental effect. Mixed-effects analysis revealed that pain scores were significantly lower during co-administration (P < 0.0001 combination vs. monotherapy). CONCLUSION: Donepezil may provide additional analgesia to neuropathic pain patients with insufficient pain relief from gabapentin as monotherapy. The promising results support controlled clinical trials of the drug combination. The usefulness of mixed-effects analysis in small-scale trials and/or for data with high intersubject variability was also demonstrated.

Enteric opportunistic parasitic infections among HIV seropositive patients in Kathmandu, Nepal.

BACKGROUND: Enteric opportunistic parasitic infections are the major source of diarrheal disease in developing countries mainly in Human Immunodeficiency virus (HIV) infected patients. OBJECTIVE: The study was to detect enteric parasites causing diarrhea and their association with immune status in HIV-seropositive patients. METHODS: The present study was conducted in Dirgh-Jeevan Health Care Research Center and Tribhuvan University Teaching Hospital, Public Health Research Laboratory, Kathmandu, Nepal between June 2010 and May 2011 involving 146 Human Immunodeficiency virus (HIV) positive patients. Serostatus from these patients were detected by Enzyme Linked Immunosorbent assay. CD4+ T cell counts were done by flow cytometry. Stool was examined for enteric parasites by microscopy with special staining methods. RESULTS: A total of 146 HIV sero-positive patients with and without diarrhea age between 20 to 45 years were included in the study. Of the 146 patients, the protozoan parasitic infection was found in 30.13% (44/146). Out of 146 patients, 78 had diarrhea in which parasitic infection was 39 (50%) and 7.35% (5/68) protozoal parasites positive cases did not have diarrhea. A significant difference (p less than 0.05) was observed in the level of infection of intestinal protozoan between the HIV seropositive with diarrhea and HIV-seropositive without diarrhea. Out of 43 patients whose CD4+ T cells were less than 200/µl, 29 (67.4%) had opportunistic parasitic infection whereas out of 103 patients whose CD4+ T cells were =200/mcl, only 15 (14.56%) had opportunistic parasitic infection (P less than 0.05). CONCLUSION: Enteric opportunistic parasitic infections were detected in 30.1% among HIV-seropositive patients and low CD4+ T count indicated high enteric opportunistic infection. Early detection of enteric parasitic infections will help in the management and to improve the quality of life for HIV-infected individuals.

Microsomal omega-hydroxylated metabolites of N-arachidonoyl dopamine are active at recombinant human TRPV1 receptors.

N-Arachidonoyl dopamine (NADA) is an endogenous lipid that modulates signal transduction in neuronal and immune pathways. NADA activates the non-selective cation channel, transient receptor potential vanilloid type 1 (TRPV(1)) and cannabinoid receptor 1. That NADA is comprised of an arachidonic acid (AA) backbone suggests that it may be metabolized through many of the enzymes that act upon AA such as the other AA-derived signaling lipids, the endogenous cannabinoids. To investigate the metabolism of NADA through the cytochrome P450 (CYP450) metabolic pathway, we studied the in vitro rat liver microsomal production of hydroxylated metabolites and their activity at recombinant human TRPV(1) receptors. We showed that following microsomal activation in the presence of NADA, omega and (omega-1) hydroxylated metabolites (19- and 20-HETE-DA) were formed. These metabolites were active at recombinant human TRPV(1) receptors, inducing a dose-dependent calcium influx. Both metabolites exhibited lower potency compared to NADA. We conclude that CYP450 enzymes are capable of metabolizing this signaling lipid forming a larger family of potential neuromodulators.

A clinicoepidemiological study of polymorphic light eruption.

BACKGROUND AND AIMS: The prevalence of polymorphic light eruption (PLE) varies between 10-20% in different countries but no such data is available from India, where exposure to sunlight is high. METHODS: A clinico-epidemiological study of PLE was done in the skin outpatient department (OPD) of Institute of Medical Sciences Hospital from January to December. RESULTS: The ages of the patients varied from 5-70 years. Out of a total of 39,112 OPD cases, 220 cases of PLE (138 females and 82 males) were recorded, giving a prevalence of 0.56% in this study population. The skin type varied between IV and VI in 96% of the cases. Housewives were 81, students 67, office persons 39, farmers 22, businessmen 6 and unemployed 5. DISCUSSION: The manifestation of PLE was most common in housewives in areas exposed to the sun. Most of the PLE patients presented with mild symptoms and rash around the neck, forearms and arms which was aggravated on exposure to sunlight. PLE was more prevalent in the months of March and September and the disease was recurrent in 31.36% of the cases. CONCLUSIONS: The prevalence of PLE was 0.56%. It was mild in nature and only areas exposed to the sun were involved.