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Abstract Background Renal neuroendocrine neoplasms (R‐NEN) are exceptionally rare tumours characterized by high mortality rates. Objective The objective of this study is to analyse prognostic factors and treatment impact on overall survival in patients with R‐NEN. Design, setting and participants We identified all patients with R‐NEN in the National Cancer Database (NCDB) from 2004 to 2019 and identified prognostic factors for improved survival. Results and limitations Of 542 R‐NEN cases, 166 (31%) were neuroendocrine tumour grade 1 (NET‐G1), 14 (3%) were neuroendocrine tumour grade 2 (NET‐G2), 169 (31%) were neuroendocrine carcinoma (NEC‐NOS), 18 (3%) were large cell neuroendocrine carcinoma (LC‐NEC) and 175 (32%) were small cell neuroendocrine carcinoma (SC‐NEC). Median overall survival for all patients in the study was 44.88 months (SE, 4.265; 95% CI, 27.57–62.19). Median overall survival was 7.89 months (SE 0.67; 95% CI, 6.58–9.20) for patients without surgical intervention and 136.61 months (SE 16.44; 95% CI, 104.38–168.84, p

Background: For females undergoing cystectomy and urinary diversion, decreases in sexual and urinary functions can have a significant impact on quality of life. Pelvic organ–preserving (POP) radical cystectomy (RC) has been proposed as an approach to improve postoperative functional outcomes. Objective: To evaluate postoperative functional outcomes of a robotic approach for female POP RC with intracorporeal urinary diversion. Design, setting, and participants: This was a multicenter retrospective study evaluating sexual, urinary, and oncological outcomes for sexually active females undergoing POP robot-assisted RC for ≤T2 bladder cancer. Exclusion criteria included multifocal, trigonal, or locally advanced tumors. Surgical procedure: We describe a step-by-step technique for POP robot-assisted RC with intracorporeal urinary diversion. Measurements: The primary outcome of the study was evaluation of sexual and urinary functions following surgery. Oncological outcomes were evaluated as a secondary endpoint. Results and limitations: Our study included 23 females who underwent POP robot-assisted RC between 2008 and 2020 with intracorporeal neobladder (87%) or ileal conduit (13%) reconstruction. The median follow-up was 20 mo. A postoperative sexual function questionnaire was completed by 15 patients (65%). Of those, 13 (87%) resumed sexual activity at a median of 6 mo after surgery. Of the patients with a neobladder, 14 (70%) achieved daytime continence and 16 (80%) achieved nighttime continence. Cancer-specific and overall survival were both 91%. The results are limited by their retrospective nature. Conclusions: POP robot-assisted RC with orthotopic neobladder allows a majority of female patients to return to sexual activity after surgery. This approach should be considered for selected sexually active women. Patient summary: We evaluated 23 women with bladder cancer who underwent surgical removal of the bladder with preservation of their reproductive organs. Following this surgery, a majority of patients resumed sexual activity. For selected patients, this technique can be performed without compromising cancer control.

Head and neck squamous cell carcinoma (HNSCC) encompasses a set of cancers arising from the epithelia of the upper aerodigestive tract, accounting for a significant burden of disease worldwide due to the disease’s mortality, morbidity, and predilection for recurrence. Prognosis of HNSCC in the recurrent and/or metastatic (R/M-HNSCC) setting is especially poor and effective treatment options increasingly rely on modulating T-cell antitumor responses. Still, immunotherapy response rates are generally low, prompting the exploration of novel strategies that incorporate other effector cells within the tumor microenvironment. Within the last decade, important advances have been made leveraging the powerful innate antitumor function of natural killer (NK) cells to treat solid tumors, including head and neck squamous cell carcinoma. NK cells are hybrid innate-adaptive effector cells capable of directly eliminating tumor cells in addition to initiating adaptive antitumor immune responses. In the setting of HNSCC, NK cells are important for tumor surveillance and control, and NK cell infiltration has repeatedly been associated with a favorable prognosis. Yet, HNSCC-infiltrating NK cells are susceptible to an array of immune evasion strategies employed by tumors that must be overcome to fully realize the antitumor potential of NK cells. We believe that a conceptual framework informed by the basic biological understanding of the mechanisms underlying NK cell activation can improve treatment of HNSCC, in part by selecting for patients most likely to respond to NK cell-based immunotherapy. Herein, we review the activity of NK cells in HNSCC, paying special attention to the role of environmental and genetic determinants of NK cell antitumor function. Moreover, we explore the evidence that NK cells are a crucial determinant of the efficacy of both established and emerging treatments for HNSCC.

Renal cell cancer (RCC) continues to be among the most lethal malignancies in the USA. Introduction of anti-vascular epidermal growth factor receptor tyrosine kinase inhibitors over a decade ago resulted in improvement in disease outcomes, but further development of new therapies largely stagnated for many years. More recently, a better understanding of disease biology and treatment-resistance patterns has led to a second renaissance in drug development, with the anti-programmed cell death protein 1 immune checkpoint inhibitor, nivolumab, paving the way for additional therapies entering clinical trial testing in the treatment of RCC.

The eMalahleni Local Municipality (eLM) in Mpumalanga province, South Africa, has a number of informal settlements because of the influx of people seeking employment in the municipal area. These informal settlements are exposed to a number of hazards, including underground fires, air and water pollution, sinkholes, abandoned mining areas and acid mining drainage. South Africa's National Development Plan (NDP) incorporates the United Nation's Sustainable Development Goals, which are intended to upgrade informal settlements on suitable land. The Department of Human Settlement recognised the gap in the policy because upgrading only included physical structures and did not include adaptive capacity for communities to create resilience to withstand disasters. The researcher used a case study research design for the inquiry intended to recommend adaptive capacity and reduce disaster risks in informal settlements in the eLM. Purposive sampling was used to select 25 participants from eLM, provincial government departments and informal settlements. The data were analysed using thematic analysis based on the study's conceptual framework. The research findings revealed that the government has not done much to involve vulnerable communities during the development of policies to reduce disaster risks within informal settlements. In particular, the failure of the government to promote and reinforce public participation in disaster risk reduction programmes leaves the vulnerable communities defenceless., Contribution: This study strengthens the intergovernmental structures and public participation to reduce disaster risks in communities. This study discourages a silos mentality and encourages coordination between government departments to identify root causes by applying the pressure and release model for effective disaster risk reduction., Competing Interests: The authors declare that they have no financial or personal relationship(s) that may have inappropriately influenced them in writing this article., (© 2024. The Authors.)

This study reviewed the impact of the coronavirus disease 2019 (COVID-19) on pre-existing vulnerabilities in rural communities using the scoping review strategy. It focused on manuscripts published on the topic in 2020. Based on 39 studies that met our inclusion criteria (out of 507 studies), we note that COVID-19 is exacerbating pre-existing rural vulnerabilities, including poverty, remoteness, socio-economic marginalisation and high unemployment. There is limited evidence that rural communities are resilient to the pandemic. Reduction in household expenditures and the community food system are the only reported forms of resilience. Although local institutions are supporting rural communities in responding to the impacts of the pandemic, several institutional dynamics undermine the effectiveness of the response. The increased risk of the pandemic is likely to reduce incomes and standards of living amongst poor communities. Thus, coping strategies were identified such as starting small gardens in communities, diet changes, targeting community markets with produce rather than retailers and food swap using social media, with food swap being the most adopted coping strategy. Although this study does not offer a comprehensive picture of the levels and nature of vulnerability, resilience and institutional dynamics of rural communities in different parts of the world reveal the limitations of existing knowledge of the vulnerability of rural communities in the context of COVID-19. This underscores the importance of further studies on rural vulnerability in the context of COVID-19 that will enable evidence-based responses to the pandemic in rural contexts., Competing Interests: The authors declare that they have no financial or personal relationships that may have inappropriately influenced them in writing this article., (© 2022. The Authors.)

Leishmania major is the causative agent of cutaneous leishmaniasis (CL). No human vaccine is available for CL, and current drug regimens present several drawbacks, such as emerging resistance, severe toxicity, medium effectiveness, and/or high cost. Thus, the need for better treatment options against CL is a priority. In the present study, we validate the enzyme methionine aminopeptidase 1 of L. major (MetAP1 Lm ), a metalloprotease that catalyzes the removal of N-terminal methionine from peptides and proteins, as a chemotherapeutic target against CL infection. The in vitro antileishmanial activities of eight novel MetAP1 inhibitors (OJT001 to OJT008) were investigated. Three compounds, OJT006, OJT007, and OJT008, demonstrated potent antiproliferative effects in macrophages infected with L. major amastigotes and promastigotes at submicromolar concentrations, with no cytotoxicity against host cells. Importantly, the leishmanicidal effect in transgenic L. major promastigotes overexpressing MetAP1 Lm was diminished by almost 10-fold in comparison to the effect in wild-type promastigotes. Furthermore, the in vivo activities of OJT006, OJT007, and OJT008 were investigated in L. major -infected BALB/c mice. In comparison to the footpad parasite load in the control group, OJT008 decreased the footpad parasite load significantly, by 86%, and exhibited no toxicity in treated mice. We propose MetAP1 inhibitor OJT008 as a potential chemotherapeutic candidate against CL infection caused by L. major infection., (Copyright © 2020 American Society for Microbiology.)

Although isoniazid (INH) has been successful in treating Tuberculosis (TB) since its introduction in 1952, there has been continual reports of drug-associated hepatotoxicity in TB patients. These toxic side effects may reveal more about the recipient of the drug, than the drug itself. A combination of pharmacogenetic and pharmacokinetic studies have identified polymorphisms within enzymes involved in INH metabolism and detoxification. These essential metabolic enzymes include N-acetyltransferase 2, Cytochrome P450 2E1, and glutathione S transferases. Different phenotypes of these enzymes can affect the rate of INH metabolism, resulting in production of hepatotoxic metabolites. This review is intended to elucidate the pharmacokinetics of INH by examining its Administration, Distribution, Metabolism, and Elimination, while suggesting potential alternatives within INH personalized treatment to help reduce hepatotoxicity., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Mycobacterium tuberculosis (Mtb) and the Human Immunodeficiency Virus (HIV) pose a major public health threat. The 2015 World Health Organization (WHO) report estimates that one in three HIV deaths is due to Mtb, the causative agent of Tuberculosis (TB). The lethal synergy between these two pathogens leads to a decline in the immune function of infected individuals as well as a rise in morbidity and mortality rates. The deadly interaction between TB and HIV, along with the heightened emergence of drug resistance, drug-drug interactions, reduced drug efficacy and increased drug toxicity, has made the therapeutic management of co-infected individuals a major challenge. Hence, the development of new drug targets and/or new drug leads are imperative for the effective therapeutic management of co-infected patients. Here, we report the characterization of 2-hydroxy-1-naphthaldehyde isonicotinoyl hydrazone (311), a known inhibitor of HIV-1 replication and transcription as a new inhibitor of methionine aminopeptidases (MetAPs) from Mycobacterium tuberculosis: MtMetAP1a and MtMetAP1c. MetAP is a metalloprotease that removes the N-terminal methionine during protein synthesis. The essential role of MetAP in microbes makes it a promising chemotherapeutic target. We demonstrated that 311 is a potent and selective inhibitor of MtMetAP1a and MtMetAP1c. Furthermore, we found that 311 is active against replicating and aged non-growing Mtb at low micromolar concentrations. These results suggest that 311 is a promising lead for the development of novel class of therapeutic agents with dual inhibition of TB and HIV for the treatment of TB-HIV co-infection., (Copyright © 2016. Published by Elsevier Ltd.)

The adhesion of three Staphylococcus epidermidis and three S aureus clinical isolates, to uncoated and hydrogel-coated polyurethane catheters was tested, following pretreatment of catheters with human plasma. Plasma significantly decreased the adhesion of S. epidermidis strains to uncoated polyurethane catheters, but had no significant effect on the adhesion to hydrogel-coated catheters. The influence of plasma on adhesion of S. aureus strains to catheters was strain dependent. Plasma significantly increased the adhesion of one strain (SA6) to uncoated catheters. For two other strains (SA3 and SA14) plasma produced no clear effect on their adhesion to uncoated catheters; adhesion values for each strain showed either a small but significant increase or a replicate-dependent increase or decrease. However, plasma significantly increased the adhesion of all S. aureus strains to hydrogel-coated polyurethane catheters. Overall, with the exception of one batch culture of S. epidermidis strain SE3 tested, attachment to plasma-treated hydrogel coated catheters was statistically significantly lower, by up to 85%, than attachment to plasma-treated uncoated catheters for both S. epidermidis and S. aureus.

Adhesion of Staphylococcus epidermidis NCTC 11047 to the external surface of polyurethane catheters was quantified by a radiolabelling assay. Maximum adhesion was achieved with an initial cell concentration of 3 x 10(8)/ml after incubation for 120 min. The assay was tested for reproducibility by analysis of variance. Adhesion of clinical strains of S. epidermidis and S. aureus to uncoated polyurethane and hydrogel (Hydromer)-coated polyurethane catheters was compared. Hydrogel coating significantly reduced adhesion for both S. epidermidis and S. aureus (mean percentage reduction 71% for S. epidermidis, 69% for S. aureus). Clinical isolates were also tested for adhesion to polystyrene by a modified microtitration well adhesion assay; there was no correlation between staphylococcal adhesion to polyurethane catheters and adhesion to polystyrene. Cell surface hydrophobicity values varied widely for both species. Positive correlations were found between cell surface hydrophobicity and adhesion to polystyrene and uncoated polyurethane catheters for S. epidermidis but not for S. aureus.