Category: Nevin Manimala

J Clin Oncol. 2023 Feb 8:JCO2201726. doi: 10.1200/JCO.22.01726. Online ahead of print.

ABSTRACT

PURPOSE: To assess the efficacy and safety of darolutamide maintenance after successful taxane chemotherapy in patients with metastatic castration-resistant prostate cancer (mCRPC).

PATIENTS AND METHODS: Swiss Group for Clinical Cancer Research (SAKK) 08/16 is a randomized phase II study. Patients with mCRPC who received prior androgen-receptor pathway inhibitors (ARPIs) and subsequently had nonprogressive disease on a taxane were randomly assigned to darolutamide 600 mg twice a day or placebo twice a day. The primary end point was radiographic progression-free survival (rPFS) at 12 weeks. Secondary end points were rPFS, event-free survival, overall survival (OS), prostate-specific antigen (PSA) 50% response rate, and adverse events.

RESULTS: Overall, 92 patients were recruited by 26 centers. Prior taxane was docetaxel in 93% and cabazitaxel in 7%. Prior ARPI was abiraterone in 60%, enzalutamide in 31%, and both in 9%. rPFS at 12 weeks was significantly improved with darolutamide (64.7% v 52.2%; P = .127). Median rPFS on darolutamide was 5.5 versus 4.5 months on placebo (hazard ratio [HR], 0.54; 95% CI, 0.32 to 0.91; P = .017), and median event-free survival was 5.4 versus 2.9 months (HR, 0.46; 95% CI, 0.29 to 0.73; P = .001). PSA 50% response rate was improved (22% v 4%; P = .014). Median OS for darolutamide was 24 versus 21.3 months for placebo (HR, 0.62; 95% CI, 0.3 to 1.26; P = .181). Treatment-related adverse events were similar in both arms.

CONCLUSION: SAKK 08/16 met its primary end point, showing that switch maintenance with darolutamide after prior taxane chemotherapy and at least one ARPI resulted in a statistically significant but clinically modest rPFS prolongation with good tolerability. The median OS with darolutamide maintenance appears promising. Should these findings be confirmed in a larger trial, maintenance treatment could be a novel strategy in managing patients with mCRPC, especially those who responded well to prior ARPI.

PMID:36753698 | DOI:10.1200/JCO.22.01726

Perfusion. 2023 Feb 8:2676591231156487. doi: 10.1177/02676591231156487. Online ahead of print.

ABSTRACT

Introduction: Obesity is associated with a worse prognosis in COVID-19 patients with acute respiratory distress syndrome (ARDS). Veno-venous (V-V) Extracorporeal Membrane Oxygenation (ECMO) can be a rescue option, however, the direct impact of morbid obesity in this select group of patients remains unclear.Methods: This is an observational study of critically ill adults with COVID-19 and ARDS supported by V-V ECMO. Data are from 82 institutions participating in the COVID-19 Critical Care Consortium international registry. Patients were admitted between 12 January 2020 to 27 April 2021. They were stratified based on Body Mass Index (BMI) at 40 kg/m². The endpoint was survival to hospital discharge.Results: Complete data available on 354 of 401 patients supported on V-V ECMO. The characteristics of the high BMI (>40 kg/m²) and lower BMI (≤40 kg/m²) groups were statistically similar. However, the ‘high BMI’ group were comparatively younger and had a lower APACHE II score. Using survival analysis, older age (Hazard Ratio, HR 1.49 per-10-years, CI 1.25-1.79) and higher BMI (HR 1.15 per-5 kg/m² increase, CI 1.03–1.28) were associated with a decreased patient survival. A safe BMI threshold above which V-V ECMO would be prohibitive was not apparent and instead, the risk of an adverse outcome increased linearly with BMI.Conclusion: In COVID-19 patients with severe ARDS who require V-V ECMO, there is an increased risk of death associated with age and BMI. The risk is linear and there is no BMI threshold beyond which the risk for death greatly increases.

PMID:36753684 | DOI:10.1177/02676591231156487

J Infect Dev Ctries. 2022 Dec 31;16(12):1906-1913. doi: 10.3855/jidc.17358.

ABSTRACT

INTRODUCTION: The role of bacteria in the pathogenesis of periodontitis, pericoronitis, and periapical infections has been well-established. However, the variation in the severity and prognosis of these lesions could suggest a potential role of other microorganisms, such as viruses and fungi. This study aims to evaluate the presence of adenovirus, human papillomavirus-16, Epstein-Barr virus, Candida, and non-Candida fungi in these infections.

METHODOLOGY: A cross-sectional study including 120 healthy adult patients presenting with dental infections requiring dental extractions were conducted to assess the prevalence and the relative quantity of viruses and fungi in saliva, infected, and healthy tissues using quantitative polymerase chain reaction tests. Samples were collected, and a categorical scale was used for the prevalence and a continuous scale for the relative quantification. Statistical analyses were performed using Chi-square for the prevalence and Wilcoxon rank test for the relative quantification.

RESULTS: Except for the Epstein-Barr virus and Candida, the presence of viruses and fungi was significantly associated with dental infections. Adenovirus showed an association with pericoronitis, while human papilloma virus-16 exhibited an association with periapical infections. Non-Candida fungi, on the other hand, showed a positive association with all infected tissues and saliva as compared to healthy control lesions except for periapical infections.

CONCLUSIONS: According to this study, viruses and fungi were found to be prevalent in dental infections. However, their associations with those infections vary depending on the types of viruses or fungi involved and the category of dental infections.

PMID:36753659 | DOI:10.3855/jidc.17358

J Infect Dev Ctries. 2022 Dec 31;16(12):1897-1905. doi: 10.3855/jidc.17233.

ABSTRACT

INTRODUCTION: Hepatitis B virus (HBV) and hepatitis C virus (HCV) represent common infections that are presumably associated with various types of lymphoma and specific clinical features. However, conclusive data are lacking and results from different regional studies are conflicting. Hence, a national study was performed in order to investigate potential associations between hepatitis infections and lymphoma in the Republic of Moldova.

METHODOLOGY: Data were collected from newly diagnosed adult lymphoma patients from January 2020 to January 2022. Patients who were not tested for HBsAg and anti-HCV and those with an undetermined lymphoma subtype diagnosis were excluded from the study. Subjects with and without viral hepatitis were then evaluated on the basis of clinical and pathological characteristics.

RESULTS: One hundred and twenty-nine lymphoma patients were included in the study; 15 (11.6%) patients were diagnosed with hepatitis B, 21 (16.3%) patients with hepatitis C, and 1 (0.78%) patient was positive for both. The majority of hepatitis patients were over 60 years old (62.2%), presented with stage III or IV (81%), had normal lactate dehydrogenase (58.3%) and 0 or 1 extranodal sites (78.4%). The most common lymphoma subtypes were diffuse large B-cell lymphoma (64.9%) and marginal zone lymphoma (8.1%). We did not find any statistically significant differences between infected and uninfected lymphoma patients in regards to clinical features, specific lymphoma subtypes, and presence and location of extranodal involvement.

CONCLUSIONS: Presence of hepatitis B or C virus infections is not associated with specific clinical and pathological features in Moldovan lymphoma patients.

PMID:36753658 | DOI:10.3855/jidc.17233

J Infect Dev Ctries. 2022 Dec 31;16(12):1887-1896. doi: 10.3855/jidc.14638.

ABSTRACT

INTRODUCTION: Culture-negative and multidrug-resistant neonatal sepsis frequently occur in developing countries and complicate neonatal sepsis management. These conditions contribute to a high neonatal mortality rate and accelerate the misuse of antibiotics. However, the extent of culture-negative and multidrug-resistant neonatal sepsis in developing countries remains poorly characterized. This study aims to describe culture-negative and culture-proven neonatal sepsis epidemiology and the antimicrobial resistance patterns in Palembang, Indonesia.

METHODOLOGY: A retrospective review of the medical records of all neonatal admissions between January 2016 and December 2018 was conducted at a tertiary-level referral hospital in Indonesia. The maternal and neonatal characteristics and microbiological results of the identified sepsis cases were obtained and analyzed.

RESULTS: Three hundred and fifty-six neonatal sepsis cases were admitted from 2016 to 2018, accounting for 14.1% of neonatal hospital admissions. The percentages of early-onset and late-onset sepsis were comparable (49.7% vs. 50.3%), with an 18.1% case fatality rate. The proportion of culture-negative sepsis was 44%. The mortality rates between culture-proven and culture-negative sepsis cases did not differ statistically (p = 0.11). Coagulase-negative staphylococci (30.9%), Klebsiella pneumoniae (18.1%), and Acinetobacter spp. (10.7%) were the most frequently isolated pathogens. Overall, 62.6% of all isolated organisms were multidrug-resistant bacteria, with a high prevalence of extended-spectrum cephalosporin-resistant and carbapenem-resistant strains.

CONCLUSIONS: Culture-negative sepsis accounts for a significant proportion of neonatal sepsis cases. Early- and late-onset and culture-negative and culture-proven neonatal sepsis contribute to a comparable proportion of neonatal sepsis morbidity and mortality. There is an alarmingly high prevalence of resistance to extended-spectrum cephalosporin and carbapenem in neonatal sepsis cases.

PMID:36753657 | DOI:10.3855/jidc.14638

J Infect Dev Ctries. 2022 Dec 19;16(12):1860-1869. doi: 10.3855/jidc.17257.

ABSTRACT

INTRODUCTION: Multi-Drug Resistance (MDR) is common in hospitalized geriatric patients. The study aims to investigate the pattern of antibiotic use and determine its association with MDR in hospitalized geriatric patients.

METHODOLOGY: A retrospective cohort study including 193 geriatric patients admitted to a Geriatric Intensive Care Unit (GICU) in a tertiary care Geriatrics hospital in Egypt, throughout a consecutive 6 months duration. A review of medical records was done to extract clinical, socio-demographic, and prescribing data on antibiotics throughout admission. The presence of MDR organisms (MDROs) was determined by reviewing culture and sensitivity reports. Descriptive statistics and logistic regression analysis were performed.

RESULTS: 181 (93.8%) patients received at least 1 antibiotic. Cephalosporins were the most commonly consumed antibiotics (24%). MDROs were significantly associated with receiving ≥ 3 antibiotics. Longer hospital stay was a predictor of multiple antibiotics use (Odds Ratio of 1.075). MDROs were prevalent in 110 (57.0 %) patients. Klebsiella species were the most frequent MDROs (26%) with the highest susceptibility to amikacin.

CONCLUSIONS: The study provides a detailed description of both antibiotics use and MDR among hospitalized geriatric patients in Egypt. It gives a novel insight into the ongoing drug-pathogen combinations in acute healthcare settings of the aged. This data has a potential role in applying antimicrobial stewardship programs for hospitalized geriatric patients to mitigate antimicrobial resistance in similar settings.

PMID:36753654 | DOI:10.3855/jidc.17257

Sci Adv. 2023 Feb 10;9(6):eade9238. doi: 10.1126/sciadv.ade9238. Epub 2023 Feb 8.

ABSTRACT

Rhabdomyosarcoma (RMS) is a group of pediatric cancers with features of developing skeletal muscle. The cellular hierarchy and mechanisms leading to developmental arrest remain elusive. Here, we combined single-cell RNA sequencing, mass cytometry, and high-content imaging to resolve intratumoral heterogeneity of patient-derived primary RMS cultures. We show that the aggressive alveolar RMS (aRMS) subtype contains plastic muscle stem-like cells and cycling progenitors that drive tumor growth, and a subpopulation of differentiated cells that lost its proliferative potential and correlates with better outcomes. While chemotherapy eliminates cycling progenitors, it enriches aRMS for muscle stem-like cells. We screened for drugs hijacking aRMS toward clinically favorable subpopulations and identified a combination of RAF and MEK inhibitors that potently induces myogenic differentiation and inhibits tumor growth. Overall, our work provides insights into the developmental states underlying aRMS aggressiveness, chemoresistance, and progression and identifies the RAS pathway as a promising therapeutic target.

PMID:36753540 | DOI:10.1126/sciadv.ade9238

PLoS Negl Trop Dis. 2023 Feb 8;17(2):e0011067. doi: 10.1371/journal.pntd.0011067. eCollection 2023 Feb.

ABSTRACT

BACKGROUND: Melioidosis is a disease caused by the bacterium Burkholderia pseudomallei, infecting humans and non-human primates (NHP) through contaminated soil or water. World-wide there are an estimated 165,000 human melioidosis cases each year, but recordings of NHP cases are sporadic. Clinical detection of melioidosis in humans is primarily by culturing B. pseudomallei, and there are no standardized detection protocols for NHP. NHP are an important animal model for melioidosis research including clinical trials and development of biodefense countermeasures.

METHODOLOGY/PRINCIPLE FINDINGS: We evaluated the diagnostic potential of the multiple antigen serological assay, BurkPx, in NHP using two sera sets: (i) 115 B. pseudomallei-challenged serum samples from 80 NHP collected each week post-exposure (n = 52) and at euthanasia (n = 47), and (ii) 126 B. pseudomallei-naïve/negative serum samples. We observed early IgM antibody responses to carbohydrate antigens followed by IgG antibody recognition to multiple B. pseudomallei protein antigens during the second week of infection. B. pseudomallei negative serum samples had low to intermediate antibody cross reactivity to the antigens in this assay. Infection time was predicted as the determining factor in the variation of antibody responses, with 77.67% of variation explained by the first component of the principal component analysis. A multiple antigen model generated a binary prediction metric ([Formula: see text]), which when applied to all data resulted in 100% specificity and 63.48% sensitivity. Removal of week 1 B. pseudomallei challenged serum samples increased the sensitivity of the model to 95%.

CONCLUSION/SIGNIFICANCE: We employed a previously standardized assay for humans, the BurkPx assay, and assessed its diagnostic potential for detection of B. pseudomallei exposure in NHP. The assay is expected to be useful for surveillance in NHP colonies, in investigations of suspected accidental releases or exposures, and for identifying vaccine correlates of protection.

PMID:36753522 | DOI:10.1371/journal.pntd.0011067

PLoS Comput Biol. 2023 Feb 8;19(2):e1010878. doi: 10.1371/journal.pcbi.1010878. Online ahead of print.

ABSTRACT

Humans constantly assess the appearance of materials to plan actions, such as stepping on icy roads without slipping. Visual inference of materials is important but challenging because a given material can appear dramatically different in various scenes. This problem especially stands out for translucent materials, whose appearance strongly depends on lighting, geometry, and viewpoint. Despite this, humans can still distinguish between different materials, and it remains unsolved how to systematically discover visual features pertinent to material inference from natural images. Here, we develop an unsupervised style-based image generation model to identify perceptually relevant dimensions for translucent material appearances from photographs. We find our model, with its layer-wise latent representation, can synthesize images of diverse and realistic materials. Importantly, without supervision, human-understandable scene attributes, including the object’s shape, material, and body color, spontaneously emerge in the model’s layer-wise latent space in a scale-specific manner. By embedding an image into the learned latent space, we can manipulate specific layers’ latent code to modify the appearance of the object in the image. Specifically, we find that manipulation on the early-layers (coarse spatial scale) transforms the object’s shape, while manipulation on the later-layers (fine spatial scale) modifies its body color. The middle-layers of the latent space selectively encode translucency features and manipulation of such layers coherently modifies the translucency appearance, without changing the object’s shape or body color. Moreover, we find the middle-layers of the latent space can successfully predict human translucency ratings, suggesting that translucent impressions are established in mid-to-low spatial scale features. This layer-wise latent representation allows us to systematically discover perceptually relevant image features for human translucency perception. Together, our findings reveal that learning the scale-specific statistical structure of natural images might be crucial for humans to efficiently represent material properties across contexts.

PMID:36753520 | DOI:10.1371/journal.pcbi.1010878

PLoS One. 2023 Feb 8;18(2):e0280623. doi: 10.1371/journal.pone.0280623. eCollection 2023.

ABSTRACT

A major limiting factor in combatting the HIV epidemic has been the identification of people living with HIV. Index testing programs were developed to face that challenge. Index testing is a focused HIV testing service approach in which family members and partners of people living with HIV are offered testing. Despite the implementation of index testing, there is still a gap between the estimated number of people living with HIV and those who know their status in Côte d’Ivoire. This study aimed to understand the implementation process of index testing in Côte d’Ivoire and to identify implementation challenges from healthcare workers perspectives. In January and February 2020, we conducted a qualitative study through 105 individual semi-structured interviews regarding index testing with clinical providers (physicians, nurses, and midwives) and non-clinical providers (community counselors and their supervisors) at 16 rural health facilities across four regions of Côte d’Ivoire. We asked questions regarding the index testing process, index client intake, contact tracing and testing, the challenges of implementation, and solicited recommendations on improving index testing in Côte d’Ivoire. The interviews revealed that index testing is implemented by non-clinical providers. Passive referral, by which the index client brought their contact to be tested, and providers referral, by which a healthcare worker reached out to the index client’s contact, were the preferred contact tracing and testing strategies. There was not statistically significant difference between immediate and delayed notification. Reported challenges of index testing implementation included index cases refusing to give their partner’s information or a partner refusing to be tested, fear of divorce, societal stigma, long distances, lack of appropriate training in index testing strategies, and lack of a private room for counseling. The recommendations given by providers to combat these was to reinforce HIV education among the population, to train healthcare workers on index testing strategies, and to improve infrastructure, transportation, and communication resources. The study showed that the elements that influenced the process of index testing in Côte d’Ivoire were multifactorial, including individual, interpersonal, health systems, and societal factors. Thus, a multi-faceted approach to overcoming challenges of index testing in Côte d’Ivoire is needed to improve the yield of index testing.

PMID:36753518 | DOI:10.1371/journal.pone.0280623