Prognostic significance of absolute lymphocyte count in patients with metastatic renal cell carcinoma receiving first-line combination immunotherapies: results from the International Metastatic Renal Cell Carcinoma Database Consortium.

BACKGROUND: Lymphocytes are closely linked to mechanisms of action of immuno-oncology (IO) agents. We aimed to assess the prognostic significance of absolute lymphocyte count (ALC) in patients with metastatic renal cell carcinoma (mRCC). PATIENTS AND METHODS: Using the International mRCC Database Consortium (IMDC), patients receiving first-line IO-based combination therapy were analysed. Baseline patient characteristics, objective response rates (ORRs), time to next treatment (TTNT), and overall survival (OS) were compared. RESULTS: Of 966 patients included, 195 (20%) had lymphopenia at baseline, and they had a lower ORR (37% versus 45%; P < 0.001), shorter TTNT (10.1 months versus 24.3 months; P < 0.001), and shorter OS (30.4 months versus 48.2 months; P < 0.001). Among 125 patients with lymphopenia at baseline, 52 (42%) experienced ALC recovery at 3 months, and they had longer OS (not reached versus 30.4 months; P = 0.012). On multivariable analysis for OS, lymphopenia was an independent adverse prognostic factor (hazard ratio 1.68; P < 0.001). Incorporation of lymphopenia into the IMDC criteria improved OS prediction accuracy (C-index from 0.688 to 0.707). CONCLUSIONS: Lymphopenia was observed in one-fifth of treatment-naive patients with mRCC and may serve as an indicator of unfavourable oncologic outcomes in the contemporary IO era.

A taste of space: Remote animal observations and discrete-choice models provide new insights into foraging and density dynamics for a large subarctic herbivore.

Competition for resources and space can drive forage selection of large herbivores from the bite through the landscape scale. Animal behaviour and foraging patterns are also influenced by abiotic and biotic factors. Fine-scale mechanisms of density-dependent foraging at the bite scale are likely consistent with density-dependent behavioural patterns observed at broader scales, but few studies have directly tested this assertion. Here, we tested if space use intensity, a proxy of spatiotemporal density, affects foraging mechanisms at fine spatial scales similarly to density-dependent effects observed at broader scales in caribou. We specifically assessed how behavioural choices are affected by space use intensity and environmental processes using behavioural state and forage selection data from caribou (Rangifer tarandus granti) observed from GPS video-camera collars using a multivariate discrete-choice modelling framework. We found that the probability of eating shrubs increased with increasing caribou space use intensity and cover of Salix spp. shrubs, whereas the probability of eating lichen decreased. Insects also affected fine-scale foraging behaviour by reducing the overall probability of eating. Strong eastward winds mitigated negative effects of insects and resulted in higher probabilities of eating lichen. At last, caribou exhibited foraging functional responses wherein their probability of selecting each food type increased as the availability (% cover) of that food increased. Space use intensity signals of fine-scale foraging were consistent with density-dependent responses observed at larger scales and with recent evidence suggesting declining reproductive rates in the same caribou population. Our results highlight potential risks of overgrazing on sensitive forage species such as lichen. Remote investigation of the functional responses of foraging behaviours provides exciting future applications where spatial models can identify high-quality habitats for conservation.

Investigation and response to an outbreak of Neisseria meningitidis serogroup Y ST-1466 urogenital infections, Australia.

Abstract: In 2023, an increased number of urogenital and anorectal infections with Neisseria meningitis serogroup Y (MenY) were reported in New South Wales (NSW). Whole genome sequencing (WGS) found a common sequence type (ST-1466), with limited sequence diversity. Confirmed outbreak cases were NSW residents with a N. meningitidis isolate matching the cluster sequence type; probable cases were NSW residents with MenY isolated from a urogenital or anorectal site from 1 July 2023 without WGS testing. Of the 41 cases, most were men (n = 27), of whom six reported recent contact with a female sex worker. Five cases were men who have sex with men and two were female sex workers. Laboratory alerts regarding the outbreak were sent to all Australian jurisdictions through the laboratories in the National Neisseria Network. Two additional states identified urogenital MenY ST-1466 infections detected in late 2023. Genomic analysis showed all MenY ST-1466 sequences were interspersed, suggestive of an Australia-wide outbreak. The incidence of these infections remains unknown, due to varied testing and reporting practices both within and across jurisdictions. Isolates causing invasive meningococcal disease (IMD) in Australia are typed, and there has been no MenY ST-1466 IMD recorded in Australia to end of March 2024. Concerns remain regarding the risk of IMD, given the similarity of these sequences with a MenY ST-1466 IMD strain causing a concurrent outbreak in the United States of America.

Impact of smoking status on clinical outcomes in patients with metastatic renal cell carcinoma treated with first-line immune checkpoint inhibitor-based regimens.

BACKGROUND: Current tobacco smoking is independently associated with decreased overall survival (OS) among patients with metastatic renal cell carcinoma (mRCC) treated with targeted monotherapy (VEGF-TKI). Herein, we assess the influence of smoking status on the outcomes of patients with mRCC treated with the current first-line standard of care of immune checkpoint inhibitor (ICI)-based regimens. MATERIALS AND METHODS: Real-world data from the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) were collected retrospectively. Patients with mRCC who received either dual ICI therapy or ICI with VEGF-TKI in the first-line setting were included and were categorized as current, former, or nonsmokers. The primary outcomes were OS, time to treatment failure (TTF), and objective response rate (ORR). OS and TTF were compared between groups using the log-rank test and multivariable Cox regression models. ORR was assessed between the 3 groups using a multivariable logistic regression model. RESULTS: A total of 989 eligible patients were included in the analysis, with 438 (44.3%) nonsmokers, 415 (42%) former, and 136 (13.7%) current smokers. Former smokers were older and included more males, while other baseline characteristics were comparable between groups. Median follow-up for OS was 21.2 months. In the univariate analysis, a significant difference between groups was observed for OS (P = .027) but not for TTF (P = .9), with current smokers having the worse 2-year OS rate (62.8% vs 70.8% and 73.1% in never and former smokers, respectively). After adjusting for potential confounders, no significant differences in OS or TTF were observed among the 3 groups. However, former smokers demonstrated a higher ORR compared to never smokers (OR 1.45, P = .02). CONCLUSION: Smoking status does not appear to independently influence the clinical outcomes to first-line ICI-based regimens in patients with mRCC. Nonetheless, patient counseling on tobacco cessation remains a crucial aspect of managing patients with mRCC, as it significantly reduces all-cause mortality.

Generational trends in the transition to womanhood in lowland rural Nepal: Changes in the meaning of early marriage.

OBJECTIVE: In South Asia, studies show secular trends toward slightly later women's marriage and first reproduction. However, data on related biological and social events, such as menarche and age of coresidence with husband, are often missing from these analyses. We assessed generational trends in key life events marking the transition to womanhood in rural lowland Nepal. METHODS: We used data on 110 co-resident mother-in-law (MIL) and daughter-in-law (DIL) dyads. We used paired t-tests and chi-squared tests to evaluate generational trends in women's education, and mean age at menarche, marriage, cohabitation with husband, and first reproduction of MIL and DIL dyads. We examined norms held by MILs and DILs on a daughter's life opportunities. RESULTS: On average, MIL was 29 years older than DIL (60 years vs. 31 years). Both groups experienced menarche at average age 13.8 years. MIL was married at average 12.4 years, before menarche, and cohabitated with husbands at average 14.8 years. DIL was simultaneously married and cohabitated with husbands after menarche, at average 15 years. DIL was marginally more educated than MIL but had their first child on average 0.8 years earlier (95% CI -1.4, -0.1). MIL and DIL held similar norms on daughters' education and marriage. CONCLUSION: While social norms remain similar, the meaning of "early marriage" and use of menarche in marriage decisions has changed in rural lowland Nepal. Compared to DIL, MIL who was married earlier transitioned to womanhood more gradually. However, DIL was still married young, and had an accelerated trajectory to childbearing.

Differentially co-expressed myofibre transcripts associated with abnormal myofibre proportion in chronic obstructive pulmonary disease.

BACKGROUND: Skeletal muscle dysfunction is a common extrapulmonary manifestation of chronic obstructive pulmonary disease (COPD). Alterations in skeletal muscle myosin heavy chain expression, with reduced type I and increased type II myosin heavy chain expression, are associated with COPD severity when studied in largely male cohorts. The objectives of this study were (1) to define an abnormal myofibre proportion phenotype in both males and females with COPD and (2) to identify transcripts and transcriptional networks associated with abnormal myofibre proportion in COPD. METHODS: Forty-six participants with COPD were assessed for body composition, strength, endurance and pulmonary function. Skeletal muscle biopsies from the vastus lateralis were assayed for fibre-type distribution and cross-sectional area via immunofluorescence microscopy and RNA-sequenced to generate transcriptome-wide gene expression data. Sex-stratified k-means clustering of type I and IIx/IIax fibre proportions was used to define abnormal myofibre proportion in participants with COPD and contrasted with previously defined criteria. Single transcripts and weighted co-expression network analysis modules were tested for correlation with the abnormal myofibre proportion phenotype. RESULTS: Abnormal myofibre proportion was defined in males with COPD (n = 29) as <18% type I and/or >22% type IIx/IIax fibres and in females with COPD (n = 17) as <36% type I and/or >12% type IIx/IIax fibres. Half of the participants with COPD were classified as having an abnormal myofibre proportion. Participants with COPD and an abnormal myofibre proportion had lower median handgrip strength (26.1 vs. 34.0 kg, P = 0.022), 6-min walk distance (300 vs. 353 m, P = 0.039) and forced expiratory volume in 1 s-to-forced vital capacity ratio (0.42 vs. 0.48, P = 0.041) compared with participants with COPD and normal myofibre proportions. Twenty-nine transcripts were associated with abnormal myofibre proportions in participants with COPD, with the upregulated NEB, TPM1 and TPM2 genes having the largest fold differences. Co-expression network analysis revealed that two transcript modules were significantly positively associated with the presence of abnormal myofibre proportions. One of these co-expression modules contained genes classically associated with muscle atrophy, as well as transcripts associated with both type I and type II myofibres, and was enriched for genetic loci associated with bone mineral density. CONCLUSIONS: Our findings indicate that there are significant transcriptional alterations associated with abnormal myofibre proportions in participants with COPD. Transcripts canonically associated with both type I and type IIa fibres were enriched in a co-expression network associated with abnormal myofibre proportion, suggesting altered transcriptional regulation across multiple fibre types.

Outcomes of patients with advanced epithelial growth factor receptor mutant lung cancer treated with first-line osimertinib who would not have met the eligibility criteria for the FLAURA clinical trial.

OBJECTIVES: Osimertinib is largely used as first-line therapy for metastatic epithelial growth factor receptor (EGFR) mutant lung cancers based on the FLAURA clinical trial. Real-world patient outcomes often differ from clinical trial outcomes. This study evaluated the efficacy of first-line osimertinib in patients treated in British Columbia (BC), Canada. Furthermore, we compared the outcomes of patients who would and would not have been eligible for the original FLAURA trial. METHODS: Consecutive patients receiving first-line osimertinib for metastatic EGFR exon19 or L858R lung cancer were identified using the BC Cancer Pharmacy Database. Patient eligibility for the FLAURA clinical trial were retrospectively reviewed based on the following criteria: ECOG ≥ 2, symptomatic brain metastases or on steroids, hemoglobin < 90 g/L, platelets < 100x109/L, or a creatinine clearance < 50 mL/min. mOS was assessed for the entire population and compared between patients who would have been eligible and ineligible for FLAURA. RESULTS: From January 2020 to October 2021, 311 patients received first-line osimertinib; 44 % (137/311) were deemed FLAURA ineligible, predominantly due to low ECOG (n = 120). After a median follow-up of 26.5 months, the mOS for the entire cohort was 27.4 months (95 %CI 23.8-30.1). The mOS for ineligible patients was 18 months shorter than eligible patients (15.8 vs 34.2, p < 0.001). Ineligible patients had higher rates of de novo stage IV disease, higher rates of stage IVB disease, and more sites of disease than eligible patients. CONCLUSION: In this real-world population, nearly half of patients would have been ineligible for FLAURA. The mOS was one year shorter than reported in FLAURA. However, patients who would have been eligible for the FLAURA clinical trial had similar OS to patients enrolled in FLAURA. Trial ineligible patients had a higher burden of disease at baseline which may have led to inferior outcomes. Further research is needed to improve outcomes in these patients.

A systematic review of the literature reporting on remote monitoring epileptic seizure detection devices.

BACKGROUND: Early detection and alert notification of an impending seizure for people with epilepsy have the potential to reduce Sudden Unexpected Death in Epilepsy (SUDEP). Current remote monitoring seizure detection devices for people with epilepsy are designed to support real-time monitoring of their vital health parameters linked to seizure alert notification. An understanding of the rapidly growing literature on remote seizure detection devices is essential to address the needs of people with epilepsy and their carers. AIM: This review aims to examine the technical characteristics, device performance, user preference, and effectiveness of remote monitoring seizure detection devices. METHODOLOGY: A systematic review referenced to PRISMA guidelines was used. RESULTS: A total of 1095 papers were identified from the initial search with 30 papers included in the review. Sixteen non-invasive remote monitoring seizure detection devices are currently available. Such seizure detection devices were found to have inbuilt intelligent sensor functionality to monitor electroencephalography, muscle movement, and accelerometer-based motion movement for detecting seizures remotely. Current challenges of these devices for people with epilepsy include skin irritation due to the type of patch electrode used and false alarm notifications, particularly during physical activity. The tight-fitted accelerometer-type devices are reported as uncomfortable from a wearability perspective for long-term monitoring. Also, continuous recording of physiological signals and triggering alert notifications significantly reduce the battery life of the devices. The literature highlights that 3.2 out of 5 people with epilepsy are not using seizure detection devices because of the cost and appearance of the device. CONCLUSION: Seizure detection devices can potentially reduce morbidity and mortality for people with epilepsy. Therefore, further collaboration of clinicians, technical experts, and researchers is needed for the future development of these devices. Finally, it is important to always take into consideration the expectations and requirements of people with epilepsy and their carers to facilitate the next generation of remote monitoring seizure detection devices.

Socio-demographic and comorbid risk factors for poor prognosis in patients hospitalized with community-acquired bacterial pneumonia in southeastern US.

BACKGROUND: How socio-demographic characteristics and comorbidities affect bacterial community-acquired pneumonia (CAP) prognosis during/after hospitalization is important in disease management. OBJECTIVES: To identify predictors of medical intensive care unit (MICU) admission, length of hospital stay (LOS), in-hospital mortality, and bacterial CAP readmission in patients hospitalized with bacterial CAP. METHODS: ICD-9/10 codes were used to query electronic medical records to identify a cohort of patients hospitalized for bacterial CAP at a tertiary hospital in Southeastern US between 01/01/2013-12/31/2019. Adjusted accelerated failure time and modified Poisson regression models were used to examine predictors of MICU admission, LOS, in-hospital mortality, and 1-year readmission. RESULTS: There were 1956 adults hospitalized with bacterial CAP. Median (interquartile range) LOS was 11 days (6-23), and there were 26 % (513) MICU admission, 14 % (266) in-hospital mortality, and 6 % (117) 1-year readmission with recurrent CAP. MICU admission was associated with heart failure (RR 1.38; 95 % CI 1.17-1.62) and obesity (RR 1.26; 95 % CI 1.04-1.52). Longer LOS was associated with heart failure (adjusted time ratio[TR] 1.27;95 %CI 1.12-1.43), stroke (TR 1.90;95 %CI 1.54,2.35), type 2 diabetes (TR 1.20;95 %CI 1.07-1.36), obesity (TR 1.50;95 %CI 1.31-1.72), Black race (TR 1.17;95 %CI 1.04-1.31), and males (TR 1.24;95 %CI 1.10-1.39). In-hospital mortality was associated with stroke (RR 1.45;95 %CI 1.03-2.04) and age ≥65 years (RR 1.34;95 %CI 1.06-1.68). 1-year readmission was associated with COPD (RR 1.55;95 %CI 1.05-2.27) and underweight BMI (RR 1.74;95 %CI 1.04-2.90). CONCLUSIONS: Comorbidities and socio-demographic characteristics have varying impacts on bacterial CAP in-hospital prognosis and readmission. More studies are warranted to confirm these findings to develop comprehensive care plans and inform public health interventions.

Development and validation of a questionnaire to assess owner and canine quality-of-life and treatment satisfaction in canine allergic dermatitis.

BACKGROUND: Animal and owner quality-of-life (QoL) is pivotal in treatment decisions. Accurate measurement of owner-reported QoL and treatment satisfaction (TS) supports disease burden and treatment benefit evaluation. OBJECTIVES: Develop and evaluate an owner-completed canine dermatitis QoL and TS questionnaire (CDQoL-TSQ) in allergic dogs. MATERIALS AND METHODS: The CDQoL-TSQ was drafted following review of existing measures and expert input. Content validity was assessed through interviews with owners of allergic dogs. Psychometric properties of the QoL domains (Canine QoL, Owner QoL) were evaluated. Score interpretation was derived. RESULTS: Twenty dog owners were interviewed. Item wording was amended following the first 10 interviews. Data from 211 owners were used in the psychometric evaluation. The Canine QoL domain demonstrated strong internal consistency (α = 0.89), test-retest reliability (ICC2,1 = 0.844), moderate convergent validity (r = 0.41) and moderate-high known-groups validity (effect size 0.37-0.64). The Owner QoL domain demonstrated strong internal consistency (α = 0.73), high convergent validity (r = 0.63) and moderate-high known-groups validity (0.43-0.63). Test-retest reliability approached moderate strength (ICC2,1 = 0.490). Group-level interpretation analysis showed minimal important difference of 7.0-13.6 points for dogs and 13.0-13.6 for owners. For individual dogs a change of 6.3 or 12.5 points for dogs, and 12.5 or 18.8 for owners indicates a response. CONCLUSIONS AND CLINICAL RELEVANCE: The CDQOL-TSQ is a two-part assessment to evaluate QoL and TS in canine allergic dermatitis. The QoL questionnaire demonstrated validity and reliability, and interpretation of scores was derived, making it suitable for use in research and practice. The TS module is suitable for clinical setting use to improve owner-veterinarian communication.

Anti-CELA1 antibody KF4 prevents emphysema by inhibiting stretch-mediated remodeling.

There are no therapies to prevent emphysema progression. Chymotrypsin-like elastase 1 (CELA1) is a serine protease that binds and cleaves lung elastin in a stretch-dependent manner and is required for emphysema in a murine antisense oligonucleotide model of α-1 antitrypsin (AAT) deficiency. This study tested whether CELA1 is important in strain-mediated lung matrix destruction in non-AAT-deficient emphysema and the efficacy of CELA1 neutralization. Airspace simplification was quantified after administration of tracheal porcine pancreatic elastase (PPE), after 8 months of cigarette smoke (CS) exposure, and in aging. In all 3 models, Cela1-/- mice had less emphysema and preserved lung elastin despite increased lung immune cells. A CELA1-neutralizing antibody was developed (KF4), and it inhibited stretch-inducible lung elastase in ex vivo mouse and human lung and immunoprecipitated CELA1 from human lung. In mice, systemically administered KF4 penetrated lung tissue in a dose-dependent manner and 5 mg/kg weekly prevented emphysema in the PPE model with both pre- and postinjury initiation and in the CS model. KF4 did not increase lung immune cells. CELA1-mediated lung matrix remodeling in response to strain is an important contributor to postnatal airspace simplification, and we believe that KF4 could be developed as a lung matrix-stabilizing therapy in emphysema.

Outcomes of Patients with Brain Metastases from Renal Cell Carcinoma Receiving First-line Therapies: Results from the International Metastatic Renal Cell Carcinoma Database Consortium.

Patients with brain metastases (BrM) from renal cell carcinoma and their outcomes are not well characterized owing to frequent exclusion of this population from clinical trials. We analyzed data for patients with or without BrM using the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC). A total of 389/4799 patients (8.1%) had BrM on initiation of systemic therapy. First-line immuno-oncology (IO)-based combination therapy was associated with longer median overall survival (OS; 32.7 mo, 95% confidence interval [CI] 22.3-not reached) versus tyrosine kinase inhibitor monotherapy (20.6 mo, 95% CI 15.7-24.5; p = 0.019), as were intensive focal therapies with stereotactic radiotherapy or neurosurgery (31.4 mo, 95% CI 22.3-37.5) versus whole-brain radiotherapy alone or no focal therapy (16.5 mo, 95% CI 10.2-21.1; p = 0.028). On multivariable analysis, IO-based regimens (HR 0.49, 95% CI 0.25-0.97; p = 0.040) and stereotactic radiotherapy or neurosurgery (HR 0.48, 95% CI 0.29-0.78; p = 0.003) were independently associated with longer OS, as was IMDC favorable or intermediate risk (HR 0.40, 95% CI 0.24-0.66; p < 0.001). Intensive systemic and focal therapies were associated with better prognosis in this population. Further studies should explore the clinical effectiveness of multimodal strategies. PATIENT SUMMARY: In a large group of patients with advanced kidney cancer, we found that 8.1% had brain metastases when starting systemic therapy. Patients with brain metastases had significantly poorer prognosis than those without brain metastases. Receipt of combination immunotherapy, stereotactic radiotherapy, or neurosurgery was associated with longer overall survival.

Associations Between Coronary Artery Calcium Score and Exacerbation Risk in BLOCK-COPD.

Introduction: In 2019, the Beta-Blockers for the Prevention of Acute Exacerbations of Chronic Obstructive Pulmonary Disease study (BLOCK-COPD) evaluated the effect of metoprolol on exacerbation risk and mortality in a COPD population without indications for beta-blocker use. We hypothesized that an imaging metric of coronary artery disease (CAD), the coronary artery calcium (CAC) score, would predict exacerbation risk and identify a differential response to metoprolol treatment. Methods: The study population includes participants in the BLOCK-COPD study from multiple study sites. Participants underwent clinically indicated thoracic computed tomography (CT) scans ± 12 months from enrollment. The Weston scoring system quantified CAC. Adjusted Cox proportional hazards models evaluated for associations between CAC and time to exacerbation. Results: Data is included for 109 participants. The mean CAC score was 5.1±3.7, and 92 participants (84%) had CAC scores greater than 0. Over a median (interquartile range) follow-up time of 350 (280 to 352) days, there were 61 mild exacerbations and 19 severe/very severe exacerbations. No associations were found between exacerbations of any severity and CAC>0 or total CAC. Associations were observed between total CAC and CAC>0 in the left circumflex (LCx) and time to exacerbation of any severity (adjusted hazard ratio [aHR]=1.39, confidence interval [CI]: 1.08-1.79, p=0.01) and (aHR=1.96, 95% CI: 1.04-3.70, p=0.04), respectively. Conclusions: CAD is a prevalent comorbidity in COPD accounting for significant mortality. Our study confirms the high prevalence of CAD using the CAC score; however, we did not discover an association between CAC and exacerbation risk. We did find novel associations between CAC in the LCx and exacerbation risk which warrant further investigation in larger cohorts.

Surgical and Radiology Trainees' Proficiency in Reading Mammograms: the Importance of Education for Cancer Localisation.

Medical imaging with mammography plays a very important role in screening and diagnosis of breast cancer, Australia's most common female cancer. The visualisation of cancers on mammograms often forms a diagnosis and guidance for radiologists and breast surgeons, and education platforms that provide real cases in a simulated testing environment have been shown to improve observer performance for radiologists. This study reports on the performance of surgical and radiology trainees in locating breast cancers. An enriched test set of 20 mammography cases (6 cancer and 14 cancer free) was created, and 18 surgical trainees and 32 radiology trainees reviewed the cases via the Breast Screen Reader Assessment Strategy (BREAST) platform and marked any lesions identifiable. Further analysis of performance with high- and low-density cases was undertaken, and standard metrics including sensitivity and specificity. Radiology trainees performed significantly better than surgical trainees in terms of specificity (0.72 vs. 0.35; P < 0.01). No significant differences were observed between the surgical and radiology trainees in sensitivity or lesion sensitivity. Mixed results were obtained with participants regarding breast density, with higher density cases generally having lower performance. The higher specificity of the radiology trainees compared to the surgical trainees likely represents less exposure to negative mammography cases. The use of high-fidelity simulated self-test environments like BREAST is able to benchmark, understand and build strategies for improving cancer education in a safe environment, including identifying challenging scenarios like breast density for enhanced training.

Machine-Learning Classification of Bacteria Using Two-Dimensional Tandem Mass Spectrometry.

Biothreat detection has continued to gain attention. Samples suspected to fall into any of the CDC's biothreat categories require identification by processes that require specialized expertise and facilities. Recent developments in analytical instrumentation and machine learning algorithms offer rapid and accurate classification of Gram-positive and Gram-negative bacterial species. This is achieved by analyzing the negative ions generated from bacterial cell extracts with a modified linear quadrupole ion-trap mass spectrometer fitted with two-dimensional tandem mass spectrometry capabilities (2D MS/MS). The 2D MS/MS data domain of a bacterial cell extract is recorded within five s using a five-scan average after sample preparation by a simple extraction. Bacteria were classified at the species level by their lipid profiles using the random forest, k-nearest neighbor, and multilayer perceptron machine learning models. 2D MS/MS data can also be treated as image data for use with image recognition algorithms such as convolutional neural networks. The classification accuracy of all models tested was greater than 99%. Adding to previously published work on the 2D MS/MS analysis of bacterial growth and the profiling of sporulating bacteria, this study demonstrates the utility and information-rich nature of 2D MS/MS in the identification of bacterial pathogens at the species level when coupled with machine learning.

Characterization of Patients with Metastatic Renal Cell Carcinoma Undergoing Deferred, Upfront, or No Cytoreductive Nephrectomy in the Era of Combination Immunotherapy: Results from the International Metastatic Renal Cell Carcinoma Database Consortium.

BACKGROUND: The role of cytoreductive nephrectomy (CN) has not yet been well characterized in the era of combination immunotherapy. OBJECTIVE: To evaluate characteristics and outcomes for patients with metastatic renal cell carcinoma (mRCC) who received immuno-oncology (IO)-based combination therapy according to CN status. DESIGN, SETTING, AND PARTICIPANTS: Using the International mRCC Database Consortium (IMDC), patients with mRCC who received frontline IO-based combinations were included. Upfront CN was defined as CN up to 3 mo before diagnosis of metastatic disease but before systemic therapy initiation. Deferred CN was defined as CN after systemic therapy initiation. OUTCOMES MEASUREMENTS AND STATISTICAL ANALYSIS: Overall survival (OS) from initiation of systemic therapy was estimated via Cox proportional-hazards regression. A 12-mo landmark time and a time-varying covariate for CN status were used to mitigate potential bias. RESULTS AND LIMITATIONS: Of the 385 patients eligible for landmark analysis, 24, 182, and 179 underwent deferred CN, upfront CN, and no CN, respectively. Patients in the no CN subgroup were older (63 yr vs 57 yr in the deferred CN subgroup and 60 yr in the upfront CN subgroup; p = 0.001) and a higher proportion had bone metastases (44% vs 26% in the deferred CN subgroup and 23% in the upfront CN subgroup; p < 0.001). A lower proportion of patients in the upfront CN subgroup had IMDC poor risk (23% vs 43% in the no CN subgroup and 47% in the deferred CN subgroup; p < 0.001). On multivariable analysis, CN receipt was an independent favorable prognostic factor (hazard ratio 0.45, 95% confidence interval 0.26-0.78; p = 0.005). The study is limited by the lack of randomization and its retrospective nature. CONCLUSIONS: Despite changes in practice patterns with the advent of novel therapeutic agents, CN may still serve as an effective surgical intervention in carefully selected patients. PATIENT SUMMARY: For patients with metastatic kidney cancer, surgery to remove the primary tumor was traditionally the treatment of choice, but immunotherapy drugs are now another option for these patients. We analyzed data for contemporary patients with metastatic kidney cancer who received combination immunotherapy as their first treatment. We found that in selected patients receiving immunotherapy, surgery to remove the primary tumor as well can result in better prognosis.

Effects of Vitamin D Supplementation on Telomere Length: An Analysis of Data from the Randomised Controlled D-Health Trial.

OBJECTIVES: Observational studies have suggested that a higher 25-hydroxyvitamin D concentration may be associated with longer telomere length; however, this has not been investigated in randomised controlled trials. We conducted an ancillary study within a randomised, double-blind, placebo-controlled trial of monthly vitamin D (the D-Health Trial) for the prevention of all-cause mortality, conducted from 2014 to 2020, to assess the effect of vitamin D supplementation on telomere length (measured as the telomere to single copy gene (T/S) ratio). DESIGN, SETTING, PARTICIPANTS, AND INTERVENTION: Participants were Australians aged 60-84 years and we randomly selected 1,519 D-Health participants (vitamin D: n=744; placebo: n=775) for this analysis. We used quantitative polymerase chain reaction to measure the relative telomere length (T/S ratio) at 4 or 5 years after randomisation. We compared the mean T/S ratio between the vitamin D and placebo groups to assess the effect of vitamin D supplementation on relative telomere length, using a linear regression model with adjustment for age, sex, and state which were used to stratify the randomisation. RESULTS: The mean T/S ratio was 0.70 for both groups (standard deviation 0.18 and 0.16 for the vitamin D and placebo groups respectively). The adjusted mean difference (vitamin D minus placebo) was -0.001 (95% CI -0.02 to 0.02). There was no effect modification by age, sex, body mass index, or predicted baseline 25-hydroxyvitamin D concentration. CONCLUSION: In conclusion, routinely supplementing older adults, who are largely vitamin D replete, with monthly doses of vitamin D is unlikely to influence telomere length.