Defibrillation Strategies for Refractory Ventricular Fibrillation.

BACKGROUND: Despite advances in defibrillation technology, shock-refractory ventricular fibrillation remains common during out-of-hospital cardiac arrest. Double sequential external defibrillation (DSED; rapid sequential shocks from two defibrillators) and vector-change (VC) defibrillation (switching defibrillation pads to an anterior-posterior position) have been proposed as defibrillation strategies to improve outcomes in patients with refractory ventricular fibrillation. METHODS: We conducted a cluster-randomized trial with crossover among six Canadian paramedic services to evaluate DSED and VC defibrillation as compared with standard defibrillation in adult patients with refractory ventricular fibrillation during out-of-hospital cardiac arrest. Patients were treated with one of these three techniques according to the strategy that was randomly assigned to the paramedic service. The primary outcome was survival to hospital discharge. Secondary outcomes included termination of ventricular fibrillation, return of spontaneous circulation, and a good neurologic outcome, defined as a modified Rankin scale score of 2 or lower (indicating no symptoms to slight disability) at hospital discharge. RESULTS: A total of 405 patients were enrolled before the data and safety monitoring board stopped the trial because of the coronavirus disease 2019 pandemic. A total of 136 patients (33.6%) were assigned to receive standard defibrillation, 144 (35.6%) to receive VC defibrillation, and 125 (30.9%) to receive DSED. Survival to hospital discharge was more common in the DSED group than in the standard group (30.4% vs. 13.3%; relative risk, 2.21; 95% confidence interval [CI], 1.33 to 3.67) and more common in the VC group than in the standard group (21.7% vs. 13.3%; relative risk, 1.71; 95% CI, 1.01 to 2.88). DSED but not VC defibrillation was associated with a higher percentage of patients having a good neurologic outcome than standard defibrillation (relative risk, 2.21 [95% CI, 1.26 to 3.88] and 1.48 [95% CI, 0.81 to 2.71], respectively). CONCLUSIONS: Among patients with refractory ventricular fibrillation, survival to hospital discharge occurred more frequently among those who received DSED or VC defibrillation than among those who received standard defibrillation. (Funded by the Heart and Stroke Foundation of Canada; DOSE VF ClinicalTrials.gov number, NCT04080986.).

Clinical manifestations and treatment outcomes for patients with Pseudomonas endocarditis.

OBJECTIVES: To investigate clinical outcomes of patients with Pseudomonas endocarditis and identify factors associated with treatment failure. METHODS: Adult patients meeting definitive Duke's criteria for Pseudomonas endocarditis at 11 hospitals were identified between May 2000 and February 2024. Failure was defined as death or microbiological failure by day 42. First-line therapy consisted of cefepime, piperacillin/tazobactam, ceftazidime or ceftolozane/tazobactam alone or in combination. RESULTS: Forty-eight patients met inclusion criteria; 29% were persons who inject drugs and 13% were organ transplant recipients. Pseudomonas aeruginosa was the causative species in 98% of cases. Patients who experienced 42 day cure were more likely to be initially managed with first-line ß-lactam agents compared with those who experienced clinical failure (97% versus 62%, P = 0.004). Treatment with first-line ß-lactams was associated with shorter time to treatment initiation and a lower likelihood of infection due to MDR Pseudomonas spp. In the univariate model, patients who experienced 90 day mortality were more likely to have prosthetic valve endocarditis (57% versus 24%, P = 0.02), an intracardiac complication (36% versus 9%, P = 0.04) and a higher median (IQR) Pitt bacteraemia score [2.5 (2-3.8) versus 1 (0-2), P = 0.048]. Combination therapy did not improve clinical outcomes but did increase the rate of adverse effects resulting in drug discontinuation compared with monotherapy, (21% versus 0%, P = 0.08). CONCLUSIONS: This is the largest study of Pseudomonas endocarditis to date. We identified improved clinical outcomes when cefepime, piperacillin/tazobactam, ceftazidime or ceftolozane/tazobactam were used for initial treatment. We did not identify a clinical benefit for combination treatment.

Nonequilibrium Transport in a Superfluid Josephson Junction Chain: Is There Negative Differential Conductivity?

We consider the far-from-equilibrium quantum transport dynamics in a 1D Josephson junction chain of multimode Bose-Einstein condensates. We develop a theoretical model to examine the experiment of Labouvie et al. [Phys. Rev. Lett. 115, 050601 (2015)PRLTAO0031-900710.1103/PhysRevLett.115.050601], wherein the phenomenon of negative differential conductivity (NDC) was reported in the refilling dynamics of an initially depleted site within the chain. We demonstrate that a unitary c-field description can quantitatively reproduce the experimental results over the full range of tunnel couplings, and requires no fitted parameters. With a view toward atomtronic implementations, we further demonstrate that the filling is strongly dependent on spatial phase variations stemming from quantum fluctuations. Our findings suggest that the interpretation of the device in terms of NDC is invalid outside of the weak coupling regime. Within this restricted regime, the device exhibits a hybrid behavior of NDC and the ac Josephson effect. A simplified circuit model of the device will require an approach tailored to atomtronics that incorporates quantum fluctuations.

Dose escalation of biologic treatment in patients with moderate-to-severe psoriasis in Japan.

Patients receiving interleukin (IL)-inhibiting biologics for moderate-to-severe psoriasis (PsO) may be treated with escalated doses to optimize outcomes. This study evaluated escalation prevalence in a Japanese claims analysis of patients with PsO diagnosis preceding IL-inhibiting biologic treatment and ≥1 post-induction maintenance claim (index date) with sufficient data availability from January 2014 to May 2022. Patients with non-persistence were excluded. Expected daily dose (EDD) was calculated as the recommended maintenance dose divided by the treatment interval. Dose escalation was defined as ≥2 claims showing a ≥20% increase in the observed average daily dose (ADD) over the EDD (with sensitivities requiring ≥1 claim and ≥30%). Significant differences were tested using multivariable regressions. The study included 982 unique patients treated with brodalumab (BRO; n = 104), guselkumab (GUS; n = 207), ixekizumab (IXE; n = 159), risankizumab (RIS; n = 135), secukinumab (SEC; n = 215) and ustekinumab (UST; n = 196). Within 12 months, dose escalation was observed for all IL-inhibiting biologics other than GUS and RIS: 44.4% for UST, 37.2% for IXE, 3.4% for SEC and 1.4% for BRO. In multivariable-adjusted analyses, odds of dose escalation were significantly lower for all products relative to UST. In sensitivities, escalation was observed for all products except RIS.

A deep learning algorithm to detect cutaneous squamous cell carcinoma on frozen sections in Mohs micrographic surgery: A retrospective assessment.

Intraoperative margin analysis is crucial for the successful removal of cutaneous squamous cell carcinomas (cSCC). Artificial intelligence technologies (AI) have previously demonstrated potential for facilitating rapid and complete tumour removal using intraoperative margin assessment for basal cell carcinoma. However, the varied morphologies of cSCC present challenges for AI margin assessment. The aim of this study was to develop and evaluate the accuracy of an AI algorithm for real-time histologic margin analysis of cSCC. To do this, a retrospective cohort study was conducted using frozen cSCC section slides. These slides were scanned and annotated, delineating benign tissue structures, inflammation and tumour to develop an AI algorithm for real-time margin analysis. A convolutional neural network workflow was used to extract histomorphological features predictive of cSCC. This algorithm demonstrated proof of concept for identifying cSCC with high accuracy, highlighting the potential for integration of AI into the surgical workflow. Incorporation of AI algorithms may improve efficiency and completeness of real-time margin assessment for cSCC removal, particularly in cases of moderately and poorly differentiated tumours/neoplasms. Further algorithmic improvement incorporating surrounding tissue context is necessary to remain sensitive to the unique epidermal landscape of well-differentiated tumours, and to map tumours to their original anatomical position/orientation.

Sustained neural rhythms reveal endogenous oscillations supporting speech perception.

Rhythmic sensory or electrical stimulation will produce rhythmic brain responses. These rhythmic responses are often interpreted as endogenous neural oscillations aligned (or "entrained") to the stimulus rhythm. However, stimulus-aligned brain responses can also be explained as a sequence of evoked responses, which only appear regular due to the rhythmicity of the stimulus, without necessarily involving underlying neural oscillations. To distinguish evoked responses from true oscillatory activity, we tested whether rhythmic stimulation produces oscillatory responses which continue after the end of the stimulus. Such sustained effects provide evidence for true involvement of neural oscillations. In Experiment 1, we found that rhythmic intelligible, but not unintelligible speech produces oscillatory responses in magnetoencephalography (MEG) which outlast the stimulus at parietal sensors. In Experiment 2, we found that transcranial alternating current stimulation (tACS) leads to rhythmic fluctuations in speech perception outcomes after the end of electrical stimulation. We further report that the phase relation between electroencephalography (EEG) responses and rhythmic intelligible speech can predict the tACS phase that leads to most accurate speech perception. Together, we provide fundamental results for several lines of research-including neural entrainment and tACS-and reveal endogenous neural oscillations as a key underlying principle for speech perception.

Impact of lymphovascular invasion on survival in surgically treated upper tract urothelial carcinoma: a nationwide analysis.

OBJECTIVES: To assess the prognostic ability of lymphovascular invasion (LVI) in upper tract urothelial carcinoma (UTUC) as a predictor of overall survival (OS) using a large North American cohort. PATIENTS AND METHODS: Our cohort included 5940 patients with clinical M0 UTUC who underwent a radical nephroureterectomy (RNU), between 2010 and 2016, within the National Cancer Database. The main variable of interest was LVI status, and its interaction with pathological nodal (pN) status. Kaplan-Meier curves were used to depict the OS also stratifying patients on LVI status. Cox regression analysis tested the impact of LVI status on OS after accounting for the available covariates. RESULTS: The median (interquartile range [IQR]) age at diagnosis was 71 (63-78) years and most patients had pathological T1 stage disease (48.6%). Nodal status was pN0, pN1 and pNx in 45.8%, 6.3% and 47.9%, respectively. Overall, 22.1% had LVI. The median (IQR) follow-up time was 32.6 (16.0-53.3) months. At the 5-year postoperative follow-up, the estimated OS rate was 28% in patients with LVI vs 66% in those without LVI (P < 0.001). When patients were stratified based on nodal status those rates were 32% vs 68% in pN0 patients (P < 0.001), 23% vs 30% in pN1 patients (P = 0.8), and 28% vs 65% in pNx patients (P < 0.001). On multivariable analysis, the presence of LVI was associated with less favourable OS (hazard ratio 1.79, 95% confidence interval 1.60-1.99; P < 0.001). CONCLUSION: Our study assessed the impact of LVI on OS in patients with UTUC in a large North American nationwide cohort. Our series, as the largest to date, indicate that LVI is associated with less favourable survival outcomes in patients with UTUC after RNU, and this variable could be used in counselling patients about their prognosis and might be a useful tool for future trials to risk-stratify patients.

Clinical outcomes of baloxavir versus oseltamivir in immunocompromised patients.

BACKGROUND: Neuraminidase inhibitors, including oseltamivir, are the treatment standard for influenza. Baloxavir, a novel antiviral, demonstrated comparable outcomes to oseltamivir in outpatients with influenza. Baloxavir was equally effective as oseltamivir in a retrospective study of hospitalized patients with influenza at our institution. However, the efficacy of baloxavir in immunocompromised patients is unclear. METHODS: We conducted a retrospective cohort study of immunocompromised adult patients hospitalized with influenza A who received baloxavir from January 2019 to April 2019 or oseltamivir from January 2018 to April 2018. Demographic and clinical outcomes were assessed. Primary outcomes were time from antiviral initiation to resolution of hypoxia and fever. Secondary outcomes were length of stay (LOS), intensive care unit (ICU) care, ICU LOS, and 30-day mortality. RESULTS: Of 95 total patients, 52 received baloxavir and 43 received oseltamivir. Other than younger age (57.5 vs. 65; p = .035) and longer duration between vaccination and symptom onset (114 vs. 86 days; p = .001) in the baloxavir group, baseline characteristics did not differ. H1 was the predominant subtype in the baloxavir group (65.3%) versus H3 in the oseltamivir group (85.7%). When comparing baloxavir to oseltamivir, there was no significant difference in median time from antiviral initiation to resolution of hypoxia (59.9 vs. 42.5 h) and to resolution of fever (21.6 vs. 26.6 h). There were no differences in secondary outcomes. CONCLUSION: Baloxavir was not associated with longer time to resolution of hypoxia or fever in comparison to oseltamivir. Results must be taken in context of variations in seasonal influenza subtype and resistance rates.

Concurrent Langerhans cell histiocytosis and acute myeloid leukemia: A rare presentation of a rare case.

A 72-year-old woman with no significant past medical history was admitted to the hospital for new-onset of leukocytosis with neutropenia, anemia, and thrombocytopenia, as well as a pruritic skin eruption. She was found to have acute myeloid leukemia (AML) with myelomonocytic differentiation. Her skin eruption consisted of widespread hemorrhagic crusted papules on the scalp and trunk. A skin biopsy was performed, which revealed a proliferation of mononuclear cells in the dermis with prominent epidermotropism and positive expression of CD1a and langerin (CD207), supporting a diagnosis of Langerhans cell histiocytosis (LCH). LCH is an uncommon proliferative disorder of activated Langerhans cells, which generally presents in children. In adults, it is exceptionally infrequent. Associated malignancies and rare reports of AML developing in subsequent years after an initial presentation of LCH have been described. Here we present an unusual concurrent presentation of LCH and AML in an adult.

Patient-reported barriers to prenatal diagnosis of congenital heart defects: A mixed-methods study.

OBJECTIVE: To ascertain patient-reported, modifiable barriers to prenatal diagnosis of congenital heart defects (CHDs). METHODS: This was a mixed-methods study among caretakers of infants who received congenital heart surgery from 2019 to 2020 in the Chicagoland area. Quantitative variables measuring sociodemographic characteristics and prenatal care utilization, and qualitative data pertaining to patient-reported barriers to prenatal diagnosis were collected from electronic health records and semi-structured phone surveys. Thematic analysis was performed using a convergent parallel approach. RESULTS: In total, 160 caretakers completed the survey, 438 were eligible for survey, and 49 (31%) received prenatal care during the COVID-19 pandemic. When comparing respondents and non-respondents, there was a lower prevalence of maternal Hispanic ethnicity and a higher prevalence of non-English/Spanish-speaking households. Of all respondents, 34% reported an undetected CHD on ultrasound or echocardiogram, while 79% reported at least one barrier to prenatal diagnosis related to social determinants of health. Among those social barriers, the most common were difficulty with appointment scheduling (n = 12, 9.5%), far distance to care/lack of access to transportation (n = 12, 9.5%) and difficulty getting time off work to attend appointments (n = 6, 4.8%). The latter two barriers were correlated. CONCLUSION: While technical improvements in the detection of CHDs remain an important area of research, it is equally critical to produce evidence for interventions that mitigate barriers to prenatal diagnosis due to social determinants of health.

Miniaturized wireless, skin-integrated sensor networks for quantifying full-body movement behaviors and vital signs in infants.

Early identification of atypical infant movement behaviors consistent with underlying neuromotor pathologies can expedite timely enrollment in therapeutic interventions that exploit inherent neuroplasticity to promote recovery. Traditional neuromotor assessments rely on qualitative evaluations performed by specially trained personnel, mostly available in tertiary medical centers or specialized facilities. Such approaches are high in cost, require geographic proximity to advanced healthcare resources, and yield mostly qualitative insight. This paper introduces a simple, low-cost alternative in the form of a technology customized for quantitatively capturing continuous, full-body kinematics of infants during free living conditions at home or in clinical settings while simultaneously recording essential vital signs data. The system consists of a wireless network of small, flexible inertial sensors placed at strategic locations across the body and operated in a wide-bandwidth and time-synchronized fashion. The data serve as the basis for reconstructing three-dimensional motions in avatar form without the need for video recordings and associated privacy concerns, for remote visual assessments by experts. These quantitative measurements can also be presented in graphical format and analyzed with machine-learning techniques, with potential to automate and systematize traditional motor assessments. Clinical implementations with infants at low and at elevated risks for atypical neuromotor development illustrates application of this system in quantitative and semiquantitative assessments of patterns of gross motor skills, along with body temperature, heart rate, and respiratory rate, from long-term and follow-up measurements over a 3-mo period following birth. The engineering aspects are compatible for scaled deployment, with the potential to improve health outcomes for children worldwide via early, pragmatic detection methods.

Perspectives of Challenges in Counseling for Congenital Heart Defects.

Prior work regarding counseling patients about congenital heart defects (CHD) has focused on their perceptions about accurate communication of cardiac anatomy, and the emotional support received from the provider. The objectives of this study were to identify the additional CHD counseling-specific challenges and areas for future intervention, using a practical communication framework. This is a secondary analysis of qualitative data provided by caretakers of infants who received congenital heart surgery from 2019 to 2020 in the Chicagoland area. While the survey in the primary study pertained to barriers in obtaining prenatal diagnosis, respondents with both prenatal and postnatal diagnosis reported challenges to effective counseling. Qualitative data measuring counseling challenges were collected from semi-structured phone interviews. Thematic analysis was performed using an inductive approach. Themes were organized into five domains using SPIKES (Setting, Perception, Invitation, Knowledge, Empathy, and Summarize/Strategy), a previously validated framework to help clinicians effectively break bad news. Among 160 survey respondents, 35 (21.9%) reported a challenge during CHD counseling that they received. In total, 12 challenges were identified and spanned all six SPIKES domains. The three most common challenges were as follows: perception of repeated imaging studies for accurate diagnosis or management (n = 19, Knowledge), the lack of cardiologist presence at the time of initial CHD detection (n = 8, Setting), and insufficient information provided about the CHD diagnosis (n = 7, Knowledge). Patients perceive counseling as a key component of prenatal diagnosis of CHD and identify the challenges that exist at all stages of the counseling process. These findings suggest that effective counseling extends beyond conveying information about anatomy and prognosis.

Comparison of patient background between a real-world North American cohort and the Göteborg-2 trial.

OBJECTIVES: To analyze the generalizability of the Göteborg-2 findings to a North American cohort. METHODS: We replicated the Göteborg-2 inclusion criteria in our Henry Ford Health (HFH) cohort, by identifying all patients 50-60 years old who had a PSA test from 2013 to 2018. The first PSA within the study period was considered PSA at entry, and included in the analysis. Chi-square test was used to compare categorical variables between the Göteborg-2 and HFH cohort, with a particular focus on Black men, who were also analyzed separately. RESULTS: The HFH patients included in the cohort were 49 456, of which 8562 were Black. In patients within the entire HFH cohort, HFH Black cohort, Göteborg Reference cohort, and Göteborg Experimental cohort, the rate of PSA ≥3 ng/mL was, respectively, 6.8%, 10.2%, 6.8%, and 6.6%. The rate of biopsy performed was, respectively, 1.8%, 4.1%, 5.8%, and 2.5%. PCa was found in, respectively, 1.4%, 3.0%, 2.3%, and 1.5%; Gleason score 3 + 3 in, respectively, 0.5%, 0.8%, 1.2%, and 0.6%; Gleason score > 3 + 3 in, respectively, 0.9%, 2.2%, 1.1%, and 0.9%. CONCLUSIONS: Our cohort had a lower biopsy rate and a lower incidence of non-csPCa diagnosis than both Göteborg cohorts, while still maintaining the same incidence of csPCa. This implies that the benefits of reducing non-csPCa diagnosis, as observed in the Experimental Göteborg cohort, are not necessarily replicable in U.S. "real-world practice" patients. Also noteworthy, we had a significantly higher percentage of Black men, who showed more aggressive disease.

Safety and Immunogenicity of a Respiratory Syncytial Virus Prefusion F (RSVPreF3) Candidate Vaccine in Older Adults: Phase 1/2 Randomized Clinical Trial.

BACKGROUND: The aim of this study was to investigate safety and immunogenicity of vaccine formulations against respiratory syncytial virus (RSV) containing the stabilized prefusion conformation of RSV fusion protein (RSVPreF3). METHODS: This phase 1/2, randomized controlled, observer-blind study enrolled 48 young adults (YAs; aged 18-40 years) and 1005 older adults (OAs; aged 60-80 years) between January and August 2019. Participants were randomized into equally sized groups to receive 2 doses of unadjuvanted (YAs and OAs) or AS01-adjuvanted (OAs) vaccine or placebo 2 months apart. Vaccine safety and immunogenicity were assessed until 1 month (YAs) or 12 months (OAs) after second vaccination. RESULTS: The RSVPreF3 vaccines boosted humoral (RSVPreF3-specific immunoglobulin G [IgG] and RSV-A neutralizing antibody) responses, which increased in an antigen concentration-dependent manner and were highest after dose 1. Compared to prevaccination, the geometric mean frequencies of polyfunctional CD4+ T cells increased after each dose and were significantly higher in adjuvanted than unadjuvanted vaccinees. Postvaccination immune responses persisted until end of follow-up. Solicited adverse events were mostly mild to moderate and transient. Despite a higher observed reactogenicity of AS01-containing vaccines, no safety concerns were identified for any assessed formulation. CONCLUSIONS: Based on safety and immunogenicity profiles, the AS01E-adjuvanted vaccine containing 120 µg of RSVPreF3 was selected for further clinical development. CLINICAL TRIALS REGISTRATION: NCT03814590.

Differential Auditory and Visual Phase-Locking Are Observed during Audio-Visual Benefit and Silent Lip-Reading for Speech Perception.

Speech perception in noisy environments is enhanced by seeing facial movements of communication partners. However, the neural mechanisms by which audio and visual speech are combined are not fully understood. We explore MEG phase-locking to auditory and visual signals in MEG recordings from 14 human participants (6 females, 8 males) that reported words from single spoken sentences. We manipulated the acoustic clarity and visual speech signals such that critical speech information is present in auditory, visual, or both modalities. MEG coherence analysis revealed that both auditory and visual speech envelopes (auditory amplitude modulations and lip aperture changes) were phase-locked to 2-6 Hz brain responses in auditory and visual cortex, consistent with entrainment to syllable-rate components. Partial coherence analysis was used to separate neural responses to correlated audio-visual signals and showed non-zero phase-locking to auditory envelope in occipital cortex during audio-visual (AV) speech. Furthermore, phase-locking to auditory signals in visual cortex was enhanced for AV speech compared with audio-only speech that was matched for intelligibility. Conversely, auditory regions of the superior temporal gyrus did not show above-chance partial coherence with visual speech signals during AV conditions but did show partial coherence in visual-only conditions. Hence, visual speech enabled stronger phase-locking to auditory signals in visual areas, whereas phase-locking of visual speech in auditory regions only occurred during silent lip-reading. Differences in these cross-modal interactions between auditory and visual speech signals are interpreted in line with cross-modal predictive mechanisms during speech perception.SIGNIFICANCE STATEMENT Verbal communication in noisy environments is challenging, especially for hearing-impaired individuals. Seeing facial movements of communication partners improves speech perception when auditory signals are degraded or absent. The neural mechanisms supporting lip-reading or audio-visual benefit are not fully understood. Using MEG recordings and partial coherence analysis, we show that speech information is used differently in brain regions that respond to auditory and visual speech. While visual areas use visual speech to improve phase-locking to auditory speech signals, auditory areas do not show phase-locking to visual speech unless auditory speech is absent and visual speech is used to substitute for missing auditory signals. These findings highlight brain processes that combine visual and auditory signals to support speech understanding.

The role of obesity and bariatric surgery-induced weight loss in breast cancer.

Obesity is a complex metabolic condition considered a worldwide public health crisis, and a deeper mechanistic understanding of obesity-associated diseases is urgently needed. Obesity comorbidities include many associated cancers and are estimated to account for 20% of female cancer deaths in the USA. Breast cancer, in particular, is associated with obesity and is the focus of this review. The exact causal links between obesity and breast cancer remain unclear. Still, interactions have emerged between body mass index, tumor molecular subtype, genetic background, and environmental factors that strongly suggest obesity influences the risk and progression of certain breast cancers. Supportive preclinical research uses various diet-induced obesity models to demonstrate that weight loss, via dietary interventions or changes in energy expenditure, reduces the onset or progression of breast cancers. Ongoing and future studies are now aimed at elucidating the underpinning mechanisms behind weight-loss-driven observations to improve therapy and outcomes in patients with breast cancer and reduce risk. This review aims to summarize the rapidly emerging literature on obesity and weight loss strategies with a focused discussion of bariatric surgery in both clinical and preclinical studies detailing the complex interactions between metabolism, immune response, and immunotherapy in the setting of obesity and breast cancer.

Conditional survival does not improve over time in metastatic castration-resistant prostate cancer patients undergoing docetaxel.

PURPOSE: To investigate the conditional overall survival (OS) of metastatic castration-resistant prostate cancer (mCRPC) patients receiving docetaxel chemotherapy. METHODS: We used deidentified patient-level data from the Prostate Cancer DREAM Challenge database and the control arm of the ENTHUSE 14 trial. We identified 2158 chemonaïve mCRPC patients undergoing docetaxel chemotherapy in the five randomized clinical trials. The 6-month conditional OS was calculated at times 0, 6, 12, 18, and 24 months from randomization. Survival curves of each group were compared using the log-rank test. Patients were then stratified into low- and high-risk groups based on the median predicted value of our recently published nomogram predicting OS in mCRPC patients. RESULTS: Nearly half (45%) of the study population was aged between 65 and 74 years. Median interquartile range prostate-specific antigen for the overall cohort was 83.2 (29.6-243) ng/mL, and 59% of patients had bone metastasis with or without lymph node involvement. The 6-month conditional survival rates at 0, 6, 12, 18, and 24 months for the entire cohort were 93% (95% confidence interval [CI]: 92-94), 82% (95% CI: 81-84), 76% (95% CI: 73-78), 75% (95% CI: 71-78), and 71% (95% CI: 65-76). These rates were, respectively, 96% (95% CI: 95-97), 92% (95% CI: 90-93), 84% (95% CI: 81-87), 81% (95% CI: 77-85), and 79% (95% CI: 72-84) in the low-risk group and 89% (95% CI: 87-91), 73% (95% CI: 70-76), 65% (95% CI: 60-69), 64% (95% CI: 58-70), and 58% (95% CI: 47-67) in the high-risk group. CONCLUSION: The conditional OS for patients undergoing docetaxel chemotherapy tends to plateau over time, with the main drop in conditional OS happening during the first year from initiating docetaxel treatment. That is the longer a patient survives, the more likely they are to survive further. This prognostic information could be a useful tool for a more accurate tailoring of both follow-up and therapies. PATIENT SUMMARY: In this report, we looked at the future survival in months of patients with metastatic castration resistant prostate cancer on chemotherapy who have already survived a certain period. We found that the longer time that a patient survives, the more likely they will continue to survive. We conclude that this information will help physicians tailor follow-ups and treatments for patients for a more accurate personalized medicine.

Serratia endocarditis: antimicrobial management strategies and clinical outcomes.

OBJECTIVES: The incidence of Serratia endocarditis is increasing, yet optimal treatment has not been defined. Our objective was to investigate the outcomes of patients with Serratia endocarditis by treatment strategy. METHODS: We reviewed adult patients with definitive Serratia endocarditis at two independent health systems between July 2001 and April 2023. Combination therapy was defined as receipt of ≥2 in vitro active agents for ≥72 h. RESULTS: Seventy-five patients were included; 64% (48/75) were male and 85% (64/75) were people who inject drugs. Compared with monotherapy, receipt of combination therapy was associated with lower rates of microbiological failure (0% versus 15%, P = 0.026) and 90 day all-cause mortality (11% versus 31%, P = 0.049). Antimicrobial discontinuation due to an adverse event was more common among patients receiving combination therapy compared with monotherapy (36% versus 8%, P = 0.058). CONCLUSIONS: In the largest series of Serratia endocarditis to date, combination antibiotic treatment was associated with improved outcomes. However, larger, prospective studies are warranted.

Rank normalization empowers a t-test for microbiome differential abundance analysis while controlling for false discoveries.

A major task in the analysis of microbiome data is to identify microbes associated with differing biological conditions. Before conducting analysis, raw data must first be adjusted so that counts from different samples are comparable. A typical approach is to estimate normalization factors by which all counts in a sample are multiplied or divided. However, the inherent variation associated with estimation of normalization factors are often not accounted for in subsequent analysis, leading to a loss of precision. Rank normalization is a nonparametric alternative to the estimation of normalization factors in which each count for a microbial feature is replaced by its intrasample rank. Although rank normalization has been successfully applied to microarray analysis in the past, it has yet to be explored for microbiome data, which is characterized by high frequencies of 0s, strongly correlated features and compositionality. We propose to use rank normalization as an alternative to the estimation of normalization factors and examine its performance when paired with a two-sample t-test. On a rigorous 3rd-party benchmarking simulation, it is shown to offer strong control over the false discovery rate, and at sample sizes greater than 50 per treatment group, to offer an improvement in performance over commonly used normalization factors paired with t-tests, Wilcoxon rank-sum tests and methodologies implemented by R packages. On two real datasets, it yielded valid and reproducible results that were strongly in agreement with the original findings and the existing literature, further demonstrating its robustness and future potential. Availability: The data underlying this article are available online along with R code and supplementary materials at https://github.com/matthewlouisdavisBioStat/Rank-Normalization-Empowers-a-T-Test.

Barriers to enrollment in a pediatric critical care biorepository.

BACKGROUND: Individuals of minority race/ethnicity have lower rates of participation in genomic research. This study evaluated sociodemographic characteristics associated with decisions to enroll in a pediatric critical care biorepository. METHODS: Parents of children admitted to the PICU between November 2014 and May 2017 were offered to enroll their child in a biorepository using a single-page opt-in consent. Missed enrollment was assessed by failure to complete the form or declining consent on the form. We conducted a retrospective chart review for sociodemographic and clinical information. Bivariate and multivariable regression analyses were performed. RESULTS: In 4055 encounters, representing 2910 patients with complete data, 1480 (50%) completed the consent form and 1223 (83%) enrolled. We found higher odds of incomplete consent for non-English-speaking parents (OR = 2.1, p < 0.0001) and parents of children of all races except non-Hispanic white (OR = 1.27-1.99, p < 0.0001). We found higher odds of declined consent in patients with Medicaid (OR = 1.67, p = 0.003) and parents of children of all races except non-Hispanic white (OR = 1.32-2.9, p < 0.0001). CONCLUSION: Inability to enroll patients in a critical care biorepository may be associated with several sociodemographic factors at various points in recruitment/enrollment. IMPACT: Individuals of minority race/ethnicity are less likely to enroll in genomic research and in critical care research. This study evaluated sociodemographic characteristics associated with decisions to enroll a child in a pediatric critical care biorepository. Sociodemographic factors including race/ethnicity, primary language, and insurance status and patient clinical characteristics are associated with differential enrollment into a pediatric critical care biorepository. More research is needed to understand how study team-participant interactions may play a role in differential enrollment. Barriers to enrollment occur both at the time of approaching and consenting for enrollment.