Clinical outcomes in patients with piperacillin/ tazobactam-non-susceptible but ceftriaxone-susceptible E. coli or K. pneumoniae bloodstream infection.

BACKGROUND: A small proportion of Escherichia coli and Klebsiella pneumoniae demonstrate in vitro non-susceptibility to piperacillin/tazobactam but retain susceptibility to ceftriaxone. Uncertainty remains regarding how best to treat these isolates. OBJECTIVES: We sought to compare clinical outcomes between patients with piperacillin/tazobactam-non-susceptible but ceftriaxone-susceptible E. coli or K. pneumoniae bloodstream infection receiving definitive therapy with ceftriaxone versus an alternative effective antibiotic. METHODS: We retrospectively identified patients with a positive blood culture for piperacillin/tazobactam-non-susceptible but ceftriaxone-susceptible E. coli or K. pneumoniae between 1 January 2013 and 31 December 2022. Patients were divided into one of two definitive treatment groups: ceftriaxone or alternative effective antibiotic. Our primary outcome was a composite of 90 day all-cause mortality, hospital readmission, or recurrence of infection. We used Cox proportional hazards models to compare time with the composite outcome between groups. RESULTS: Sixty-two patients were included in our analysis. Overall, median age was 63 years (IQR 49.5-71.0), the most common source of infection was intra-abdominal (25/62; 40.3%) and the median total duration of therapy was 12.0 days (IQR 9.0-16.8). A total of 9/22 (40.9%) patients in the ceftriaxone treatment group and 18/40 (45.0%) patients in the alternative effective antibiotic group met the composite endpoint. In an adjusted time-to-event analysis, there was no difference in the composite endpoint between groups (HR 0.67, 95% CI 0.30-1.50). The adjusted Bayesian posterior probability that the HR was less than or equal to 1 (i.e. ceftriaxone is as good or better than alternative therapy) was 85%. CONCLUSIONS: These findings suggest that ceftriaxone can be used to effectively treat bloodstream infections with E. coli or K. pneumoniae that are non-susceptible to piperacillin/tazobactam but susceptible to ceftriaxone.

Sleep quality during and after severe acute respiratory syndrome coronavirus 2 (COVID-19) lockdowns in the UK: Results from the SleepQuest study.

Sleep is fundamental to health. The aim of this study was to analyse and determine factors predicting sleep quality during and after national lockdowns due to severe acute respiratory syndrome coronavirus 2 (COVID-19) in the UK. A longitudinal online survey-based study (SleepQuest) involving UK adults was administered in Spring 2020, Winter 2020, and Winter 2022 including questionnaires probing sleep quality, depression, anxiety, beliefs about sleep, demographics, COVID-19 status, and exercise. The primary outcome was sleep quality (Pittsburgh Sleep Quality Index). A linear mixed-effects model evaluated factors associated with baseline and longitudinal sleep quality. Complete data were provided by 3306 participants in Spring 2020, 2196 participants in Winter 2020, and 1193 in Winter 2022. Participants were mostly female (73.8%), white (97.4%), and aged over 50 years (81.0%). On average, participants reported poor sleep quality in Spring 2020 (mean [SD] Pittsburgh Sleep Quality Index score = 6.59 [3.6]) and Winter 2020 (mean [SD] Pittsburgh Sleep Quality Index score = 6.44 [3.6]), with improved but still poor sleep quality in Winter 2022 (mean [SD] Pittsburgh Sleep Quality Index score = 6.17 [3.5]). Improved sleep quality was driven by better subjective sleep and reduced daytime dysfunction and sleep latency. Being female, older, having caring responsibilities, working nightshifts, and reporting higher levels of depression, anxiety, and unhelpful beliefs about sleep were associated with worse baseline PSQI scores. Better sleep quality was associated with more days exercising per week at baseline. Interventions focusing on improving mental health, exercise, and attitudes towards sleep, particularly in at-risk groups, may improve sleep-related outcomes in future pandemics.

Performance of Urinalysis Parameters in Predicting Urinary Tract Infection: Does One Size Fit all?

In a multi-hospital cohort study of 3392 patients, positive urinalysis parameters had poor positive predictive value for diagnosing urinary tract infection (UTI). Combined urinalysis parameters (pyuria or nitrite) performed better than pyuria alone for ruling out UTI. However, performance of all urinalysis parameters was poor in older women.

Monitoring the electroactive cargo of extracellular vesicles can differentiate various cancer cell lines.

Extracellular vesicles (EVs) are pivotal in cell-to-cell communication due to the array of cargo contained within these vesicles. EVs are considered important biomarkers for identification of disease, however most measurement approaches have focused on monitoring specific surface macromolecular targets. Our study focuses on exploring the electroactive component present within cargo from EVs obtained from various cancer and non-cancer cell lines using a disk carbon fiber microelectrode. Variations in the presence of oxidizable components were observed when the total cargo from EVs were measured, with the highest current detected in EVs from MCF7 cells. There were differences observed in the types of oxidizable species present within EVs from MCF7 and A549 cells. Single entity measurements showed clear spikes due to the detection of oxidizable cargo within EVs from MCF7 and A549 cells. These studies highlight the promise of monitoring EVs through the presence of varying electroactive components within the cargo and can drive a wave of new strategies towards specific detection of EVs for diagnosis and prognosis of various diseases.

The rapid recovery study: Cyclobenzaprine's effect on recovery following joint arthroplasty.

Introduction: Skeletal muscle relaxants have previously not been examined in multimodal anesthesia regimens following joint arthroplasty. We sought to evaluate cyclobenzaprine's effect on postoperative opioid consumption as well as surgical recovery following joint arthroplasty. Materials and methods: In this retrospective cohort study, 471 patients undergoing 554 joint arthroplasty procedures were evaluated. Patients were divided into cohorts who did and did not receive cyclobenzaprine postoperatively, and postoperative opioid consumption and functional recovery measures were recorded in each cohort. Results: In the unadjusted model, the cyclobenzaprine cohort experienced a 1.11 increase in pain scores on postoperative day zero (95% CI (0.60, 1.62), p < 0.0001). After adjusting for age, sex, BMI, CCI, perioperative MME, laterality, procedure, anesthesia, pre-op opioid use, pre-operative other controlled substance uses and pre-op benzodiazepine use, the cyclobenzaprine cohort's pain scores were 1.08 units higher at rest (95% CI (0.59, 1.56), p < 0.0001) and 1.25 units higher with activity on postoperative-day-zero (95% CI (0.78, 1.72), p < 0.0001). Both cohorts experienced statistically insignificantly different changes in mobility scores between postoperative day zero and postoperative day one, range of motion at 6 and 12 weeks, and readmission in <90 days. Postoperative morphine milliequivalents were insignificantly different between cohorts after controlling for pain in all models (base model mean ratio: 1.06, 95% CI (0.87,1.29), p = 0.5599) (Full model mean ratio: 1.09, 95% CI (0.91,1.30), p = 0.3608). Conclusions: Cyclobenzaprine shows utility in a multimodal anesthetic approach after joint arthroplasty in patients with higher baseline pain.

Multifunctional Biocatalysts for Organic Synthesis.

Biocatalysis is becoming an indispensable tool in organic synthesis due to high enzymatic catalytic efficiency as well as exquisite chemo- and stereoselectivity. Some biocatalysts display great promiscuity including a broad substrate scope as well as the ability to catalyze more than one type of transformation. These promiscuous activities have been applied individually to efficiently access numerous valuable target molecules. However, systems in which enzymes possessing multiple different catalytic activities are applied in the synthesis are less well developed. Such multifunctional biocatalysts (MFBs) would simplify chemical synthesis by reducing the number of operational steps and enzyme count, as well as simplifying the sequence space that needs to be engineered to develop an efficient biocatalyst. In this Perspective, we highlight recently reported MFBs focusing on their synthetic utility and mechanism. We also offer insight into their origin as well as comment on potential strategies for their discovery and engineering.

Optimal targeting of PI3K-AKT and mTOR in advanced oestrogen receptor-positive breast cancer.

The growing availability of targeted therapies for patients with advanced oestrogen receptor-positive breast cancer has improved survival, but there remains much to learn about the optimal management of these patients. The PI3K-AKT and mTOR pathways are among the most commonly activated pathways in breast cancer, whose crucial role in the pathogenesis of this tumour type has spurred major efforts to target this pathway at specific kinase hubs. Approvals for oestrogen receptor-positive advanced breast cancer include the PI3K inhibitor alpelisib for PIK3CA-mutated tumours, the AKT inhibitor capivasertib for tumours with alterations in PIK3CA, AKT1, or PTEN, and the mTOR inhibitor everolimus, which is used irrespective of mutation status. The availability of different inhibitors leaves physicians with a potentially challenging decision over which of these therapies should be used for individual patients and when. In this Review, we present a comprehensive summary of our current understanding of the pathways and the three inhibitors and discuss strategies for the optimal sequencing of therapies in the clinic, particularly after progression on a CDK4/6 inhibitor.

The Impact of Metagenomics on Biocatalysis.

In the ever-growing demand for sustainable ways to produce high-value small molecules, biocatalysis has come to the forefront of greener routes to these chemicals. As such, the need to constantly find and optimise suitable biocatalysts for specific transformations has never been greater. Metagenome mining has been shown to rapidly expand the toolkit of promiscuous enzymes needed for new transformations, without requiring protein engineering steps. If protein engineering is needed, the metagenomic candidate can often provide a better starting point for engineering than a previously discovered enzyme on the open database or from literature, for instance. In this review, we highlight where metagenomics has made substantial impact on the area of biocatalysis in recent years. We review the discovery of enzymes in previously unexplored or 'hidden' sequence space, leading to the characterisation of enzymes with enhanced properties that originate from natural selection pressures in native environments.

Remote Evaluation of Sleep and Circadian Rhythms in Older Adults With Mild Cognitive Impairment and Dementia: Protocol for a Feasibility and Acceptability Mixed Methods Study.

BACKGROUND: Sleep disturbances are a potentially modifiable risk factor for neurodegenerative dementia secondary to Alzheimer disease (AD) and Lewy body disease (LBD). Therefore, we need to identify the best methods to study sleep in this population. OBJECTIVE: This study will assess the feasibility and acceptability of various wearable devices, smart devices, and remote study tasks in sleep and cognition research for people with AD and LBD. METHODS: We will deliver a feasibility and acceptability study alongside a prospective observational cohort study assessing sleep and cognition longitudinally in the home environment. Adults aged older than 50 years who were diagnosed with mild to moderate dementia or mild cognitive impairment (MCI) due to probable AD or LBD and age-matched controls will be eligible. Exclusion criteria include lack of capacity to consent to research, other causes of MCI or dementia, and clinically significant sleep disorders. Participants will complete a cognitive assessment and questionnaires with a researcher and receive training and instructions for at-home study tasks across 8 weeks. At-home study tasks include remote sleep assessments using wearable devices (electroencephalography headband and actigraphy watch), app-based sleep diaries, online cognitive assessments, and saliva samples for melatonin- and cortisol-derived circadian markers. Feasibility outcomes will be assessed relating to recruitment and retention, data completeness, data quality, and support required. Feedback on acceptability and usability will be collected throughout the study period and end-of-study interviews will be analyzed using thematic analysis. RESULTS: Recruitment started in February 2022. Data collection is ongoing, with final data expected in February 2024 and data analysis and publication of findings scheduled for the summer of 2024. CONCLUSIONS: This study will allow us to assess if remote testing using smart devices and wearable technology is a viable alternative to traditional sleep measurements, such as polysomnography and questionnaires, in older adults with and without MCI or dementia due to AD or LBD. Understanding participant experience and the barriers and facilitators to technology use for research purposes and remote research in this population will assist with the development of, recruitment to, and retention within future research projects studying sleep and cognition outside of the clinic or laboratory. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/52652.

Late cardiotoxicity related to HER2-targeted cancer therapy.

Long-term anti-HER2 therapy in metastatic HER2 + cancers is increasing, but data about the incidence and risk factors for developing late Cancer therapy-related cardiac dysfunction (CTRCD) are missing. We conducted a single-centre, retrospective analysis of a cohort of late anti-HER2 related cardiac dysfunction referred to our Cardio-Oncology service. We include seventeen patients with metastatic disease who developed CTRCD after at least five years of continuous anti-HER2 therapy. Events occurred after a median time of 6.5 years (IQR 5.3-9.0) on anti-HER2 therapy. The lowest (median) LVEF and GLS were 49% (IQR 45-55) and - 15.4% (IQR - 14.9 - -16.3) respectively. All our patients continued or restarted, after a brief interruption, their anti-HER2 therapy. Most (16/17) were started on heart failure medical therapy and normalized their left ventricular ejection fraction at a follow-up. Our study has demonstrated that CTRCD can occur after many years of stability on anti-HER2 therapy and reinforces the importance of continuing cardiovascular surveillance in this population.

Immunogenicity of Monovalent mRNA-1273 and BNT162b2 Vaccines in Children Less Than 5 Years of Age.

BACKGROUND AND OBJECTIVES: The mRNA-based COVID-19 vaccines approved for use in children less than 5 years of age have different antigen doses and administration schedules that could affect vaccine immunogenicity and effectiveness. We sought to compare the strength and breadth of serum binding and neutralizing antibodies to SARS-CoV-2 elicited by monovalent mRNA-based COVID-19 vaccines in young children. METHODS: We conducted a prospective cohort study of children 6 months to 4 years of age who completed primary series vaccination with monovalent mRNA-1273 or BNT162b2 vaccines. Serum was collected one month after primary vaccine series completion for measurement of SARS-CoV-2-specific humoral immune responses, including antibody binding responses to Spike proteins from an ancestral strain (D614G) and major variants of SARS-CoV-2 and antibody neutralizing activity against D614G and Omicron subvariants (BA.1, BA.4/5). RESULTS: Of 75 participants, 40 (53%) received mRNA-1273 and 35 (47%) received BNT162b2. Children receiving either primary vaccine series developed robust and broad SARS-CoV-2-specific binding and neutralizing antibodies, including to Omicron subvariants. Children with a prior history of SARS-CoV-2 infection developed significantly higher antibody binding responses and neutralization titers to Omicron subvariants, consistent with the occurrence of identified infections during the circulation of Omicron subvariants in the region. CONCLUSIONS: Monovalent mRNA-1273 and BNT162b2 elicited similar antibody responses one month after vaccination in young children. Further, prior infection significantly enhanced the strength of antibody responses to Omicron subvariants. Future studies should evaluate incorporation of these vaccines into the standard childhood immunization schedule.

CDC's Hospital-Onset Clostridioides difficile Prevention Framework in a Regional Hospital Network.

Importance: Despite modest reductions in the incidence of hospital-onset Clostridioides difficile infection (HO-CDI), CDI remains a leading cause of health care-associated infection. As no single intervention has proven highly effective on its own, a multifaceted approach to controlling HO-CDI is needed. Objective: To assess the effectiveness of the Centers for Disease Control and Prevention's Strategies to Prevent Clostridioides difficile Infection in Acute Care Facilities Framework (hereafter, the Framework) in reducing HO-CDI incidence. Design, Setting, and Participants: This quality improvement study was performed within the Duke Infection Control Outreach Network from July 1, 2019, through March 31, 2022. In all, 20 hospitals in the network participated in an implementation study of the Framework recommendations, and 26 hospitals did not participate and served as controls. The Framework has 39 discrete intervention categories organized into 5 focal areas for CDI prevention: (1) isolation and contact precautions, (2) CDI confirmation, (3) environmental cleaning, (4) infrastructure development, and (5) antimicrobial stewardship engagement. Exposures: Monthly teleconferences supporting Framework implementation for the participating hospitals. Main Outcomes and Measures: Primary outcomes were HO-CDI incidence trends at participating hospitals compared with controls and postintervention HO-CDI incidence at intervention sites compared with rates during the 24 months before the intervention. Results: The study sample included a total of 2184 HO-CDI cases and 7 269 429 patient-days. In the intervention cohort of 20 participating hospitals, there were 1403 HO-CDI cases and 3 513 755 patient-days, with a median (IQR) HO-CDI incidence of 2.8 (2.0-4.3) cases per 10 000 patient-days. The first analysis included an additional 3 755 674 patient-days and 781 HO-CDI cases among the 26 controls, with a median (IQR) HO-CDI incidence of 1.1 (0.7-2.7) case per 10 000 patient-days. The second analysis included an additional 2 538 874 patient-days and 1751 HO-CDI cases, with a median (IQR) HO-CDI incidence of 5.9 (2.7-8.9) cases per 10 000 patient-days, from participating hospitals 24 months before the intervention. In the first analysis, intervention sites had a steeper decline in HO-CDI incidence over time relative to controls (yearly incidence rate ratio [IRR], 0.79 [95% CI, 0.67-0.94]; P = .01), but the decline was not temporally associated with study participation. In the second analysis, HO-CDI incidence was declining in participating hospitals before the intervention, and the rate of decline did not change during the intervention. The degree to which hospitals implemented the Framework was associated with steeper declines in HO-CDI incidence (yearly IRR, 0.95 [95% CI, 0.90-0.99]; P = .03). Conclusions and Relevance: In this quality improvement study of a regional hospital network, implementation of the Framework was not temporally associated with declining HO-CDI incidence. Further study of the effectiveness of multimodal prevention measures for controlling HO-CDI is warranted.

Racial and Ethnic Disparities in Patient Restraint in Emergency Departments by Police Transport Status.

Importance: Black patients are more likely than White patients to be restrained during behavioral crises in emergency departments (EDs). Although the perils of policing mental health for Black individuals are recognized, it is unclear whether or to what extent police transport mediates the association between Black race and use of physical restraint in EDs. Objective: To evaluate the degree to which police transport mediates the association between Black race and use of physical restraint in EDs. Design, Setting, and Participants: This retrospective, cross-sectional study used electronic health record data from ED visits by adults (aged ≥18 years) to 3 hospitals in the southeastern US and 10 in the northeastern US between January 1, 2015, and December 31, 2022. Data were analyzed from September 1, 2022, to May 30, 2023. Exposures: Race, ethnicity, and police transport to the hospital. Main Outcomes and Measures: The primary outcome variable was the presence of an order for restraints during an ED visit. Results: A total of 4 263 437 ED visits by 1 257 339 patients (55.5% of visits by female and 44.5% by male patients; 26.1% by patients 65 years or older) were included in the study. Black patients accounted for 27.5% of visits; Hispanic patients, 17.6%; White patients, 50.3%; and other or unknown race or ethnicity, 4.6%. In models adjusted for age, sex, site, previous behavioral or psychiatric history, and visit diagnoses, Black patients were at increased odds of experiencing restraint compared with White patients (adjusted odds ratio [AOR], 1.33 [95% CI, 1.28-1.37]). Within the mediation analysis, Black patients had higher odds of being brought to the hospital by police compared with all other patients (AOR, 1.38 [95% CI, 1.34-1.42]). Patients brought to the ED under police transport had increased odds of experiencing restraint compared with all other modes of transport (AOR, 5.51 [95% CI, 5.21-5.82]). The estimated proportion of use of restraints for Black patients mediated by police transport was 10.70% (95% CI, 9.26%-12.53%). Conclusions and Relevance: In this cross-sectional study of ED visits across 13 hospitals, police transport may have mediated the association between Black race and use of physical restraint. These findings suggest a need to further explore the mechanisms by which transport to emergency care may influence disparate restrictive interventions for patients experiencing behavioral emergencies.

The devil's in the defaults: An interrupted time-series analysis of the impact of default duration elimination on exposure to fluoroquinolone therapy.

OBJECTIVE: To determine whether removal of default duration, embedded in electronic prescription (e-script), influenced antibiotic days of therapy. DESIGN: Interrupted time-series analysis. SETTING: The study was conducted across 2 community hospitals, 1 academic hospital, 3 emergency departments, and 86 ambulatory clinics. PATIENTS: Adults prescribed a fluoroquinolone with a duration <31 days. INTERVENTIONS: Removal of standard 10-day fluoroquinolone default duration and addition of literature-based duration guidance in the order entry on December 19, 2017. The study period included data for 12 months before and after the intervention. RESULTS: The study included 35,609 fluoroquinolone e-scripts from the preintervention period and 31,303 fluoroquinolone e-scripts from the postintervention period, accounting for 520,388 cumulative fluoroquinolone DOT. Mean durations before and after the intervention were 7.8 (SD, 4.3) and 7.7 (SD, 4.5), a nonsignificant change. E-scripts with a 10-day duration decreased prior to and after the default removal. The inpatient setting showed a significant 8% drop in 10-day e-scripts after default removal and a reduced median duration by 1 day; 10-day scripts declined nonsignificantly in ED and ambulatory settings. In the ambulatory settings, both 7- and 14-day e-script durations increased after default removal. CONCLUSION: Removal of default 10-day antibiotic durations did not affect overall mean duration but did shift patterns in prescribing, depending on practice setting. Stewardship interventions must be studied in the context of practice setting. Ambulatory stewardship efforts separate from inpatient programs are needed because interventions cannot be assumed to have similar effects.

Proposing the "Continuum of UTI" for a Nuanced Approach to Diagnosis and Management of Urinary Tract Infections.

PURPOSE: Patients with suspected UTIs are categorized into 3 clinical phenotypes based on current guidelines: no UTI, asymptomatic bacteriuria (ASB), or UTI. However, all patients may not fit neatly into these groups. Our objective was to characterize clinical presentations of patients who receive urine tests using the "continuum of UTI" approach. MATERIALS AND METHODS: This was a retrospective cohort study of a random sample of adult noncatheterized inpatient and emergency department encounters with paired urinalysis and urine cultures from 5 hospitals in 3 states between January 01, 2017, and December 31, 2019. Trained abstractors collected clinical (eg, symptom) and demographic data. A focus group discussion with multidisciplinary experts was conducted to define the continuum of UTI, a 5-level classification scheme that includes 2 new categories: lower urinary tract symptoms/other urologic symptoms and bacteriuria of unclear significance. The newly defined continuum of UTI categories were compared to the current UTI classification scheme. RESULTS: Of 220,531 encounters, 3392 randomly selected encounters were reviewed. Based on the current classification scheme, 32.1% (n = 704) had ASB and 53% (n = 1614) did not have a UTI. When applying the continuum of UTI categories, 68% of patients (n = 478) with ASB were reclassified as bacteriuria of unclear significance and 29% of patients (n = 467) with "no UTI" were reclassified to lower urinary tract symptoms/other urologic symptoms. CONCLUSIONS: Our data suggest the need to reframe our conceptual model of UTI vs ASB to reflect the full spectrum of clinical presentations, acknowledge the diagnostic uncertainty faced by frontline clinicians, and promote a nuanced approach to diagnosis and management of UTIs.

Sertraline for anxiety in adults with a diagnosis of autism (STRATA): study protocol for a pragmatic, multicentre, double-blind, placebo-controlled randomised controlled trial.

BACKGROUND: Selective serotonin reuptake inhibitors (SSRIs) are commonly prescribed to manage anxiety in adults with an autism diagnosis. However, their effectiveness and adverse effect profile in the autistic population are not well known. This trial aims to determine the effectiveness and cost-effectiveness of the SSRI sertraline in reducing symptoms of anxiety and improving quality of life in adults with a diagnosis of autism compared with placebo and to quantify any adverse effects. METHODS: STRATA is a two-parallel group, multi-centre, pragmatic, double-blind, randomised placebo-controlled trial with allocation at the level of the individual. It will be delivered through recruiting sites with autism services in 4 regional centres in the United Kingdom (UK) and 1 in Australia. Adults with an autism diagnosis and a Generalised Anxiety Disorder Assessment (GAD-7) score ≥ 10 at screening will be randomised 1:1 to either 25 mg sertraline or placebo, with subsequent flexible dose titration up to 200 mg. The primary outcome is GAD-7 scores at 16 weeks post-randomisation. Secondary outcomes include adverse effects, proportionate change in GAD-7 scores including 50% reduction, social anxiety, obsessive-compulsive symptoms, panic attacks, repetitive behaviours, meltdowns, depressive symptoms, composite depression and anxiety, functioning and disability and quality of life. Carer burden will be assessed in a linked carer sub-study. Outcome data will be collected using online/paper methods via video call, face-to-face or telephone according to participant preference at 16, 24 and 52 weeks post-randomisation, with brief safety checks and data collection at 1-2, 4, 8, 12 and 36 weeks. An economic evaluation to study the cost-effectiveness of sertraline vs placebo and a QuinteT Recruitment Intervention (QRI) to optimise recruitment and informed consent are embedded within the trial. Qualitative interviews at various times during the study will explore experiences of participating and taking the trial medication. DISCUSSION: Results from this study should help autistic adults and their clinicians make evidence-based decisions on the use of sertraline for managing anxiety in this population. TRIAL REGISTRATION: ISRCTN, ISRCTN15984604 . Registered on 08 February 2021. EudraCT 2019-004312-66. ANZCTR ACTRN12621000801819. Registered on 07 April 2021.

Cell-type-specific inhibitory circuitry from a connectomic census of mouse visual cortex.

Mammalian cortex features a vast diversity of neuronal cell types, each with characteristic anatomical, molecular and functional properties. Synaptic connectivity powerfully shapes how each cell type participates in the cortical circuit, but mapping connectivity rules at the resolution of distinct cell types remains difficult. Here, we used millimeter-scale volumetric electron microscopy1 to investigate the connectivity of all inhibitory neurons across a densely-segmented neuronal population of 1352 cells spanning all layers of mouse visual cortex, producing a wiring diagram of inhibitory connections with more than 70,000 synapses. Taking a data-driven approach inspired by classical neuroanatomy, we classified inhibitory neurons based on the relative targeting of dendritic compartments and other inhibitory cells and developed a novel classification of excitatory neurons based on the morphological and synaptic input properties. The synaptic connectivity between inhibitory cells revealed a novel class of disinhibitory specialist targeting basket cells, in addition to familiar subclasses. Analysis of the inhibitory connectivity onto excitatory neurons found widespread specificity, with many interneurons exhibiting differential targeting of certain subpopulations spatially intermingled with other potential targets. Inhibitory targeting was organized into "motif groups," diverse sets of cells that collectively target both perisomatic and dendritic compartments of the same excitatory targets. Collectively, our analysis identified new organizing principles for cortical inhibition and will serve as a foundation for linking modern multimodal neuronal atlases with the cortical wiring diagram.

First-Line Ipatasertib, Atezolizumab, and Taxane Triplet for Metastatic Triple-Negative Breast Cancer: Clinical and Biomarker Results.

PURPOSE: To evaluate a triplet regimen combining immune checkpoint blockade, AKT pathway inhibition, and (nab-) paclitaxel as first-line therapy for locally advanced/metastatic triple-negative breast cancer (mTNBC). PATIENTS AND METHODS: The single-arm CO40151 phase Ib study (NCT03800836), the single-arm signal-seeking cohort of IPATunity130 (NCT03337724), and the randomized phase III IPATunity170 trial (NCT04177108) enrolled patients with previously untreated mTNBC. Triplet therapy comprised intravenous atezolizumab 840 mg (days 1 and 15), oral ipatasertib 400 mg/day (days 1-21), and intravenous paclitaxel 80 mg/m2 (or nab-paclitaxel 100 mg/m2; days 1, 8, and 15) every 28 days. Exploratory translational research aimed to elucidate mechanisms and molecular markers of sensitivity and resistance. RESULTS: Among 317 patients treated with the triplet, efficacy ranged across studies as follows: median progression-free survival (PFS) 5.4 to 7.4 months, objective response rate 44% to 63%, median duration of response 5.6 to 11.1 months, and median overall survival 15.7 to 28.3 months. The safety profile was consistent with the known toxicities of each agent. Grade ≥3 adverse events were more frequent with the triplet than with doublets or single-agent paclitaxel. Patients with PFS >10 months were characterized by NF1, CCND3, and PIK3CA alterations and increased immune pathway activity. PFS <5 months was associated with CDKN2A/CDKN2B/MTAP alterations and lower predicted phosphorylated AKT-S473 levels. CONCLUSIONS: In patients with mTNBC receiving an ipatasertib/atezolizumab/taxane triplet regimen, molecular characteristics may identify those with particularly favorable or unfavorable outcomes, potentially guiding future research efforts.