Mass cytometry reveals a conserved immune trajectory of recovery in hospitalized COVID-19 patients.

While studies have elucidated many pathophysiological elements of COVID-19, little is known about immunological changes during COVID-19 resolution. We analyzed immune cells and phosphorylated signaling states at single-cell resolution from longitudinal blood samples of patients hospitalized with COVID-19, pneumonia and/or sepsis, and healthy individuals by mass cytometry. COVID-19 patients showed distinct immune compositions and an early, coordinated, and elevated immune cell signaling profile associated with early hospital discharge. Intra-patient longitudinal analysis revealed changes in myeloid and T cell frequencies and a reduction in immune cell signaling across cell types that accompanied disease resolution and discharge. These changes, together with increases in regulatory T cells and reduced signaling in basophils, also accompanied recovery from respiratory failure and were associated with better outcomes at time of admission. Therefore, although patients have heterogeneous immunological baselines and highly variable disease courses, a core immunological trajectory exists that defines recovery from severe SARS-CoV-2 infection.

Prevention of respiratory virus transmission by resident memory CD8+ T cells.

An ideal vaccine both attenuates virus growth and disease in infected individuals and reduces the spread of infections in the population, thereby generating herd immunity. Although this strategy has proved successful by generating humoral immunity to measles, yellow fever and polio, many respiratory viruses evolve to evade pre-existing antibodies1. One approach for improving the breadth of antiviral immunity against escape variants is through the generation of memory T cells in the respiratory tract, which are positioned to respond rapidly to respiratory virus infections2-6. However, it is unknown whether memory T cells alone can effectively surveil the respiratory tract to the extent that they eliminate or greatly reduce viral transmission following exposure of an individual to infection. Here we use a mouse model of natural parainfluenza virus transmission to quantify the extent to which memory CD8+ T cells resident in the respiratory tract can provide herd immunity by reducing both the susceptibility of acquiring infection and the extent of transmission, even in the absence of virus-specific antibodies. We demonstrate that protection by resident memory CD8+ T cells requires the antiviral cytokine interferon-γ (IFNγ) and leads to altered transcriptional programming of epithelial cells within the respiratory tract. These results suggest that tissue-resident CD8+ T cells in the respiratory tract can have important roles in protecting the host against viral disease and limiting viral spread throughout the population.

All human social groups are human, but some are more human than others: A comprehensive investigation of the implicit association of "Human" to US racial/ethnic groups.

All human groups are equally human, but are they automatically represented as such? Harnessing data from 61,377 participants across 13 experiments (six primary and seven supplemental), a sharp dissociation between implicit and explicit measures emerged. Despite explicitly affirming the equal humanity of all racial/ethnic groups, White participants consistently associated Human (relative to Animal) more with White than Black, Hispanic, and Asian groups on Implicit Association Tests (IATs; experiments 1-4). This effect emerged across diverse representations of Animal that varied in valence (pets, farm animals, wild animals, and vermin; experiments 1-2). Non-White participants showed no such Human=Own Group bias (e.g., Black participants on a White-Black/Human-Animal IAT). However, when the test included two outgroups (e.g., Asian participants on a White-Black/Human-Animal IAT), non-White participants displayed Human=White associations. The overall effect was largely invariant across demographic variations in age, religion, and education but did vary by political ideology and gender, with self-identified conservatives and men displaying stronger Human=White associations (experiment 3). Using a variance decomposition method, experiment 4 showed that the Human=White effect cannot be attributed to valence alone; the semantic meaning of Human and Animal accounted for a unique proportion of variance. Similarly, the effect persisted even when Human was contrasted with positive attributes (e.g., God, Gods, and Dessert; experiment 5a). Experiments 5a-b clarified the primacy of Human=White rather than Animal=Black associations. Together, these experiments document a factually erroneous but robust Human=Own Group implicit stereotype among US White participants (and globally), with suggestive evidence of its presence in other socially dominant groups.

Host and Microbe Blood Metagenomics Reveals Key Pathways Characterizing Critical Illness Phenotypes.

Rationale: Two molecular phenotypes of sepsis and acute respiratory distress syndrome, termed hyperinflammatory and hypoinflammatory, have been consistently identified by latent class analysis in numerous cohorts, with widely divergent clinical outcomes and differential responses to some treatments; however, the key biological differences between these phenotypes remain poorly understood.Objectives: We used host and microbe metagenomic sequencing data from blood to deepen our understanding of biological differences between latent class analysis-derived phenotypes and to assess concordance between the latent class analysis-derived phenotypes and phenotypes reported by other investigative groups (e.g., Sepsis Response Signature [SRS1-2], molecular diagnosis and risk stratification of sepsis [MARS1-4], reactive and uninflamed).Methods: We analyzed data from 113 patients with hypoinflammatory sepsis and 76 patients with hyperinflammatory sepsis enrolled in a two-hospital prospective cohort study. Molecular phenotypes had been previously assigned using latent class analysis.Measurements and Main Results: The hyperinflammatory and hypoinflammatory phenotypes of sepsis had distinct gene expression signatures, with 5,755 genes (31%) differentially expressed. The hyperinflammatory phenotype was associated with elevated expression of innate immune response genes, whereas the hypoinflammatory phenotype was associated with elevated expression of adaptive immune response genes and, notably, T cell response genes. Plasma metagenomic analysis identified differences in prevalence of bacteremia, bacterial DNA abundance, and composition between the phenotypes, with an increased presence and abundance of Enterobacteriaceae in the hyperinflammatory phenotype. Significant overlap was observed between these phenotypes and previously identified transcriptional subtypes of acute respiratory distress syndrome (reactive and uninflamed) and sepsis (SRS1-2). Analysis of data from the VANISH trial indicated that corticosteroids might have a detrimental effect in patients with the hypoinflammatory phenotype.Conclusions: The hyperinflammatory and hypoinflammatory phenotypes have distinct transcriptional and metagenomic features that could be leveraged for precision treatment strategies.

Interleukin-15 and high-intensity exercise: relationship with inflammation, body composition and fitness in cancer survivors.

Pre-clinical murine and in vitro models have demonstrated that exercise suppresses tumour and cancer cell growth. These anti-oncogenic effects of exercise were associated with the exercise-mediated release of myokines such as interleukin (IL)-15. However, no study has quantified the acute IL-15 response in human cancer survivors, and whether physiological adaptations to exercise training (i.e. body composition and cardiorespiratory fitness) influence this response. In the present study breast, prostate and colorectal cancer survivors (n = 14) completed a single bout of high-intensity interval exercise (HIIE) [4×4 min at 85-95% heart rate (HR) peak, 3 min at 50-70% HR peak] before and after 7 months of three times weekly high-intensity interval training (HIIT) on a cycle ergometer. At each time point venous blood was sampled before and immediately after HIIE to assess the acute myokine (IL-15, IL-6, IL-10, IL-1ra) responses. Markers of inflammation, cardiorespiratory fitness and measures of body composition were obtained at baseline and 7 months. An acute bout of HIIE resulted in a significant increase in IL-15 concentrations (pre-intervention: 113%; P = 0.013, post-intervention: 102%; P = 0.005). Post-exercise IL-15 concentrations were associated with all other post-exercise myokine concentrations, lean mass (P = 0.031), visceral adipose tissue (P = 0.039) and absolute V ̇ O 2 ${{\dot{V}}_{{{{\mathrm{O}}}_{\mathrm{2}}}}}$ peak (P = 0.032). There was no significant effect of 7 months of HIIT on pre- or post-HIIE IL-15 concentrations (P > 0.05). This study demonstrates HIIE is a sufficient stimulus to increase circulating IL-15 and other myokines including IL-6, IL-10 and IL-1ra which may be clinically relevant in the anti-oncogenic effect of exercise and repetitive exposure to these effects may contribute to the positive relationship between exercise and cancer recurrence. KEY POINTS: Exercise has been demonstrated to reduce the risk of cancer recurrence. Pre-clinical murine and in vitro models have demonstrated that exercise suppresses tumour and cancer cell growth, mediated by exercise-induced myokines (IL-6 and IL-15). High-intensity interval exercise significantly increased myokines associated with the anti-oncogenic effect of exercise and the magnitude of response was associated with lean mass, but training did not appear to influence this response. Given IL-15 has been implicated in the anti-oncogenic effect of exercise and is being explored as an immunotherapy agent, high-intensity interval exercise may improve outcomes for people living beyond cancer through IL-15-mediated pathways. Interventions that increase lean mass may also enhance this response.

The prognostic impact of BMI in patients with HR+/HER2- advanced breast cancer: a study of the SONABRE registry.

PURPOSE: This study determines the prognostic impact of body mass index (BMI) in patients with hormone receptor-positive/human epidermal growth factor receptor-2-negative (HR+/HER2-) advanced (i.e., metastatic) breast cancer (ABC). METHODS: All patients with HR+/HER2- ABC who received endocrine therapy +-a cyclin-dependent kinase 4/6 inhibitor as first-given systemic therapy in 2007-2020 in the Netherlands were identified from the Southeast Netherlands Advanced Breast Cancer (SONABRE) registry (NCT03577197). Patients were categorised as underweight (BMI: < 18.5 kg/m2), normal weight (18.5-24.9 kg/m2), overweight (25.0-29.9 kg/m2), or obese (≥ 30.0 kg/m2). Overall survival (OS) and progression-free survival (PFS) were compared between BMI classes using multivariable Cox regression analyses. RESULTS: This study included 1456 patients, of whom 35 (2%) were underweight, 580 (40%) normal weight, 479 (33%) overweight, and 362 (25%) obese. No differences in OS were observed between normal weight patients and respectively overweight (HR 0.99; 95% CI 0.85-1.16; p = 0.93) and obese patients (HR 1.04; 95% CI 0.88-1.24; p = 0.62). However, the OS of underweight patients (HR 1.45; 95% CI 0.97-2.15; p = 0.07) tended to be worse than the OS of normal weight patients. When compared with normal weight patients, the PFS was similar in underweight (HR 1.05; 95% CI 0.73-1.51; p = 0.81), overweight (HR 0.90; 95% CI 0.79-1.03; p = 0.14), and obese patients (HR 0.88; 95% CI 0.76-1.02; p = 0.10). CONCLUSION: In this study among 1456 patients with HR+/HER2- ABC, overweight and obesity were prevalent, whereas underweight was uncommon. When compared with normal weight, overweight and obesity were not associated with either OS or PFS. However, underweight seemed to be an adverse prognostic factor for OS.

Time trends in real-world treatment patterns and survival in patients diagnosed with de novo HER2+ metastatic breast cancer: an analysis of the SONABRE registry.

PURPOSE: The aim was to determine whether the real-world first-line progression-free survival (PFS) of patients diagnosed with de novo human epidermal growth factor receptor 2 positive (HER2+) advanced breast cancer (ABC) has improved since the introduction of pertuzumab in 2013. In addition to PFS, we aimed to determine differences in overall survival (OS) and the use of systemic and locoregional therapies. METHODS: Included were patients systemically treated for de novo HER2+ ABC in ten hospitals in 2008-2017 from the SONABRE Registry (NCT-03577197). First-line PFS and OS in 2013-2017 versus 2008-2012 was determined using Kaplan-Meier analyses and multivariable Cox proportional hazards modelling. First-given systemic therapy and the use of locoregional therapy within the first year following diagnosis were determined per period of diagnosis. RESULTS: Median and five-year PFS were 26.6 months and 24% in 2013-2017 (n = 85) versus 14.5 months and 10% in 2008-2012 (n = 81) (adjusted HR = 0.65, 95%CI:0.45-0.94). Median and five-year OS were 61.2 months and 51% in 2013-2017 versus 26.1 months and 28% in 2008-2012 (adjusted HR = 0.55, 95%CI:0.37-0.81). Of patients diagnosed in 2013-2017 versus 2008-2012, 84% versus 60% received HER2-targeted therapy and 59% versus 0% pertuzumab-based therapy as first-given therapy. Respectively, 27% and 23% of patients underwent locoregional breast surgery, and 6% and 7% surgery of a metastatic site during the first year following diagnosis. CONCLUSION: The prognosis of patients with de novo HER2 + ABC has improved considerably. Since 2013 one in four patients were alive and free from progression on first-given therapy for at least five years.

Rapidly improving ARDS differs clinically and biologically from persistent ARDS.

BACKGROUND: Rapidly improving acute respiratory distress syndrome (RIARDS) is an increasingly appreciated subgroup of ARDS in which hypoxemia improves within 24 h after initiation of mechanical ventilation. Detailed clinical and biological features of RIARDS have not been clearly defined, and it is unknown whether RIARDS is associated with the hypoinflammatory or hyperinflammatory phenotype of ARDS. The purpose of this study was to define the clinical and biological features of RIARDS and its association with inflammatory subphenotypes. METHODS: We analyzed data from 215 patients who met Berlin criteria for ARDS (endotracheally intubated) and were enrolled in a prospective observational cohort conducted at two sites, one tertiary care center and one urban safety net hospital. RIARDS was defined according to previous studies as improvement of hypoxemia defined as (i) PaO2:FiO2 > 300 or (ii) SpO2: FiO2 > 315 on the day following diagnosis of ARDS (day 2) or (iii) unassisted breathing by day 2 and for the next 48 h (defined as absence of endotracheal intubation on day 2 through day 4). Plasma biomarkers were measured on samples collected on the day of study enrollment, and ARDS phenotypes were allocated as previously described. RESULTS: RIARDS accounted for 21% of all ARDS participants. Patients with RIARDS had better clinical outcomes compared to those with persistent ARDS, with lower hospital mortality (13% vs. 57%; p value < 0.001) and more ICU-free days (median 24 vs. 0; p value < 0.001). Plasma levels of interleukin-6, interleukin-8, and plasminogen activator inhibitor-1 were significantly lower among patients with RIARDS. The hypoinflammatory phenotype of ARDS was more common among patients with RIARDS (78% vs. 51% in persistent ARDS; p value = 0.001). CONCLUSIONS: This study identifies a high prevalence of RIARDS in a multicenter observational cohort and confirms the more benign clinical course of these patients. We report the novel finding that RIARDS is characterized by lower concentrations of plasma biomarkers of inflammation compared to persistent ARDS, and that hypoinflammatory ARDS is more prevalent among patients with RIARDS. Identification and exclusion of RIARDS could potentially improve prognostic and predictive enrichment in clinical trials.

Causes and attributable fraction of death from ARDS in inflammatory phenotypes of sepsis.

BACKGROUND: Hypoinflammatory and hyperinflammatory phenotypes have been identified in both Acute Respiratory Distress Syndrome (ARDS) and sepsis. Attributable mortality of ARDS in each phenotype of sepsis is yet to be determined. We aimed to estimate the population attributable fraction of death from ARDS (PAFARDS) in hypoinflammatory and hyperinflammatory sepsis, and to determine the primary cause of death within each phenotype. METHODS: We studied 1737 patients with sepsis from two prospective cohorts. Patients were previously assigned to the hyperinflammatory or hypoinflammatory phenotype using latent class analysis. The PAFARDS in patients with sepsis was estimated separately in the hypo and hyperinflammatory phenotypes. Organ dysfunction, severe comorbidities, and withdrawal of life support were abstracted from the medical record in a subset of patients from the EARLI cohort who died (n = 130/179). Primary cause of death was defined as the organ system that most directly contributed to death or withdrawal of life support. RESULTS: The PAFARDS was 19% (95%CI 10,28%) in hypoinflammatory sepsis and, 14% (95%CI 6,20%) in hyperinflammatory sepsis. Cause of death differed between the two phenotypes (p < 0.001). Respiratory failure was the most common cause of death in hypoinflammatory sepsis, whereas circulatory shock was the most common cause in hyperinflammatory sepsis. Death with severe underlying comorbidities was more frequent in hypoinflammatory sepsis (81% vs. 67%, p = 0.004). CONCLUSIONS: The PAFARDS is modest in both phenotypes whereas primary cause of death among patients with sepsis differed substantially by phenotype. This study identifies challenges in powering future clinical trials to detect changes in mortality outcomes among patients with sepsis and ARDS.

Plasma metabolic profiling implicates dysregulated lipid metabolism and glycolytic shift in hyperinflammatory ARDS.

Using latent class analysis (LCA) of clinical and protein biomarkers, researchers have identified two phenotypes of the acute respiratory distress syndrome (ARDS) with divergent clinical trajectories and treatment responses. We investigated whether plasma metabolites differed among patients with LCA-derived hyperinflammatory and hypoinflammatory ARDS, and we tested the prognostic utility of adding metabolic clusters to LCA phenotypes. We analyzed data from 93 patients with ARDS and sepsis enrolled in a multicenter prospective cohort of critically ill patients, comparing 970 metabolites between the two LCA-derived phenotypes. In all, 188 metabolites were differentially abundant between the two LCA-derived phenotypes. After adjusting for age, sex, confounding medications, and comorbid liver and kidney disease, 82 metabolites remained significantly different. Patients with hyperinflammatory ARDS had reduced circulating lipids but high levels of pyruvate, lactate, and malate. Metabolic cluster and LCA-derived phenotypes were each significantly and independently associated with survival. Patients with hyperinflammatory ARDS may be experiencing a glycolytic shift leading to dysregulated lipid metabolism. Metabolic profiling offers prognostic information beyond what is captured by LCA phenotypes alone. Deeper biological profiling may identify key differences in pathogenesis among patients with ARDS and may lead to novel targeted therapies.

Outcomes for the first four lines of therapy in patients with HER2-positive advanced breast cancer: results from the SONABRE registry.

PURPOSE: We assessed the systemic treatment choices and outcomes in patients diagnosed with human epidermal growth factor receptor-2-positive (HER2 +) advanced breast cancer (ABC), for the first four lines of systemic therapy and by hormone receptor (HR) status. METHODS: We identified 330 patients diagnosed with HER2 + ABC in 2013-2018 in the Southeast of The Netherlands, of whom 64% with HR + /HER2 + and 36% with HR-/HER2 + disease. Overall survival (OS) from start of therapy was calculated using the Kaplan-Meier method. RESULTS: In real world, 95% of patients with HR + /HER2 + and 74% of patients with HR-/HER2 + disease received systemic therapy. In HR + /HER2 + disease, use of endocrine, chemo- and HER2-targeted therapy was , respectively, 64%, 46% and 60% in first line, and 39%, 64% and 75% in fourth line. In HR-/HER2 + disease, 91-96% of patients received chemotherapy and 77-91% HER2-targeted therapy, irrespective of line of therapy. In patients with HR + /HER2 + disease, median OS was 34.9 months (95%CI:25.8-44.0) for the first line and 12.8 months (95%CI:10.7-14.9) for the fourth line. In HR-/HER2 + disease, median OS was 39.9 months (95%CI:23.9-55.8) for the first line and 15.2 months (95%CI:10.9-19.5) for the fourth line. For patients treated with first-line pertuzumab, trastuzumab plus chemotherapy, median OS was not reached at 56.0 months in HR + /HER2 + disease and 48.4 months (95%CI:32.6-64.3) in HR-/HER2 + disease. CONCLUSION: Survival times for later lines of therapy are surprisingly long and justify the use of multiple lines of systemic therapy in well-selected patients with HER2 + ABC. Our real-world evidence adds valuable observations to the accumulating evidence that within HER2 + ABC, the HR status defines two distinct disease subtypes.

Exploring the Impact of COVID-19 on Women Hospitalists: A Mixed-Gender Qualitative Analysis.

BACKGROUND: Women physicians have faced persistent challenges, including gender bias, salary inequities, a disproportionate share of caregiving and domestic responsibilities, and limited representation in leadership. Data indicate the COVID-19 pandemic further highlighted and exacerbated these inequities. OBJECTIVE: To understand the pandemic's impact on women physicians and to brainstorm solutions to better support women physicians. DESIGN: Mixed-gender semi-structured focus groups. PARTICIPANTS: Hospitalists in the Hospital Medicine Reengineering Network (HOMERuN). APPROACH: Six semi-structured virtual focus groups were held with 22 individuals from 13 institutions comprised primarily of academic hospitalist physicians. Rapid qualitative methods including templated summaries and matrix analysis were applied to identify major themes and subthemes. KEY RESULTS: Four key themes emerged: (1) the pandemic exacerbated perceived gender inequities, (2) women's academic productivity and career development were negatively impacted, (3) women held disproportionate roles as caregivers and household managers, and (4) institutional pandemic responses were often misaligned with workforce needs, especially those of women hospitalists. Multiple interventions were proposed including: creating targeted workforce solutions and benefits to address the disproportionate caregiving burden placed on women, addressing hospitalist scheduling and leave practices, ensuring promotion pathways value clinical and COVID-19 contributions, creating transparency around salary and non-clinical time allocation, and ensuring women are better represented in leadership roles. CONCLUSIONS: Hospitalists perceived and experienced that women physicians faced negative impacts from the pandemic in multiple domains including leadership opportunities and scholarship, while also shouldering larger caregiving duties than men. There are many opportunities to improve workplace conditions for women; however, current institutional efforts were perceived as misaligned to actual needs. Thus, policy and programmatic changes, such as those proposed by this cohort of hospitalists, are needed to advance equity in the workplace.

Delayed circadian rhythms in older Africans living with human immunodeficiency virus (HIV).

The increasing number of people living with human immunodeficiency virus, HIV, (PLWH) have an elevated incidence of risk for noncommunicable comorbidities, the aetiology of which remains incompletely understood. While sleep disturbances are often reported in PLWH, it is unknown to what extent they relate to changes in the circadian and/or sleep homeostatic processes. We studied the relationship between sleep characteristics, circadian phase, and HIV status in older adults from the HAALSI (Health and Ageing in Africa: a Longitudinal Study of an INDEPTH Community in South Africa) subsample of the Agincourt Health and Demographic Surveillance System in South Africa (n = 187, 36 human immunodeficiency virus positive [HIV+], age: 66.7 ± 11.5 years, range 45-93 years), where HIV prevalence is high and (in contrast to the global north) does not associate significantly with potentially confounding behavioural differences. In participants with valid actigraphy data (n = 172), regression analyses adjusted for age and sex indicated that HIV+ participants had slightly later sleep onset (ß = .16, p = .039), earlier sleep offset times (ß = -.16, p = .049) and shorter total sleep times (ß = -.20, p = .009) compared to the HIV negative (HIV-) participants. In a subset of participants (n = 51, 11 HIV+), we observed a later dim light melatonin onset (DLMO) in HIV+ (21:16 ± 01:47) than in HIV- (20:06 ± 00:58) participants (p = .006). This substantial difference remained when adjusted for age and sex (ß = 1.21; p = .006). In 36 participants (6 HIV+) with DLMO and actigraphy data, median phase angle of entrainment was -6 min in the HIV+ group and +1 h 25 min in the HIV- group. DLMO time correlated with sleep offset (ρ = 0.47, p = .005) but not sleep onset (ρ = -0.086, p = .623). Collectively, our data suggest that the sleep phase occurred earlier than what would be biologically optimal among the HIV+ participants. This is the first report of a mistimed circadian phase in PLWH, which has important potential implications for their health and well-being, especially given the well-established relationships between circadian asynchrony and sleep deprivation with poorer health outcomes.

Early plasma angiopoietin-2 is prognostic for ARDS and mortality among critically ill patients with sepsis.

Angiopoietin-2 (Ang-2) is associated with vascular endothelial injury and permeability in the acute respiratory distress syndrome (ARDS) and sepsis. Elevated circulating Ang-2 levels may identify critically ill patients with distinct pathobiology amenable to targeted therapy. We hypothesized that plasma Ang-2 measured shortly after hospitalization among patients with sepsis would be associated with the development of ARDS and poor clinical outcomes. To test this hypothesis, we measured plasma Ang-2 in a cohort of 757 patients with sepsis, including 267 with ARDS, enrolled in the emergency department or early in their ICU course before the COVID-19 pandemic. Multivariable models were used to test the association of Ang-2 with the development of ARDS and 30-day morality. We found that early plasma Ang-2 in sepsis was associated with higher baseline severity of illness, the development of ARDS, and mortality risk. The association between Ang-2 and mortality was strongest among patients with ARDS and sepsis as compared to those with sepsis alone (OR 1.81 vs. 1.52 per log Ang-2 increase). These findings might inform models testing patient risk prediction and strengthen the evidence for Ang-2 as an appealing biomarker for patient selection for novel therapeutic agents to target vascular injury in sepsis and ARDS.

Beyond Clinical Care: The Role of Pediatric Psychology in Supporting Postpartum Depression Screening in Primary Care.

Maternal health is a critical component of optimal child health and development. Consequently, the American Academy of Pediatrics added postpartum depression (PPD) screening to their psychosocial screening guidelines in 2017. The Healthy Mothers, Healthy Children Project (HMHCP) was an interprofessional initiative aimed at preparing for, then implementing and maintaining pediatrician-completed PPD screening at 1-month well visits in a pediatric primary care clinic. Roles of pediatric psychology and rates of PPD screening were examined. Pediatric psychologists actively participated as leaders and collaborators in a variety of non-clinical roles from HMHCP preparation through maintenance. The clinic achieved high and continuously improving PPD screening rates following HMHCP implementation. Importantly, PPD screening rates were equitable across race and gender. The current study outlines feasible non-clinical roles that pediatric psychologists can fulfill in support of routine PPD screening within pediatric primary care. It also highlights associated benefits and outcomes for the clinic, providers, and patients.

The implementation of CDK 4/6 inhibitors and its impact on treatment choices in HR+/HER2- advanced breast cancer patients: A study of the Dutch SONABRE Registry.

In August 2017, cyclin-dependent kinase 4/6 (CDK4/6) inhibitors combined with endocrine therapy have been reimbursed in the Netherlands for patients with hormone receptor positive (HR+), HER2 negative (HER2-) advanced breast cancer (ABC). This study evaluates the implementation of CDK4/6 inhibitors and changes in treatment choices in the Netherlands. All patients diagnosed with HR+/HER2- ABC in 2009 to 2018 in seven hospitals were selected from the Southeast Netherlands Advanced Breast cancer (SONABRE) registry. The 2-year cumulative use of CDK4/6 inhibitors since reimbursement date (August 2017) was assessed using competing-risk methodology in two cohorts. The first cohort included patients with ABC diagnosis between August 2017 and December 2018. The second cohort included patients with ABC diagnosis between 2009 and August 2017, and still alive on August 1, 2017. In addition, treatment choices in the first three lines of therapy in calendar years 2009 to 2018 were evaluated for the total study population. Among patients diagnosed since August 2017 (n = 214), 50% (95% confidence interval [CI] = 43-57) received CDK4/6 inhibitors within 2 years beyond diagnosis. Of eligible patients diagnosed before August 2017 (n = 417), 31% (95% CI = 27-36) received CDK4/6 inhibitors within 2 years following reimbursement. Another 20% of both cohorts are still CDK4/6 inhibitor naïve and on first-line therapy. The use of chemotherapy decreased in first two lines of therapy between 2009 and 2018 (first-line: 29%-13%; second-line: 26%-19%). The implementation rate of CDK4/6 inhibitors since reimbursement is currently 50% within 2 years beyond diagnosis and is expected to increase further. The implementation of targeted therapy decreased the use of chemotherapy as first-line therapy.

Latent class analysis-derived subphenotypes are generalisable to observational cohorts of acute respiratory distress syndrome: a prospective study.

RATIONALE: Using latent class analysis (LCA), two subphenotypes of acute respiratory distress syndrome (ARDS) have consistently been identified in five randomised controlled trials (RCTs), with distinct biological characteristics, divergent outcomes and differential treatment responses to randomised interventions. Their existence in unselected populations of ARDS remains unknown. We sought to identify subphenotypes in observational cohorts of ARDS using LCA. METHODS: LCA was independently applied to patients with ARDS from two prospective observational cohorts of patients admitted to the intensive care unit, derived from the Validating Acute Lung Injury markers for Diagnosis (VALID) (n=624) and Early Assessment of Renal and Lung Injury (EARLI) (n=335) studies. Clinical and biological data were used as class-defining variables. To test for concordance with prior ARDS subphenotypes, the performance metrics of parsimonious classifier models (interleukin 8, bicarbonate, protein C and vasopressor-use), previously developed in RCTs, were evaluated in EARLI and VALID with LCA-derived subphenotypes as the gold-standard. RESULTS: A 2-class model best fit the population in VALID (p=0.0010) and in EARLI (p<0.0001). Class 2 comprised 27% and 37% of the populations in VALID and EARLI, respectively. Consistent with the previously described 'hyperinflammatory' subphenotype, Class 2 was characterised by higher proinflammatory biomarkers, acidosis and increased shock and worse clinical outcomes. The similarities between these and prior RCT-derived subphenotypes were further substantiated by the performance of the parsimonious classifier models in both cohorts (area under the curves 0.92-0.94). The hyperinflammatory subphenotype was associated with increased prevalence of chronic liver disease and neutropenia and reduced incidence of chronic obstructive pulmonary disease. Measurement of novel biomarkers showed significantly higher levels of matrix metalloproteinase-8 and markers of endothelial injury in the hyperinflammatory subphenotype, whereas, matrix metalloproteinase-9 was significantly lower. CONCLUSION: Previously described subphenotypes are generalisable to unselected populations of non-trauma ARDS.

The initial hormone receptor/HER2 subtype is the main determinator of subtype discordance in advanced breast cancer: a study of the SONABRE registry.

PURPOSE: The hormone receptor (HR) and human epidermal growth factor receptor 2 (HER2) are the main parameters in guiding systemic treatment choices in breast cancer, but can change during the disease course. This study aims to evaluate the biopsy rate and receptor subtype discordance rate in patients diagnosed with advanced breast cancer (ABC). METHODS: Patients diagnosed with ABC in seven hospitals in 2007-2018 were selected from the SOutheast Netherlands Advanced BREast cancer (SONABRE) registry. Multivariable logistic regression analyses were performed to identify factors influencing biopsy and discordance rates. RESULTS: Overall, 60% of 2854 patients had a biopsy of a metastatic site at diagnosis. One of the factors associated with a reduced biopsy rate was the HR + /HER2 + primary tumor subtype (versus HR + /HER2- subtype: OR = 0.68; 95% CI: 0.51-0.90). Among the 748 patients with a biopsy of the primary tumor and a metastatic site, the overall receptor discordance rate was 18%. This was the highest for the HR + /HER2 + primary tumor subtype, with 55%. In 624 patients with metachronous metastases, the HR + /HER2 + subtype remained the only predictor significantly related to a higher discordance rate, irrespective of prior (neo-)adjuvant therapies (OR = 7.49; 95% CI: 3.69-15.20). CONCLUSION: The HR + /HER2 + subtype has the highest discordance rate, but the lowest biopsy rate of all four receptor subtypes. Prior systemic therapy was not independently related to subtype discordance. This study highlights the importance of obtaining a biopsy of metastatic disease, especially in the HR + /HER2 + subtype to determine the most optimal treatment strategy.

Adaptability on Shifting Ground: a Rapid Qualitative Assessment of Multi-institutional Inpatient Surge Planning and Workforce Deployment During the COVID-19 Pandemic.

BACKGROUND: During the initial wave of COVID-19 hospitalizations, care delivery and workforce adaptations were rapidly implemented. In response to subsequent surges of patients, institutions have deployed, modified, and/or discontinued their workforce plans. OBJECTIVE: Using rapid qualitative methods, we sought to explore hospitalists' experiences with workforce deployment, types of clinicians deployed, and challenges encountered with subsequent iterations of surge planning during the COVID-19 pandemic across a collaborative of hospital medicine groups. APPROACH: Using rapid qualitative methods, focus groups were conducted in partnership with the Hospital Medicine Reengineering Network (HOMERuN). We interviewed physicians, advanced practice providers (APP), and physician researchers about (1) ongoing adaptations to the workforce as a result of the COVID-19 pandemic, (2) current struggles with workforce planning, and (3) evolution of workforce planning. KEY RESULTS: We conducted five focus groups with 33 individuals from 24 institutions, representing 52% of HOMERuN sites. A variety of adaptations was described by participants, some common across institutions and others specific to the institution's location and context. Adaptations implemented shifted from the first waves of COVID patients to subsequent waves. Three global themes also emerged: (1) adaptability and comfort with dynamic change, (2) the importance of the unique hospitalist skillset for effective surge planning and redeployment, and (3) the lack of universal solutions. CONCLUSIONS: Hospital workforce adaptations to the COVID pandemic continued to evolve. While few approaches were universally effective in managing surges of patients, and successful adaptations were highly context dependent, the ability to navigate a complex system, adaptability, and comfort in a chaotic, dynamic environment were themes considered most critical to successful surge management. However, resource constraints and sustained high workload levels raised issues of burnout.

Metabolic rate increases with acclimation temperature and is associated with mitochondrial function in some tissues of threespine stickleback.

The metabolic rate (MO2) of eurythermal fishes changes in response to temperature, yet it is unclear how changes in mitochondrial function contribute to changes in MO2. We hypothesized that MO2 would increase with acclimation temperature in the threespine stickleback (Gasterosteus aculeatus) in parallel with metabolic remodeling at the cellular level but that changes in metabolism in some tissues, such as liver, would contribute more to changes in MO2 than others. Threespine stickleback were acclimated to 5, 12 and 20°C for 7 to 21 weeks. At each temperature, standard and maximum metabolic rate (SMR and MMR, respectively), and absolute aerobic scope (AAS) were quantified, along with mitochondrial respiration rates in liver, oxidative skeletal and cardiac muscles, and the maximal activity of citrate synthase (CS) and lactate dehydrogenase (LDH) in liver, and oxidative and glycolytic skeletal muscles. SMR, MMR and AAS increased with acclimation temperature, along with rates of mitochondrial phosphorylating respiration in all tissues. Low SMR and MMR at 5°C were associated with low or undetectable rates of mitochondrial complex II activity and a greater reliance on complex I activity in liver, oxidative skeletal muscle and heart. SMR was positively correlated with cytochrome c oxidase (CCO) activity in liver and oxidative muscle, but not mitochondrial proton leak, whereas MMR was positively correlated with CCO activity in liver. Overall, the results suggest that changes in MO2 in response to temperature are driven by changes in some aspects of mitochondrial function in some, but not all, tissues of threespine stickleback.