The PARTNER trial of neoadjuvant olaparib with chemotherapy in triple-negative breast cancer.

PARTNER is a prospective, phase II-III, randomized controlled clinical trial that recruited patients with triple-negative breast cancer1,2, who were germline BRCA1 and BRCA2 wild type3. Here we report the results of the trial. Patients (n = 559) were randomized on a 1:1 basis to receive neoadjuvant carboplatin-paclitaxel with or without 150 mg olaparib twice daily, on days 3 to 14, of each of four cycles (gap schedule olaparib, research arm) followed by three cycles of anthracycline-based chemotherapy before surgery. The primary end point was pathologic complete response (pCR)4, and secondary end points included event-free survival (EFS) and overall survival (OS)5. pCR was achieved in 51% of patients in the research arm and 52% in the control arm (P = 0.753). Estimated EFS at 36 months in the research and control arms was 80% and 79% (log-rank P > 0.9), respectively; OS was 90% and 87.2% (log-rank P = 0.8), respectively. In patients with pCR, estimated EFS at 36 months was 90%, and in those with non-pCR it was 70% (log-rank P < 0.001), and OS was 96% and 83% (log-rank P < 0.001), respectively. Neoadjuvant olaparib did not improve pCR rates, EFS or OS when added to carboplatin-paclitaxel and anthracycline-based chemotherapy in patients with triple-negative breast cancer who were germline BRCA1 and BRCA2 wild type. ClinicalTrials.gov ID: NCT03150576 .

Multi-omic machine learning predictor of breast cancer therapy response.

Breast cancers are complex ecosystems of malignant cells and the tumour microenvironment1. The composition of these tumour ecosystems and interactions within them contribute to responses to cytotoxic therapy2. Efforts to build response predictors have not incorporated this knowledge. We collected clinical, digital pathology, genomic and transcriptomic profiles of pre-treatment biopsies of breast tumours from 168 patients treated with chemotherapy with or without HER2 (encoded by ERBB2)-targeted therapy before surgery. Pathology end points (complete response or residual disease) at surgery3 were then correlated with multi-omic features in these diagnostic biopsies. Here we show that response to treatment is modulated by the pre-treated tumour ecosystem, and its multi-omics landscape can be integrated in predictive models using machine learning. The degree of residual disease following therapy is monotonically associated with pre-therapy features, including tumour mutational and copy number landscapes, tumour proliferation, immune infiltration and T cell dysfunction and exclusion. Combining these features into a multi-omic machine learning model predicted a pathological complete response in an external validation cohort (75 patients) with an area under the curve of 0.87. In conclusion, response to therapy is determined by the baseline characteristics of the totality of the tumour ecosystem captured through data integration and machine learning. This approach could be used to develop predictors for other cancers.

Nucleation of fibronectin fibril assembly requires binding between heparin and the 13th type III module of fibronectin.

Fibronectin (FN), a critical component of the extracellular matrix, is assembled into fibrils through a cell-mediated process. Heparan sulfate (HS) binds to the III13 module of FN, and fibroblasts lacking this glycosaminoglycan exhibit reduced FN fibril assembly. To determine if HS depends on III13 to control FN assembly, we deleted both III13 alleles in NIH 3T3 cells using the CRISPR-Cas9 system. ΔIII13 cells assembled fewer FN matrix fibrils and less DOC-insoluble FN matrix than wildtype cells. Little if any mutant FN matrix was assembled when purified ΔIII13 FN was provided to Chinese hamster ovary (CHO) cells, showing that lack of III13 caused the deficiency in assembly by ΔIII13 cells. Addition of heparin promoted the assembly of wildtype FN by CHO cells, but it had no effect on the assembly of ΔIII13 FN. Furthermore, heparin binding stabilized the folded conformation of III13 and prevented it from self-associating with increasing temperature suggesting that stabilization by HS/heparin binding might regulate interactions between III13 and other FN modules. This effect would be particularly important at matrix assembly sites where our data show that ΔIII13 cells require both exogenous wildtype FN and heparin in the culture medium to maximize assembly site formation. Our results show that heparin-promoted growth of fibril nucleation sites is dependent on III13. We conclude that HS/heparin binds to III13 to promote and control the nucleation and development of FN fibrils.

A new mechanism of fibronectin fibril assembly revealed by live imaging and super-resolution microscopy.

Fibronectin (Fn1) fibrils have long been viewed as continuous fibers composed of extended, periodically aligned Fn1 molecules. However, our live-imaging and single-molecule localization microscopy data are inconsistent with this traditional view and show that Fn1 fibrils are composed of roughly spherical nanodomains containing six to eleven Fn1 dimers. As they move toward the cell center, Fn1 nanodomains become organized into linear arrays, in which nanodomains are spaced with an average periodicity of 105±17 nm. Periodical Fn1 nanodomain arrays can be visualized between cells in culture and within tissues; they are resistant to deoxycholate treatment and retain nanodomain periodicity in the absence of cells. The nanodomain periodicity in fibrils remained constant when probed with antibodies recognizing distinct Fn1 epitopes or combinations of antibodies recognizing epitopes spanning the length of Fn1. Treatment with FUD, a peptide that binds the Fn1 N-terminus and disrupts Fn1 fibrillogenesis, blocked the organization of Fn1 nanodomains into periodical arrays. These studies establish a new paradigm of Fn1 fibrillogenesis. This article has an associated First Person interview with the first author of the paper.

Experimental phase diagram and its temporal evolution for submicron 2-methylglutaric acid and ammonium sulfate aerosol particles.

Liquid-liquid phase separation (LLPS) in aerosol particles is important for the climate system due to its potential to impact heterogeneous chemistry, cloud condensation nuclei, and new particle growth. Our group and others have shown a lower separation relative humidity for submicron particles, but whether the suppression is due to thermodynamics or kinetics is unclear. Herein, we characterize the experimental LLPS phase diagram of submicron 2-methylglutaric acid and ammonium sulfate aerosol particles and compare it to that of supermicron-sized particles. Surprisingly, as the equilibration time of submicron-sized aerosol particles was increased from 20 min to 60 min, the experimental phase diagram converges with the results for supermicron-sized particles. Our findings indicate that nucleation kinetics are responsible for the observed lower separation relative humidities in submicron aerosol particles. Therefore, experiments and models that investigate atmospheric processes of organic aerosol particles may need to consider the temporal evolution of aerosol LLPS.

Assembly of fibronectin extracellular matrix.

In the process of matrix assembly, multivalent extracellular matrix (ECM) proteins are induced to self-associate and to interact with other ECM proteins to form fibrillar networks. Matrix assembly is usually initiated by ECM glycoproteins binding to cell surface receptors, such as fibronectin (FN) dimers binding to α5ß1 integrin. Receptor binding stimulates FN self-association mediated by the N-terminal assembly domain and organizes the actin cytoskeleton to promote cell contractility. FN conformational changes expose additional binding sites that participate in fibril formation and in conversion of fibrils into a stabilized, insoluble form. Once assembled, the FN matrix impacts tissue organization by contributing to the assembly of other ECM proteins. Here, we describe the major steps, molecular interactions, and cellular mechanisms involved in assembling FN dimers into fibrillar matrix while highlighting important issues and major questions that require further investigation.

Using a Mock Circulatory Loop as a Regulatory Science Tool to Simulate Different Heart Failure Conditions.

Mechanical circulatory support (MCS) device therapy is one of the primary treatment options for end-stage heart failure (HF), whereby a mechanical pump is integrated with the failing heart to maintain adequate tissue perfusion. The ISO 14708-5:2020 standard prescribes generic guidelines for nonclinical device evaluation and system performance testing of MCS devices using a mock circulatory loop (MCL). However, the utility of MCLs in premarket regulatory submissions of MCS devices is ambiguous, and the specific disease states that the device is intended to treat are not usually simulated. Hence, we aim to outline the potential of MCLs as a valuable regulatory science tool for characterizing MCS device systems by adequately representing target clinical-use HF conditions on the bench. Target pathophysiologic hemodynamics of HF conditions (i.e., cardiogenic shock (CS), left ventricular (LV) hypertrophy secondary to hypertension, and coronary artery disease), along with a healthy adult at rest and a healthy adult during exercise are provided as recommended test conditions. The conditions are characterized based on LV, aorta, and left atrium pressures using recommended cardiac hemodynamic indices such as systolic, diastolic, and mean arterial pressure, mean cardiac output (CO), cardiac cycle time, and systemic vascular resistance. This study is a first step toward standardizing MCLs to generate well-defined target HF conditions used to evaluate MCS devices.

Facilitating the transition to residency: A resident-as-coach pilot program.

BACKGROUND: The transition from medical school to residency is a critical developmental phase; coaching may help students prepare for this role transition. AIMS: We explored whether near-peer coaching could improve a specific workplace skill prior to residency. METHODS: A resident-as-coach program was piloted for the medicine sub-internship, an advanced acting internship rotation. Between March and June 2021, 26 students were assigned a resident coach (n = 16). Resident coaches completed one training session, and student-coach dyads met for one coaching session on 'pre-rounding'- gathering patient data before rounds. The program was evaluated through surveys and focus groups. RESULTS: 20/26 students and 14/16 residents completed the survey. 19/20 students identified a pre-rounding challenge and reported increased pre-rounding efficiency; all committed to one actionable step for improvement. All 16 residents felt their coaching skills improved. In focus groups, students valued the program's focus on honing a relevant skill in a safe, near-peer setting. Residents expressed their intent to incorporate coaching into their future work. CONCLUSIONS: A resident-as-coach model can be effective in preparing students for residency, while concurrently building residents' coaching skills.

Closing the empathy gap in health care: Connection First - before "intake".

In this article, a communication framework of Connection First is presented to help close the empathy gap in mainstream health care, including palliative and end-of-life care. Expanding beyond biomedicine, Connection First involves rethinking and restructuring business-as-usual in health care. It shifts the typical transactional process during the initial intake session into one that is transformational. Connection First is a structural intervention and skillset comprised of the following elements: disrupting diagnosis, humanizing history, and repairing ruptures. These elements combine to help close the empathy gap in health care during the initial clinical encounter, before intake, and improve outcomes.

Heparan sulfate is necessary for the early formation of nascent fibronectin and collagen I fibrils at matrix assembly sites.

Fibronectin (FN), an essential component of the extracellular matrix (ECM), is assembled via a cell-mediated process in which integrin receptors bind secreted FN and mediate its polymerization into fibrils that extend between cells, ultimately forming an insoluble matrix. Our previous work using mutant Chinese hamster ovary (CHO) cells identified the glycosaminoglycan heparan sulfate (HS) and its binding to FN as essential for the formation of insoluble FN fibrils. In this study, we investigated the contributions of HS at an early stage of the assembly process using knockdown of exostosin-1 (EXT1), one of the glycosyltransferases required for HS chain synthesis. NIH 3T3 fibroblasts with decreased EXT1 expression exhibited a significant reduction in both FN and type I collagen in the insoluble matrix. We show that FN fibril formation is initiated at matrix assembly sites, and while these sites were formed by cells with EXT1 knockdown, their growth was stunted compared with wild-type cells. The most severe defect observed was in the polymerization of nascent FN fibrils, which was reduced 2.5-fold upon EXT1 knockdown. This defect was rescued by the addition of exogenous soluble heparin chains long enough to simultaneously bind multiple FN molecules. The activity of soluble heparin in this process indicates that nascent fibril formation depends on HS more so than on the protein component of a specific HS proteoglycan. Together, our results suggest that heparin or HS is necessary for concentrating and localizing FN molecules at sites of early fibril assembly.

External Validation of the UTICalc with and Without Race for Pediatric Urinary Tract Infection.

OBJECTIVE: To validate externally the UTICalc, a popular clinical decision support tool used to determine the risk of urinary tract infections (UTIs) in febrile children, and compare its performance with and without the inclusion of race and at differing risk thresholds. METHODS: We performed a retrospective, singlecenter case-control study of febrile children (2-24 months) in an emergency department. Cases with culture-confirmed UTI were matched 1:1 to controls. We compared the performance of the original model which included race (version 1.0) to a revised model which did not consider race (version 3.0). We evaluated model performance at risk thresholds between 2% and 5%. RESULTS: We included 185 cases and 197 controls (median age 8.4 months; IQR, 4.4-13.0 months; 60.5% girls). When using UTICalc version 1.0, the model area under the receiver operator characteristic curve (AUROC) was 73.4% (95% CI 68.4%-78.5%), which was similar to the version 3.0 model (73.8%; 95% CI 68.7%-78.8%). When using a 2% risk threshold, the version 3.0 model demonstrated a sensitivity of 96.7% and a specificity of 25.0%, with declines in sensitivity and gains in specificity at higher risk thresholds. Version 1.0 of the UTICalc had 12 false negatives, of whom 10 were Black (83%); whereas version 3.0 had 6 false negatives, of whom 2 were Black (33%). CONCLUSIONS: Versions of the UTICalc with and without race had similar performance to each other with a slight decline from the original derivation sample. The removal of race did not adversely affect the accuracy of the UTICalc.

A longitudinal study of creatine kinase and creatinine levels in Duchenne muscular dystrophy.

INTRODUCTION/AIMS: Management of Duchenne muscular dystrophy (DMD) has entered an era featuring novel treatments. Trackable noninvasive biomarkers could improve disease progression monitoring and drug effect detection. Our aim in this study was to measure changes in selected noninvasive biomarkers and assess their relationship to age and motor function. METHODS: We retrospectively studied 555 patients with DMD who had at least 12 months of treatment of glucocorticoids and were not enrolled in trials of potential disease-modifying therapies. We extracted biomarker data of serum creatine kinase (CK), serum creatinine (Cr), urine Cr, and urine Cr/urine osmolality (osm), as well as functional data for age at loss of ambulation and Functional Motor Scale (FMS) values from patients' clinical records. Data were analyzed using linear mixed-model analyses. RESULTS: CK, serum Cr, urine Cr, and urine Cr/urine osm all decreased with declining motor function. CK consistently decreased and FMS score consistently worsened with age without clear inflection points. There was an increased odds ratio for LOA with lower values of CK, serum Cr, urine Cr, and urine Cr/urine osm, most notably for urine Cr. DISCUSSION: Although individual biomarker values are challenging to directly apply clinically, our study has demonstrated that trends over time may complement functional measures in the assessment of individuals with DMD. Future studies could elucidate predictive utility of these biomarkers in assessing motor function changes in DMD.

Periodontitis and metabolic diseases (diabetes and obesity): Tackling multimorbidity.

Noncommunicable diseases (NCDs) are multifactorial, long-term, chronic conditions that represent a burden to health-care systems worldwide as they can only be controlled rather than cured; hence, they require long-term care. With the exponential increase in NCDs, the occurrence of individuals presenting with more than one chronic disease is also rapidly rising. "Multimorbidity," defined as the presence of two or more long-term physical or mental disorders, is now considered a worldwide epidemic, affecting around 20% of the adult population. Periodontitis, diabetes, and obesity, all chronic inflammatory diseases, are an example of multimorbidity highly relevant to dental practitioners. Over the last three decades, the three-way relationship among the diseases has been vastly researched and accepted, with important contributions by European researchers. The interplay among periodontitis, diabetes, and obesity is sustained by shared biological mechanisms, such as systemic inflammation, insulin resistance, and metabolic dysfunction, as well as common lifestyle-related risk factors. As such, unhealthy lifestyles were found to generally increase systemic inflammation and insulin resistance and decrease immune function, hence, eventually increasing the risk of NCDs onset and the development of multimorbidity. This narrative review of the evidence supports the need for a paradigm shift from a "single-disease" to a "multiple-disease" framework, characterized by an integrated multidisciplinary approach, which should include lifestyle modification interventions to successfully tackle multimorbid periodontitis and metabolic diseases (diabetes and obesity). A multidisciplinary integrated care pathway in both dental and medical settings should be considered to further tackle the global health challenge of multimorbidity.

Assessing the impact of rainwater harvesting infrastructure and gardening trends on microbial indicator organism presence in harvested rainwater and garden soils.

AIM: To assess the microbial water quality of harvested rainwater infrastructure used to supplement household water uses for homegrown produce. METHODS AND RESULTS: Using a co-created community science methodology, between 2017 and 2020, a total of 587 harvested rainwater samples and 147 garden soil samples irrigated with harvested rainwater were collected from four Arizona communities and analyzed for coliform, Escherichia coli, and/or Salmonella. Participants also completed a home description survey regarding their home and surrounding area, water harvesting infrastructure, and gardening habits. CONCLUSION: Chi-Square tests revealed that the quality of harvested rainwater is affected by proximity to a waste disposal or incineration facility, animal presence, cistern treatment, and cistern age (P < 0.05), while soil samples were associated with community (P < 0.05). Coliform and E. coli concentrations in both sample types were greater in the monsoon season.

LACTB is a tumour suppressor that modulates lipid metabolism and cell state.

Post-mitotic, differentiated cells exhibit a variety of characteristics that contrast with those of actively growing neoplastic cells, such as the expression of cell-cycle inhibitors and differentiation factors. We hypothesized that the gene expression profiles of these differentiated cells could reveal the identities of genes that may function as tumour suppressors. Here we show, using in vitro and in vivo studies in mice and humans, that the mitochondrial protein LACTB potently inhibits the proliferation of breast cancer cells. Its mechanism of action involves alteration of mitochondrial lipid metabolism and differentiation of breast cancer cells. This is achieved, at least in part, through reduction of the levels of mitochondrial phosphatidylserine decarboxylase, which is involved in the synthesis of mitochondrial phosphatidylethanolamine. These observations uncover a novel mitochondrial tumour suppressor and demonstrate a connection between mitochondrial lipid metabolism and the differentiation program of breast cancer cells, thereby revealing a previously undescribed mechanism of tumour suppression.

Effects of chronotype-tailored bright light intervention on post-treatment symptoms and quality of life in breast cancer survivors.

PURPOSE: Bright light therapy holds promise for reducing common symptoms, e.g., fatigue, experienced by individuals with cancer. This study aimed to examine the effects of a chronotype-tailored bright light intervention on sleep disturbance, fatigue, depressive mood, cognitive dysfunction, and quality of life among post-treatment breast cancer survivors. METHODS: In this two-group randomized controlled trial (NCT03304587), participants were randomized to receive 30-min daily bright blue-green light (12,000 lx) or dim red light (5 lx) either between 19:00 and 20:00 h or within 30 min of waking in the morning. Self-reported outcomes and in-lab overnight polysomnography sleep study were assessed before (pre-test) and after the 14-day light intervention (post-test). RESULTS: The sample included 30 women 1-3 years post-completion of chemotherapy and/or radiation for stage I to III breast cancer (mean age = 52.5 ± 8.4 years). There were no significant between-group differences in any of the symptoms or quality of life (all p > 0.05). However, within each group, self-reported sleep disturbance, fatigue, depressive mood, cognitive dysfunction, and quality of life-related functioning showed significant improvements over time (all p < 0.05); the extent of improvement for fatigue and depressive mood was clinically relevant. Polysomnography sleep findings showed that a number of awakenings significantly decreased (p = 0.011) among participants who received bright light, while stage 2 sleep significantly increased (p = 0.015) among participants who received dim-red light. CONCLUSION: The findings support using light therapy to manage post-treatment symptoms in breast cancer survivors. The unexpected symptom improvements among dim-red light controls remain unexplained and require further investigation. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03304587, October 19, 2017.

Correlations among common emergency medicine physician performance measures: Mixed messages or balancing forces?

The increasing complexity of ED physician performance measures has resulted in significant challenges, including duplicative and conflicting measures that fail to account for different ED settings. We performed a cross sectional analysis of correlations between measures to characterize their relationships and determine if differences exist between academic versus non-academic ED settings. Pearson correlations were calculated for 12 measures among 220 ED physicians at 11 EDs. Higher admission rate was strongly correlated with higher CT utilization rate (R = 0.7, p < 0.01) and longer room to discharge time (R = 0.7, p < 0.01). Higher patients per hour was strongly correlated with shorter room to doctor time (R = -0.7, p < 0.01). Stronger measure correlations were found in the academic setting compared to the non-academic setting. Strong correlations between ED measures imply opportunities to reduce competing performance demands on clinicians. Differences in correlations at academic versus non-academic settings suggest that it may be inappropriate to apply the same performance standards across settings.

Imaging breast cancer using hyperpolarized carbon-13 MRI.

Our purpose is to investigate the feasibility of imaging tumor metabolism in breast cancer patients using 13C magnetic resonance spectroscopic imaging (MRSI) of hyperpolarized 13C label exchange between injected [1-13C]pyruvate and the endogenous tumor lactate pool. Treatment-naïve breast cancer patients were recruited: four triple-negative grade 3 cancers; two invasive ductal carcinomas that were estrogen and progesterone receptor-positive (ER/PR+) and HER2/neu-negative (HER2-), one grade 2 and one grade 3; and one grade 2 ER/PR+ HER2- invasive lobular carcinoma (ILC). Dynamic 13C MRSI was performed following injection of hyperpolarized [1-13C]pyruvate. Expression of lactate dehydrogenase A (LDHA), which catalyzes 13C label exchange between pyruvate and lactate, hypoxia-inducible factor-1 (HIF1α), and the monocarboxylate transporters MCT1 and MCT4 were quantified using immunohistochemistry and RNA sequencing. We have demonstrated the feasibility and safety of hyperpolarized 13C MRI in early breast cancer. Both intertumoral and intratumoral heterogeneity of the hyperpolarized pyruvate and lactate signals were observed. The lactate-to-pyruvate signal ratio (LAC/PYR) ranged from 0.021 to 0.473 across the tumor subtypes (mean ± SD: 0.145 ± 0.164), and a lactate signal was observed in all of the grade 3 tumors. The LAC/PYR was significantly correlated with tumor volume (R = 0.903, P = 0.005) and MCT 1 (R = 0.85, P = 0.032) and HIF1α expression (R = 0.83, P = 0.043). Imaging of hyperpolarized [1-13C]pyruvate metabolism in breast cancer is feasible and demonstrated significant intertumoral and intratumoral metabolic heterogeneity, where lactate labeling correlated with MCT1 expression and hypoxia.

Providing Human Support for the Use of Digital Mental Health Interventions: Systematic Meta-review.

BACKGROUND: Digital mental health interventions (DMHIs) have been increasingly deployed to bridge gaps in mental health care, particularly given their promising efficacy. Nevertheless, attrition among DMHI users remains high. In response, human support has been studied as a means of improving retention to and outcomes of DMHIs. Although a growing number of studies and meta-analyses have investigated the effects of human support for DMHIs on mental health outcomes, systematic empirical evidence of its effectiveness across mental health domains remains scant. OBJECTIVE: We aimed to summarize the results of meta-analyses of human support versus no support for DMHI use across various outcome domains, participant samples, and support providers. METHODS: We conducted a systematic meta-review of meta-analyses, comparing the effects of human support with those of no support for DMHI use, with the goal of qualitatively summarizing data across various outcome domains, participant samples, and support providers. We used MEDLINE, PubMed, and PsycINFO electronic databases. Articles were included if the study had a quantitative meta-analysis study design; the intervention targeted mental health symptoms and was delivered via a technology platform (excluding person-delivered interventions mediated through telehealth, text messages, or social media); the outcome variables included mental health symptoms such as anxiety, depression, stress, posttraumatic stress disorder symptoms, or a number of these symptoms together; and the study included quantitative comparisons of outcomes in which human support versus those when no or minimal human support was provided. RESULTS: The results of 31 meta-analyses (505 unique primary studies) were analyzed. The meta-analyses reported 45 effect sizes; almost half (n=22, 48%) of them showed that human-supported DMHIs were significantly more effective than unsupported DMHIs. A total of 9% (4/45) of effect sizes showed that unsupported DMHIs were significantly more effective. No clear patterns of results emerged regarding the efficacy of human support for the outcomes assessed (including anxiety, depression, posttraumatic stress disorder, stress, and multiple outcomes). Human-supported DMHIs may be more effective than unsupported DMHIs for individuals with elevated mental health symptoms. There were no clear results regarding the type of training for those providing support. CONCLUSIONS: Our findings highlight the potential of human support in improving the effects of DMHIs. Specifically, evidence emerged for stronger effects of human support for individuals with greater symptom severity. There was considerable heterogeneity across meta-analyses in the level of detail regarding the nature of the interventions, population served, and support delivered, making it difficult to draw strong conclusions regarding the circumstances under which human support is most effective. Future research should emphasize reporting detailed descriptions of sample and intervention characteristics and describe the mechanism through which they believe the coach will be most useful for the DMHI.