Lasofoxifene as a potential treatment for aromatase inhibitor-resistant ER-positive breast cancer.

BACKGROUND: Breast cancers treated with aromatase inhibitors (AIs) can develop AI resistance, which is often driven by estrogen receptor-alpha (ERα/ESR1) activating mutations, as well as by ER-independent signaling pathways. The breast ER antagonist lasofoxifene, alone or combined with palbociclib, elicited antitumor activities in a xenograft model of ER + metastatic breast cancer (mBC) harboring ESR1 mutations. The current study investigated the activity of LAS in a letrozole-resistant breast tumor model that does not have ESR1 mutations. METHODS: Letrozole-resistant, MCF7 LTLT cells tagged with luciferase-GFP were injected into the mammary duct inguinal glands of NSG mice (MIND model; 6 mice/group). Mice were randomized to vehicle, lasofoxifene ± palbociclib, fulvestrant ± palbociclib, or palbociclib alone 2-3 weeks after cell injections. Tumor growth and metastases were monitored with in vivo and ex vivo luminescence imaging, terminal tumor weight measurements, and histological analysis. The experiment was repeated with the same design and 8-9 mice in each treatment group. RESULTS: Western blot analysis showed that the MCF7 LTLT cells had lower ERα and higher HER2 expressions compared with normal MCF7 cells. Lasofoxifene ± palbociclib, but not fulvestrant, significantly reduced primary tumor growth versus vehicle as assessed by in vivo imaging of tumors at study ends. Percent tumor area in excised mammary glands was significantly lower for lasofoxifene plus palbociclib versus vehicle. Ki67 staining showed decreased overall tumor cell proliferation with lasofoxifene ± palbociclib. The lasofoxifene + palbociclib combination was also associated with significantly fewer bone metastases compared with vehicle. Similar results were observed in the repeat experiment. CONCLUSIONS: In a mouse model of letrozole-resistant breast cancer with no ESR1 mutations, reduced levels of ERα, and overexpression of HER2, lasofoxifene alone or combined with palbociclib inhibited primary tumor growth more effectively than fulvestrant. Lasofoxifene plus palbociclib also reduced bone metastases. These results suggest that lasofoxifene alone or combined with a CDK4/6 inhibitor may offer benefits to patients who have ER-low and HER2-positive, AI-resistant breast cancer, independent of ESR1 mutations.

Contributions of loneliness to cognitive impairment and dementia in older adults are independent of other risk factors and Alzheimer's pathology: a narrative review.

Loneliness significantly contributes to cognitive impairment and dementia in older adults. Loneliness is a distressing feeling resulting from a perceived lack of social connection (i.e., a discrepancy between desired and actual social relationships), while social isolation is a related term that can be defined by number and type of social relationships. Importantly, loneliness is distinct from social isolation in that it is associated with a distressing self-perception. The primary focus of this narrative review is the impact of chronic loneliness on cognitive impairment and dementia among older adults. Loneliness has a significant association with many factors that are related to worse cognition, and therefore we include discussion on health, mental health, as well as the physiological effects of loneliness, neuropathology, and potential treatments. Loneliness has been shown to be related to development of dementia with a hazard ratio (HR) risk comparable to having a single APOE4 gene. The relationship of dementia to loneliness appears to be at least partially independent of other known dementia risk factors that are possibly associated with loneliness, such as depression, educational status, social isolation, and physical activity. Episodic memory is not consistently impacted by loneliness, which would be more typically impaired if the mild cognitive impairment (MCI) or dementia was due to Alzheimer's disease (AD) pathology. In addition, the several longitudinal studies that included neuropathology showed no evidence for a relationship between loneliness and AD neuropathology. Loneliness may decrease resilience, or produce greater cognitive change associated with the same level of AD neuropathology. Intervention strategies to decrease loneliness in older adults have been developed but need to consider key treatment targets beyond social isolation. Loneliness needs to be assessed in all studies of cognitive decline in elders, since it significantly contributes to the variance of cognitive function. It will be useful to better define the underlying mechanism of loneliness effects on cognition to determine if it is similar to other psychological factors related to excessive stress reactivity, such as neuroticism or even depression, which are also associated with cognitive decline. It is important from a health perspective to develop better strategies to decrease loneliness in older adults.

Testing the Validity and Reliability of a Standardized Virtual Examination for Concussion.

Background and Objectives: We determined inter-modality (in-person vs telemedicine examination) and inter-rater agreement for telemedicine assessments (2 different examiners) using the Telemedicine Buffalo Concussion Physical Examination (Tele-BCPE), a standardized concussion examination designed for remote use. Methods: Patients referred for an initial evaluation for concussion were invited to participate. Participants had a brief initial assessment by the treating neurologist. After a patient granted informed consent to participate in the study, the treating neurologist obtained a concussion-related history before leaving the examination room. Using the Tele-BCPE, 2 virtual examinations in no specific sequence were then performed from nearby rooms by the treating neurologist and another neurologist. After the 2 telemedicine examinations, the treating physician returned to the examination room to perform the in-person examination. Intraclass correlation coefficients (ICC) determined inter-modality validity (in-person vs remote examination by the same examiner) and inter-rater reliability (between remote examinations done by 2 examiners) of overall scores of the Tele-BCPE within the comparison datasets. Cohen's kappa, κ, measured levels of agreement of dichotomous ratings (abnormality present vs absent) on individual components of the Tele-BCPE to determine inter-modality and inter-rater agreement. Results: For total scores of the Tele-BCPE, both inter-modality agreement (ICC = 0.95 [95% CI 0.86-0.98, p < 0.001]) and inter-rater agreement (ICC = 0.88 [95% CI 0.71-0.95, p < 0.001]) were reliable (ICC >0.70). There was at least substantial inter-modality agreement (κ ≥ 0.61) for 25 of 29 examination elements. For inter-rater agreement (2 telemedicine examinations), there was at least substantial agreement for 8 of 29 examination elements. Discussion: Our study demonstrates that the Tele-BCPE yielded consistent clinical results, whether conducted in-person or virtually by the same examiner, or when performed virtually by 2 different examiners. The Tele-BCPE is a valid indicator of neurologic examination findings as determined by an in-person concussion assessment. The Tele-BCPE may also be performed with excellent levels of reliability by neurologists with different training and backgrounds in the virtual setting. These findings suggest that a combination of in-person and telemedicine modalities, or involvement of 2 telemedicine examiners for the same patient, can provide consistent concussion assessments across the continuum of care.

A convenient model of serum-induced reactivity of human astrocytes to investigate astrocyte-derived extracellular vesicles.

Extracellular vesicles (EVs) are secreted by all cells in the CNS, including neurons and astrocytes. EVs are lipid membrane enclosed particles loaded with various bioactive cargoes reflecting the dynamic activities of cells of origin. In contrast to neurons, the specific role of EVs released by astrocytes is less well understood, partly due to the difficulty in maintaining primary astrocyte cultures in a quiescent state. The aim of this study was to establish a human serum-free astrocyte culture system that maintains primary astrocytes in a quiescent state to study the morphology, function, and protein cargoes of astrocyte-derived EVs. Serum-free medium with G5 supplement and serum-supplemented medium with 2% FBS were compared for the culture of commercially available human primary fetal astrocytes. Serum-free astrocytes displayed morphologies similar to in vivo astrocytes, and surprisingly, higher levels of astrocyte markers compared to astrocytes chronically cultured in FBS. In contrast, astrocyte and inflammatory markers in serum-free astrocytes were upregulated 24 h after either acute 2% FBS or cytokine exposure, confirming their capacity to become reactive. Importantly, this suggests that distinct signaling pathways are involved in acute and chronic astrocyte reactivity. Despite having a similar morphology, chronically serum-cultured astrocyte-derived EVs (ADEVs) were smaller in size compared to serum-free ADEVs and could reactivate serum-free astrocytes. Proteomic analysis identified distinct protein datasets for both types of ADEVs with enrichment of complement and coagulation cascades for chronically serum-cultured astrocyte-derived EVs, offering insights into their roles in the CNS. Collectively, these results suggest that human primary astrocytes cultured in serum-free medium bear similarities with in vivo quiescent astrocytes and the addition of serum induces multiple morphological and transcriptional changes that are specific to human reactive astrocytes and their ADEVs. Thus, more emphasis should be made on using multiple structural, molecular, and functional parameters when evaluating ADEVs as biomarkers of astrocyte health.

Microscopic Small Airway Abnormalities Identified in Early Idiopathic Pulmonary Fibrosis In Vivo Using Endobronchial Optical Coherence Tomography.

RATIONALE: Idiopathic pulmonary fibrosis (IPF) affects subpleural lung, but is considered to spare small airways. Micro-CT studies demonstrated small airway reduction in end-stage IPF explanted lungs, raising questions about small airway involvement in early-stage disease. Endobronchial optical coherence tomography (EB-OCT) is a volumetric imaging modality that detects microscopic features from subpleural to proximal airways. We use EB-OCT to evaluate small airways in early IPF and control subjects in vivo. METHODS: EB-OCT was performed in 12 IPF and 5 control subjects (matched by age, sex, smoking-history, height, BMI). IPF subjects had early disease with mild restriction (FVC: 83.5% predicted), diagnosed per current guidelines and confirmed by surgical biopsy. EB-OCT volumetric imaging was acquired bronchoscopically in multiple, distinct, bilateral lung locations (total: 97 sites). IPF imaging sites were classified by severity into affected (all criteria for UIP present) and less affected (some but not all criteria for UIP present) sites. Bronchiole count and small airway stereology metrics were measured for each EB-OCT imaging site. RESULTS: Compared to control subjects (mean: 11.2 bronchioles/cm3; SD: 6.2), there was significant bronchiole reduction in IPF subjects (42% loss; mean: 6.5/cm3; SD: 3.4; p=0.0039), including in IPF affected (48% loss; mean: 5.8/cm3; SD: 2.8; p<0.00001) and IPF less affected (33% loss; mean: 7.5/cm3; SD: 4.1; p=0.024) sites. Stereology metrics showed IPF affected small airways were significantly larger and more distorted/irregular than in IPF less affected sites and control subjects. IPF less affected and control airways were statistically indistinguishable for all stereology parameters (p=0.36-1.0). CONCLUSION: EB-OCT demonstrated marked bronchiolar loss in early IPF (between 30 and 50%), even in areas minimally affected by disease, compared to matched controls. These findings support small airway disease as a feature of early IPF, providing novel insight into pathogenesis and potential therapeutic targets.

Liver Transplant Costs and Activity After United Network for Organ Sharing Allocation Policy Changes.

Importance: A new liver allocation policy was implemented by United Network for Organ Sharing (UNOS) in February 2020 with the stated intent of improving access to liver transplant (LT). There are growing concerns nationally regarding the implications this new system may have on LT costs, as well as access to a chance for LT, which have not been captured at a multicenter level. Objective: To characterize LT volume and cost changes across the US and within specific center groups and demographics after the policy implementation. Design, Setting, and Participants: This cross-sectional study collected and reviewed LT volume from multiple centers across the US and cost data with attention to 8 specific center demographics. Two separate 12-month eras were compared, before and after the new UNOS allocation policy: March 4, 2019, to March 4, 2020, and March 5, 2020, to March 5, 2021. Data analysis was performed from May to December 2022. Main Outcomes and Measures: Center volume, changes in cost. Results: A total of 22 of 68 centers responded comparing 1948 LTs before the policy change and 1837 LTs postpolicy, resulting in a 6% volume decrease. Transplants using local donations after brain death decreased 54% (P < .001) while imported donations after brain death increased 133% (P = .003). Imported fly-outs and dry runs increased 163% (median, 19; range, 1-75, vs 50, range, 2-91; P = .009) and 33% (median, 3; range, 0-16, vs 7, range, 0-24; P = .02). Overall hospital costs increased 10.9% to a total of $46 360 176 (P = .94) for participating centers. There was a 77% fly-out cost increase postpolicy ($10 600 234; P = .03). On subanalysis, centers with decreased LT volume postpolicy observed higher overall hospital costs ($41 720 365; P = .048), and specifically, a 122% cost increase for liver imports ($6 508 480; P = .002). Transplant centers from low-income states showed a significant increase in hospital (12%) and import (94%) costs. Centers serving populations with larger proportions of racial and ethnic minority candidates and specifically Black candidates significantly increased costs by more than 90% for imported livers, fly-outs, and dry runs despite lower LT volume. Similarly, costs increased significantly (>100%) for fly-outs and dry runs in centers from worse-performing health systems. Conclusions and Relevance: Based on this large multicenter effort and contrary to current assumptions, the new liver distribution system appears to place a disproportionate burden on populations of the current LT community who already experience disparities in health care. The continuous allocation policies being promoted by UNOS could make the situation even worse.

Pregnancy and childbirth in patients with Glanzmann Thrombasthenia.

Glanzmann thrombasthenia (GT) is a rare inherited platelet bleeding disorder caused by a quantitative and/or qualitative defect of the αIIbß3 integrin. Pregnancy and delivery pose special challenges as they entail increased risks of both maternal and foetal bleeding that may be life-threatening. Multidisciplinary management throughout the preconception, intrapartum and peripartum periods is vital to optimize pregnancy outcomes. This Nutshell review focuses on the challenging management of pregnancy and childbirth in patients with GT.

Potential for Glove Risk Amplification via Direct Physical, Chemical, and Microbiological Contamination.

This review focuses on the potential direct physical, chemical, and microbiological contamination from disposable gloves when utilized in food environments, inclusive of the risks posed to food products as well as worker safety. Unrecognized problems endemic to glove manufacturing were magnified during the COVID-19 pandemic due to high demand, increased focus on PPE performance, availability, supply chain instability, and labor shortages. Multiple evidence-based reports of contamination, toxicity, illness, deaths, and related regulatory action linked to contaminated gloves in food and healthcare have highlighted problems indicative of systemic glove industry shortcomings. The glove manufacturing process was diagramed with sources and pathways of contamination identified, indicating weak points with documented occurrences detailed. Numerous unsafe ingredients can introduce chemical contaminants, potentially posing risks to food and to glove users. Microbial hazards present significant challenges to overall glove safety as contaminants appear to be introduced via polluted water sources or flawed glove manufacturing processes, resulting in increased risks within food and healthcare environments. Frank and opportunistic pathogens along with food spoilage organisms can be introduced to foods and wearers. When the sources and pathways of glove-borne contamination were explored, it was found that physical failures play a pivotal role in the release of sweat build-up, liquefaction of chemical residues, and incubation of microbial contaminants from hands and gloves. Thus, with glove physical integrity issues, including punctures in new, unused gloves that can develop into significant rips and tears, not only can direct physical food contamination occur but also chemical and microbiological contamination can find their way into food. Enhanced regulatory requirements for Acceptable Quality Limits of food-grade gloves, and the establishment of appropriate bioburden standards would enhance safety in food applications. Based on the information provided, together with a false sense of security associated with glove use, the unconditional belief in glove chemical and microbiological purity may be unfounded.

Oral lasofoxifene's effects on moderate to severe vaginal atrophy in postmenopausal women: two phase 3, randomized, controlled trials.

OBJECTIVE: The aim of this study was to demonstrate whether lasofoxifene improves vaginal signs/symptoms of genitourinary syndrome of menopause. METHODS: Two identical, phase 3 trials randomized postmenopausal women with moderate to severe vaginal symptoms to oral lasofoxifene 0.25 or 0.5 mg/d, or placebo, for 12 week. Changes from baseline to week 12 in most bothersome symptom, vaginal pH, and percentages of vaginal parabasal and superficial cells were evaluated. These coprimary endpoints were analyzed using analysis of covariance, except superficial cells, which were analyzed by the nonparametric, rank-based Kruskal-Wallis test. RESULTS: The two studies enrolled 444 and 445 women (mean age, ~60 y), respectively. Coprimary endpoints at week 12 improved with lasofoxifene 0.25 and 0.5 mg/d greater than with placebo ( P < 0.0125 for all). Study 1: most bothersome symptom (least square mean difference from placebo: -0.4 and -0.5 for 0.25 and 0.5 mg/d, respectively), vaginal pH (-0.65, -0.58), and vaginal superficial (5.2%, 5.4%), and parabasal (-39.9%, -34.9%) cells; study 2: most bothersome symptom (-0.4, -0.5), vaginal pH (-0.57, -0.67), and vaginal superficial (3.5%, 2.2%) and parabasal (-34.1%, -33.5%) cells. Some improvements occurred as early as week 2. Most treatment-emergent adverse events were mild or moderate and hot flushes were most frequently reported (lasofoxifene vs placebo: 13%-23% vs 9%-11%). Serious adverse events were infrequent and no deaths occurred. CONCLUSIONS: In two phase 3 trials, oral lasofoxifene 0.25 and 0.5 mg/d provided significant and clinically meaningful improvements in vaginal signs/symptoms with a favorable safety profile, suggesting beneficial effects of lasofoxifene on genitourinary syndrome of menopause.

HealthCall: Smartphone Enhancement of Brief Interventions to Improve HIV Medication Adherence Among Patients in HIV Care.

Heavy drinking among people living with HIV (PLWH) reduces ART adherence and worsens health outcomes. Lengthy interventions are not feasible in most HIV care settings, and patients infrequently follow referrals to outside treatment. Utilizing visual and video features of smartphone technology, we developed HealthCall as an electronic means of increasing patient involvement in a brief intervention to reduce drinking and improve ART adherence. The objective of the current study is to evaluate the efficacy of HealthCall to improve ART adherence among PLWH who drink heavily when paired with two brief interventions: the National Institute on Alcoholism and Alcohol Abuse (NIAAA) Clinician's Guide (CG) or Motivational Interviewing (MI). Therefore, we conducted a 1:1:1 randomized trial among 114 participants with alcohol dependence at a large urban HIV clinic. Participants were randomized to one of three groups: (1) CG only (n = 37), (2) CG and HealthCall (n = 38), or (3) MI and HealthCall (n = 39). Baseline interventions targeting drinking reduction and ART adherence were ~ 25 min, with brief (10-15 min) booster sessions at 30 and 60 days. The outcome was ART adherence assessed using unannounced phone pill-count method (possible adherence scores: 0-100%) at 30-day, 60-day, 3, 6, and 12 months. Analyses were conducted using generalized linear mixed models with pre-planned contrasts. Of the 114 enrolled patients, 58% were male, 75% identified as Black/African American, 28% were Hispanic, and 62% had less than a high school education. The mean age was 47.5 years (standard deviation [SD] 10 years) and the mean number of years since they were diagnosed with HIV was 18.6 (SD 7.6). Participants assigned to HealthCall to extend the CG had increased levels of ART adherence at 60-day and 6-month follow-up (compared to CG only), although there was no statistically significant difference by 12-month follow-up. Participants who were assigned to HealthCall to extend the MI never had statistically significant higher levels of ART adherence. These results suggest that the use of a smartphone app can be used to initially extend the reach of a brief drinking intervention to improve ART adherence over a short period of time; however, sustained long-term improvements in ART adherence after intervention activity ends remains a challenge.

A phase I clinical trial assessing the safety, tolerability, and pharmacokinetics of inhaled ethanol in humans as a potential treatment for respiratory tract infections.

Background: Current treatments for respiratory infections are severely limited. Ethanol's unique properties including antimicrobial, immunomodulatory, and surfactant-like activity make it a promising candidate treatment for respiratory infections if it can be delivered safely to the airway by inhalation. Here, we explore the safety, tolerability, and pharmacokinetics of inhaled ethanol in a phase I clinical trial. Methods: The study was conducted as a single-centre, open-label clinical trial in 18 healthy adult volunteers, six with no significant medical comorbidities, four with stable asthma, four with stable cystic fibrosis, and four active smokers. A dose-escalating design was used, with participants receiving three dosing cycles of 40, 60%, and then 80% ethanol v/v in water, 2 h apart, in a single visit. Ethanol was nebulised using a standard jet nebuliser, delivered through a novel closed-circuit reservoir system, and inhaled nasally for 10 min, then orally for 30 min. Safety assessments included adverse events and vital sign monitoring, blood alcohol concentrations, clinical examination, spirometry, electrocardiogram, and blood tests. Results: No serious adverse events were recorded. The maximum blood alcohol concentration observed was 0.011% immediately following 80% ethanol dosing. Breath alcohol concentrations were high (median 0.26%) following dosing suggesting high tissue levels were achieved. Small transient increases in heart rate, blood pressure, and blood neutrophil levels were observed, with these normalising after dosing, with no other significant safety concerns. Of 18 participants, 15 completed all dosing cycles with three not completing all cycles due to tolerability. The closed-circuit reservoir system significantly reduced fugitive aerosol loss during dosing. Conclusion: These data support the safety of inhaled ethanol at concentrations up to 80%, supporting its further investigation as a treatment for respiratory infections.Clinical trial registration: identifier ACTRN12621000067875.

Evidence That Anemia Accelerates AS Progression Via Shear-Induced TGF-ß1 Activation: Heyde's Syndrome Comes Full Circle.

The severity of aortic stenosis (AS) is associated with acquired von Willebrand syndrome (AVWS) and gastrointestinal bleeding, leading to anemia (Heyde's syndrome). We investigated how anemia is linked with AS and AVWS using the LA100 mouse model and patients with AS. Induction of anemia in LA100 mice increased transforming growth factor (TGF)-ß1 activation, AVWS, and AS progression. Patients age >75 years with severe AS had higher plasma TGF-ß1 levels and more severe anemia than AS patients age <75 years, and there was a correlation between TGF-ß1 and anemia. These data are compatible with the hypothesis that the blood loss anemia of Heyde's syndrome contributes to AS progression via WSS-induced activation of platelet TGF-ß1 and additional gastrointestinal bleeding via WSS-induced AVWS.

Accuracy and Performance of Triage Blood Pressure Measurements in A Real-World Clinic Setting.

OBJECTIVES: To investigate the agreement and accuracy of triage blood pressure (BP) in a real-world clinic setting, compared with the reference standard. STUDY DESIGN: Paired triage and standardized BP measurements from patients 4 through 21 years old evaluated in an obesity-related hypertension clinic were obtained via chart-review. Triage BPs were measured by a medical assistant or nurse, often by automated device. Triplicate manual BPs were obtained by the clinic physician. Bland-Altman analyses determined mean differences between paired triage and mean standardized BPs. GEE-based multivariable relative risk (RR) regression determined the RR of triage BP overestimation by ≥ 5 mmHg. Overall agreement, sensitivity, specificity, positive predictive value, and negative predictive value of triage BP measurements identifying hypertensive BP were determined. RESULTS: One hundred thirty participants with 347 clinic encounters were included. Mean age was 13.3 years (SD 3.94), 76% were Black, and 58% were male. Overall mean systolic and diastolic BP difference was 8.7 mmHg (95% limits on agreement: -16.66, 34.07) and 4.1 mmHg (95% limits on agreement: -18.56, 26.68), respectively. Triage systolic BP was more likely overestimated by ≥ 5 mmHg when a large adult (RR = 1.49; 95% CI: 1.00, 2.21) or thigh cuff (RR = 1.94; 95% CI: 1.08, 3.51) was required compared with when a child/adult cuff was required. Overall agreement in identifying hypertensive BP was 57.6%. Sensitivity (52.6%), specificity (63.4%), positive predictive value (60.8%), and negative predictive value (55.3%) were low across all cuffs. CONCLUSIONS: There was poor agreement between usual triage and standardized BP measurements, with potential for significant clinical implications. CLINICAL TRIAL REGISTRATION: ReNEW Clinic Cohort Study (ReNEW), NCT03816462, https://clinicaltrials.gov/ct2/show/NCT03816462.

Early targeted heart rate exercise is safe and May hasten return-to-duty in service members with acute concussion, a preliminary study.

OBJECTIVE: To evaluate the feasibility of an exercise tolerance assessment and intervention added to the Progressive Return to Activity Clinical Recommendations (PRA-CR) in acutely concussed service members (SMs). METHODS: This non-randomized, pilot trial was performed at one center. SMs in the experimental group (ERG) performed the Buffalo Concussion March-in-place Test (BCMT) at every clinic visit and were prescribed at least 20 minutes/day of targeted exercise in addition to PRA-CR. Data for the control group (SCG) were extracted from the same clinic immediately prior to ERG. SMs in both groups were assessed by the same clinician to determine return-to-duty. RESULTS: BCMT identified concussion-related exercise intolerance in 100% (n = 14) at screening visit (mean 3.4 days after injury) and in 0% (n = 7) who had recovered. No adverse effects were associated with BCMT. The estimated recovery time for ERG who performed the exercise intervention (n = 12) was 17.0 (12.8, 21.2) days and for SCG (n = 15) was 23.7 (19.9, 27.5) days (p = 0.039). CONCLUSION: Assessment of exercise tolerance was feasible and could be incorporated into the PRA-CR. Future definitive, randomized controlled trials should be performed to assess the effectiveness of exercise reset program for SMs after concussion.

An Exploratory Analysis of Physical Examination Subtypes in Pediatric Athletes With Concussion.

OBJECTIVE: Pediatric athletes with concussion present with a variety of impairments on clinical assessment and require individualized treatment. The Buffalo Concussion Physical Examination is a brief, pertinent clinical assessment for individuals with concussion. The purpose of this study was to identify physical examination subtypes in pediatric athletes with concussion within 2 weeks of injury that are relevant to diagnosis and treatment. DESIGN: Secondary analysis of a published cohort study and clinician consensus. SETTING: Three university-affiliated sports medicine centers. PARTICIPANTS: Two hundred seventy children (14.9 ± 1.9 years). INDEPENDENT VARIABLES: Orthostatic intolerance, horizontal and vertical saccades, smooth pursuits, vestibulo-ocular reflex, near-point convergence, complex tandem gait, neck range of motion, neck tenderness, and neck spasm. MAIN OUTCOME MEASURES: Correlations between independent variables were calculated, and network graphs were made. k-means and hierarchical clustering were used to identify clusters of impairments. Optimal number of clusters was assessed. Results were reviewed by experienced clinicians and consensus was reached on proposed subtypes. RESULTS: Physical examination clusters overlapped with each other, and no optimal number of clusters was identified. Clinician consensus suggested 3 possible subtypes: (1) visio-vestibular (horizontal and vertical saccades, smooth pursuits, and vestibulo-ocular reflex), (2) cervicogenic (neck range of motion and spasm), and (3) autonomic/balance (orthostatic intolerance and complex tandem gait). CONCLUSIONS: Although we identified 3 physical examination subtypes, it seemed that physical examination findings alone are not enough to define subtypes that are both statistically supported and clinically relevant, likely because they do not include symptoms, assessment of mood or cognitive problems, or graded exertion testing.

Convergent evolution of BRCA2 reversion mutations under therapeutic pressure by PARP inhibition and platinum chemotherapy.

Reversion mutations that restore wild-type function of the BRCA gene have been described as a key mechanism of resistance to Poly(ADP-ribose) polymerase (PARP) inhibitor therapy in BRCA-associated cancers. Here, we report a case of a patient with metastatic castration-resistant prostate cancer (mCRPC) with a germline BRCA2 mutation who developed acquired resistance to PARP inhibition. Extensive genomic interrogation of cell-free DNA (cfDNA) and tissue at baseline, post-progression, and postmortem revealed ten unique BRCA2 reversion mutations across ten sites. While several of the reversion mutations were private to a specific site, nine out of ten tumors contained at least one mutation, suggesting a powerful clonal selection for reversion mutations in the presence of therapeutic pressure by PARP inhibition. Variable cfDNA shed was seen across tumor sites, emphasizing a potential shortcoming of cfDNA monitoring for PARPi resistance. This report provides a genomic portrait of the temporal and spatial heterogeneity of prostate cancer under the selective pressure of a PARP inhibition and exposes limitations in the current strategies for detection of reversion mutations.

Pediatric advocacy: Advancement in academic institutions.

IMPACT: Children are facing many threats to their health today that require system change at a sweeping level to have real-world impact. Pediatricians are positioned as natural leaders to advocate for these critical community and policy changes. Academic medical center (AMC) leaders recognize the importance of this advocacy and clear steps can be taken to improve the structure to support pediatricians in their advocacy careers through faculty development and promotion, including standardized scholarly measurement of the outcomes.