A Phase 1 dose escalation and expansion trial of the next-generation oral SERD camizestrant in women with ER-positive, HER2-negative advanced breast cancer: SERENA-1 monotherapy results.

BACKGROUND: SERENA-1 (NCT03616587) is a Phase 1, multi-part, open-label study of camizestrant in pre- and post-menopausal women with ER+, HER2- advanced breast cancer. Parts A and B aim to determine the safety and tolerability of camizestrant monotherapy and define doses for clinical evaluation. Patients and Methods Women aged 18 years or older with metastatic or recurrent ER+, HER2- breast cancer, refractory (or intolerant) to therapy were assigned 25 mg up to 450 mg once daily (QD; escalation) or 75, 150, or 300 mg QD (expansion). Safety and tolerability, anti-tumor efficacy, pharmacokinetics, and impact on ESR1m circulating tumor (ct)DNA levels were assessed. RESULTS: By 9 March 2021, 108 patients received camizestrant monotherapy at 25-450 mg doses. Of these, 93 (86.1%) experienced treatment-related adverse events (TRAEs), 82.4% of which were grade 1 or 2. The most common TRAEs were visual effects (56%), (sinus) bradycardia (44%), fatigue (26%), and nausea (15%). There were no TRAEs grade 3 or higher, or treatment-related serious adverse events (TRSAEs) at doses ≤150 mg. Median tmax was achieved ∼2-4 hours post-dose at all doses investigated, with an estimated half-life of 20-23 hours. Efficacy was observed at all doses investigated, including in patients with prior CDK4/6 inhibitor and/or fulvestrant treatment, with and without baseline ESR1 mutations, and with visceral disease, including liver metastases. CONCLUSIONS: Camizestrant is a next-generation oral SERD and pure ER antagonist with a tolerable safety profile. The pharmacokinetics profile supports once-daily dosing, with evidence of pharmacodynamic and clinical efficacy in heavily pre-treated patients, regardless of ESR1m. This study established 75, 150 and 300 mg QD doses for Phase 2 testing (SERENA-2, NCT04214288 and SERENA-3, NCT04588298).

Impact and correlates of sub-optimal social support among patients in HIV care.

Social support (SS) predicts health outcomes among patients living with HIV. We administered a brief, validated measure of SS, the Multifactoral Assessment of Perceived Social Support, within a patient-reported outcomes assessment of health domains in HIV care at 4 U.S. clinics in English and Spanish (n = 708). In univariate analysis, low SS was associated with poorer engagement in care, antiretroviral adherence, and health-related quality of life; current methamphetamine/crystal use, depression, anxiety, and HIV stigma (all p < 0.001); any use of either methamphetamines/crystal, illicit opioids, or cocaine/crack (p = 0.001), current marijuana use (p = 0.012), nicotine use (p = 0.005), and concern for sexually transmitted infection exposure (p = 0.001). High SS was associated with undetectable viral load (p = 0.031). Multivariate analyses found low SS independently associated with depression (risk ratio (RR) 3.72, 95% CI 2.93-4.72), lower adherence (RR 0.76, 95% CI 0.64-0.89), poor engagement in care (RR 2.05, 95% CI 1.44-2.96), and having more symptoms (RR 2.29, 95% CI 1.92-2.75). Medium SS was independently associated with depression (RR 2.59, 95% CI 2.00-3.36), poor engagement in care (RR 1.62, 95% CI 1.15-2.29) and having more symptoms (RR 1.75, 95% CI 1.44-2.13). SS assessment may help identify patients at risk for these outcomes.

Surprisingly long body length of the lungworm Parafilaroides gymnurus from common seals of the Dutch North Sea.

Lungworms of the genera Parafilaroides and Otostrongylus are responsible for parasitic bronchopneumonia, the foremost disease of eastern Atlantic common seals (EACS, Phoca vitulina vitulina) in the Dutch North Sea. Recently, there have been increased reports of lungworm cases and observations of unusually long Parafilaroides sp. adults in this location. The initial aim of this study was to confirm the identity of the Parafilaroides species infecting this population. Parafilaroides are usually small and delicate, making them difficult to extract from host tissue, and there is often difficulty accessing fresh specimens for morphological study. The large size of the Dutch worms and the accessibility of specimens from numerous animals enabled the description and measurement of many intact specimens (N = 64) from multiple host animals (N = 20). Species identity was confirmed by targeted sequencing of ribosomal and mitochondrial DNA amplicons from a subset of worms. Worm morphology was consistent with descriptions for P. gymnurus, but the mature females were 1.9-fold and 3.4-fold longer than those recovered from French EACS (P ≤ 0.001) and Canadian western Atlantic common seals (Phoca vitulina concolor; P ≤ 0.0001). They were also significantly longer than mature female P. gymnurus described from other seal species, with the exception of those from harp seals of Les Escoumins, Quebec. We suggest that intraspecific genetic differences in P. gymnurus and the environment within the host could contribute to the variation reported here. This study is the first to describe P. gymnurus using morphological and molecular methods and should serve as a reference for identification of the species.

Impact assessment of the incorporation of the rotavirus vaccine in the province of San Luis - Argentina.

Rotavirus (RV) is the main cause of acute gastroenteritis (AGE) in young children. The San Luis province of Argentina introduced RV vaccination in May 2013. We estimate vaccine impact (RVI) using real-world data. Data on all-cause AGE cases and AGE-related hospitalisations for San Luis and the adjacent Mendoza province (control group) were obtained and analysed by interrupted time-series methods. Regardless of the model used for counterfactual predictions, we estimated a reduction in the number of all-cause AGE cases of 20-25% and a reduction in AGE-related hospitalisations of 55-60%. The vaccine impact was similar for each age group considered (<1 year, <2 years and <5 years). RV vaccination was estimated to have reduced direct medical costs in the province by about 4.5 million pesos from May 2013 to December 2014. Similar to previous studies, we found a higher impact of RV vaccination in preventing severe all-cause AGE cases requiring hospitalisation than in preventing all-cases AGE cases presenting for medical care. An assessment of the economic value of RV vaccination could take other benefits into account in addition to the avoided medical costs and the costs of vaccination.

Development and content validation of measures assessing adherence barriers and behaviors for use in clinical care.

BACKGROUND: Providers are often unaware of poor adherence to prescribed medications for their patients with chronic diseases. OBJECTIVE: To develop brief, computer-administered patient-reported measures in English and Spanish assessing adherence behaviors and barriers. Design, Participants, and Main Measures: Item pools were constructed from existing measures of medication adherence behaviors and barriers, which informed development of a patient concept elicitation interview guide to identify medication adherence behavior and barrier-related concepts. Two hundred six patients either living with HIV (PLWH) or without were interviewed. Interviews were coded, concepts matched to item pool content, and new items were developed for novel concepts. A provider/investigator team highlighted clinically relevant items. Cognitive interviews were conducted with patients on final candidate items (n = 37). The instruments were administered to 2081 PLWH. KEY RESULTS: Behavioral themes from concept elicitation interviews included routines incorporating time of day, placement, visual cues, and intentionality to miss or skip doses. Barrier themes included health-related (e.g. depressed mood, feeling ill), attitudes/beliefs (e.g., need for medication), access (e.g., cost/insurance problems), and circumstantial barriers (e.g., lack of privacy, disruption of daily routine). The final instruments included 6 behavior items, and 1 barrier item with up to 23 response options. PLWH endorsed a mean (SD) of 3.5 (1.1) behaviors. The 201 PLWH who missed ≥2 doses in the previous week endorsed a mean (SD) of 3.1 (2.5) barriers. The intraclass correlation coefficient (ICC) for the numbers of behaviors endorsed in 61 PLWH after 4-16 days was 0.54 and for the number of barriers for the 20 PLWH with ≥2 missed doses the ICC was 0.89, representing fair and excellent test-retest reliability. CONCLUSION: Measures of medication adherence behaviors and barriers were developed for use with patients living with chronic diseases focusing on clinical relevance, brevity, and content validity for use in clinical care.

Circumstances Surrounding High-risk Sexual Experiences Among Primary Care Patients Living With and Without HIV.

INTRODUCTION: Rates of sexually transmitted infection (STI) are rising in the USA, yet STI risk remains under-addressed by providers, even in HIV care, and with high-risk patients. We interviewed primary care patients living with and without HIV regarding circumstances surrounding sexual risk behavior to identify opportunities for providers to address and reduce STI risk. METHODS: We conducted semi-structured 1:1 interviews with patients living with and without HIV reporting ≥ 1 sex partner and varying STI exposure risk in the past 12 months from four geographically diverse US HIV and primary care clinics. We audio-recorded, transcribed, and coded interviews by circumstance type, using double-coding to ensure inter-coder reliability. We used Fisher's exact and T tests to determine associations with demographic/risk factors. RESULTS: Patients (n = 91) identified a mean of 3 of 11 circumstances. These included substance use (54%), desire for physical/emotional intimacy (48%), lack of HIV/STI status disclosure (44%), psychological drivers (i.e., coping, depression; 38%), personal dislike of condoms (22%), partner condom dislike/refusal (19%), receiving payment for sex (13%), and condom unavailability (9%). Higher proportions of those who were high STI-exposure risk patients, defined as those with ≥ 2 sex partners in the past 3 months reporting never or sometimes using condoms, reported disliking condoms (p = .006); higher proportions of the high-risk and moderate-risk (≥ 2 partners and condom use "most of the time") groups reported substance use as a circumstance (p = .04). CONCLUSION: Circumstances surrounding perceived STI exposure risk were diverse, often overlapping, and dependent on internal, environmental, and partner-related factors and inadequate communication. Meaningful care-based interventions regarding HIV/STI transmission behavior must address the diversity and interplay of these factors.

Medication understanding among patients living with multiple chronic conditions: Implications for patient-reported measures of adherence.

BACKGROUND: Low health literacy is associated with poor medication adherence and poor health outcomes. Limited understanding of prescribed medications may decrease validity of patient-reported adherence measures. OBJECTIVES: To assess knowledge of names and purposes of prescribed medications among patients with multiple chronic conditions. METHODS: Individual interviews were conducted with a convenience sample of patients from six U.S. primary care clinics. Participants (n = 57) were English and/or Spanish-speaking patients prescribed 3+ medications for chronic conditions, for which non-adherence may lead to disability or death. In individual interviews, patients were asked to name their medications, explain the purpose of each, and to explain how they distinguish them from one another. Interviews were audio recorded, transcribed, and coded; coded content was quantified by 1) whether or not the patient could name medications; 2) method of categorizing medications; 3) whether or not the purpose of the medication was understood. Descriptive statistics were compiled using Fisher's exact test to determine the relationship between patient knowledge and medication characteristics. RESULTS: Thirty percent of patients could not name at least one of their medications; 19% did not know their purpose; 30% held misconceptions about the purpose of one or more medications. There was no significant difference in ability to name medications or state their medication's purpose between patients using medi-sets, pre-packaged rolls, or blister packs, and patients who stored pills in their original containers (p = 0.56 and p = 0.73, respectively), or across demographic groups (p = 0.085 to 0.767). CONCLUSIONS: Many patients demonstrated difficulty identifying the name and purpose of prescribed medications; this did not differ by demographic group or medication storage type. Patients may benefit from routine review of medications with their provider in order to improve health literacy, outcomes, and patient-reported adherence measurement.

Validity assessment of the PROMIS fatigue domain among people living with HIV.

PURPOSE: To evaluate psychometric characteristics and cross-sectional and longitudinal validity of the 7-item PROMIS® Fatigue Short Form and additional fatigue items among people living with HIV (PLWH) in a nationally distributed network of clinics collecting patient reported data at the time of routine clinical care. METHODS: Cross-sectional and longitudinal fatigue data were collected from September 2012 through April 2013 across clinics participating in the Centers for AIDS Research Network of Integrated Clinical Systems (CNICS). We analyzed data regarding psychometric characteristics including simulated computerized adaptive testing and differential item functioning, and regarding associations with clinical characteristics. RESULTS: We analyzed data from 1597 PLWH. Fatigue was common in this cohort. Scores from the PROMIS® Fatigue Short Form and from the item bank had acceptable psychometric characteristics and strong evidence for validity, but neither performed better than shorter instruments already integrated in CNICS. CONCLUSIONS: The PROMIS® Fatigue Item Bank is a valid approach to measuring fatigue in clinical care settings among PLWH, but in our analyses did not perform better than instruments associated with less respondent burden.

Anxiety symptoms bias memory assessment in older adults.

BACKGROUND: Older adults with anxiety and/or depression experience additional memory dysfunction beyond that of the normal aging process. However, few studies have examined test bias in memory assessments due to anxiety and/or depressive symptoms. The current study investigated the influence of self-reported symptoms of anxiety and depression on the measurement equivalence of memory tests in older adults. METHOD: This is a secondary analysis of the Advanced Cognitive Training for Independent and Vital Elderly dataset, a randomized controlled trial of community-dwelling older adults. Baseline data were included in this study (n = 2802). Multiple indicators multiple causes modeling was employed to assess for measurement equivalence, differential item functioning (DIF), in memory tests. RESULTS: The DIF was present for anxiety symptoms but not for depressive symptoms, such that higher anxiety placed older adults at a disadvantage on measures of memory performance. Analysis of DIF impact showed that compared with participants scoring in the bottom quartile of anxious symptoms, participants in the upper quartile exhibited memory performance scores that were 0.26 standard deviation lower. CONCLUSION: Anxious but not depressive symptoms introduce test bias into the measurement of memory in older adults. This indicates that memory models for research and clinical purposes should account for the direct relationship between anxiety symptoms and memory tests in addition to the true relationship between anxiety symptoms and memory construct. These findings support routine assessments of anxiety symptoms among older adults in settings in which cognitive testing is being conducted. Copyright © 2016 John Wiley & Sons, Ltd.

Thermodynamic approach to boron nitride nanotube solubility and dispersion.

Inadequate dispersion of nanomaterials is a critical issue that significantly limits the potential properties of nanocomposites and when overcome, will enable further enhancement of material properties. The most common methods used to improve dispersion include surface functionalization, surfactants, polymer wrapping, and sonication. Although these approaches have proven effective, they often achieve dispersion by altering the surface or structure of the nanomaterial and ultimately, their intrinsic properties. Co-solvents are commonly utilized in the polymer, paint, and art conservation industries to selectively dissolve materials. These co-solvents are utilized based on thermodynamic interaction parameters and are chosen so that the original materials are not affected. The same concept was applied to enhance the dispersion of boron nitride nanotubes (BNNTs) to facilitate the fabrication of BNNT nanocomposites. Of the solvents tested, dimethylacetamide (DMAc) exhibited the most stable, uniform dispersion of BNNTs, followed by N,N-dimethylformamide (DMF), acetone, and N-methyl-2-pyrrolidone (NMP). Utilizing the known Hansen solubility parameters of these solvents in comparison to the BNNT dispersion state, a region of good solubility was proposed. This solubility region was used to identify co-solvent systems that led to improved BNNT dispersion in poor solvents such as toluene, hexane, and ethanol. Incorporating the data from the co-solvent studies further refined the proposed solubility region. From this region, the Hansen solubility parameters for BNNTs are thought to lie at the midpoint of the solubility sphere: 16.8, 10.7, and 9.0 MPa(1/2) for δd, δp, and δh, respectively, with a calculated Hildebrand parameter of 21.8 MPa(1/2).

Do variations in paraspinal muscle morphology and composition predict low back pain in men?

This longitudinal study aimed to clarify the longstanding controversy over whether variations in paraspinal muscle morphology (e.g., size, composition and asymmetry) are predictors of low back pain (LBP). A sample of 99 Finnish men were included in this population-based longitudinal study. Data were collected through a structured interview, physical examination and magnetic resonance imaging (MRI). Baseline measurements of the lumbar multifidus and erector spinae muscles were obtained from T2-weighted axial images at L3-L4 and L5-S1, and interview data were obtained at baseline, 1- and 15-year follow-ups. Few of the paraspinal muscle parameters investigated were predictors of change in LBP frequency, intensity or sciatica at 1- and 15-year follow-ups in the population-based sample, and findings were not consistent across muscles and spinal levels. However, greater multifidus and erector spinae fatty infiltration at L5-S1 was associated with a higher risk of having continued, frequent, persistent LBP at 1-year follow-up. None of the relationships observed was confounded by body mass index or the amount of physical activity at work or leisure. This longitudinal study provided evidence that variations in paraspinal muscle morphology on MRI have a limited, if not uncertain, role in the short- and long-term predictions of LBP in men.

A cluster randomized controlled trial of the non-pneumatic anti-shock garment for obstetric haemorrhage: sub-analysis of the Zimbabwean Arm.

Objectives: To determine whether earlier application of the Non-pneumatic Anti-Shock Garment (NASG) at clinic level compared to the referral hospital level reduces maternal morbidity and mortality and recovery time from shock due to severe Obstetric Haemorrhage (OH) and to determine the safety of the NASG when applied at clinic level. Design: A cluster Randomized Controlled Trial (RCT) Setting: Harare and Parirenyatwa Referral Hospitals (RH) in Harare and the twelve Harare City Council clinics that offer maternity care. Subjects: Women who had suffered severe OH at clinic level and were being transferred to a Referral Hospital (RH). Iterventions: The clinics were randomized into two groups. In the early NASG group eligible women were given the standard management for OH and had the NASG applied at the clinic level before transport to RH. In the control group, eligible women were given the standard management for OH at the clinic level, transferred to the RH, and received the NASG at the RH. All women received equivalent OH/hypovolemic shock management at the RH. Main Outcome Measures: The main outcome measures were maternal mortality and morbidity, blood loss, recovery from shock and the occurrence of side effects whilst in the NASG. Results: There were few maternal deaths and morbidities, and no statistically significant differences between the two groups were noted. Women in the early NASG group spent a statistically significant shorter time in the NASG at referral hospital level (OR 0.64, 95% CI 0.52 - 0.79, p < 0.001) and had a non-significant 40% faster recovery from shock (HR 1.39; 95% CI 0.98-1.97, p=0.07). There were no differences in reported side effects. Conclusion: Earlier NASG application at the clinic level was associated with faster recovery from shock in women who had suffered severe OH and appears safe to use.

Fears of compassion and happiness in relation to alexithymia, mindfulness, and self-criticism.

BACKGROUND: There is increasing research to suggest that fears of, and resistances to, affiliative and positive emotions are linked to self-criticism and a range of psychopathologies. It is unclear how these fears and resistances are linked to each other and how these in turn are linked to psychological processes, such as abilities to be mindful and recognize and describe emotions. OBJECTIVES: This research explores the relationship between fears of compassion and happiness in general, with capacities for emotional processing (alexithymia), capacities for mindfulness, and empathic abilities. To advance this research, a new scale was developed to measure general fears of positive feelings - the Fear of Happiness Scale. RESULTS: The results showed that fears of compassion for self, from others and in particular fear of happiness, were highly linked to different aspects of alexithymia, mindfulness, empathy, self-criticism and depression, anxiety and stress. Especially noteworthy was the very high correlation between fear of happiness and depression (r= .70). CONCLUSION: While the development of positive emotions, especially those linked to affiliation and connectedness are increasingly seen as important therapeutic targets, little research has focused on the blocks and fears to positive emotions. This study used newly developed fears of positive affect scales (e.g., compassion and happiness) to explore these aspects and found they were significantly linked to psychopathology variables self-criticism and difficulties such as alexithymia.

Women's preference for caesarean section: a systematic review and meta-analysis of observational studies.

BACKGROUND: The striking increase in caesarean section rates in middle- and high-income countries has been partly attributed to maternal request. We conducted a systematic review and meta-analysis of women's preferences for caesarean section. OBJECTIVES: To review the published literature on women's preferences for caesarean section. SEARCH STRATEGY: A systematic search of MEDLINE, EMBASE, LILACS and PsychINFO was performed. References of all included articles were examined. SELECTION CRITERIA: We included studies that quantitatively evaluated women's preferences for caesarean section in any country. We excluded articles assessing health providers' preferences and qualitative studies. DATA COLLECTION AND ANALYSIS: Two reviewers independently screened abstracts of all identified citations, selected potentially eligible studies, and assessed their full-text versions. We conducted a meta-analysis of proportions, and a meta-regression analysis to determine variables significantly associated with caesarean section preference. MAIN RESULTS: Thirty-eight studies were included (n = 19,403). The overall pooled preference for caesarean section was 15.6% (95% CI 12.5-18.9). Higher preference for caesarean section was reported in women with a previous caesarean section versus women without a previous caesarean section (29.4%; 95% CI 24.4-34.8 versus 10.1%; 95% CI 7.5-13.1), and those living in a middle-income country versus a high-income country (22.1%; 95% CI 17.6-26.9 versus 11.8%; 95% CI 8.9-15.1). AUTHORS' CONCLUSIONS: Only a minority of women in a wide variety of countries expressed a preference for caesarean delivery. Further research is needed to better estimate the contribution of women's demand to the rising caesarean section rates.

Measuring depression levels in HIV-infected patients as part of routine clinical care using the nine-item Patient Health Questionnaire (PHQ-9).

Little is known about the psychometric properties of depression instruments among persons infected with HIV. We analyzed data from a large sample of patients in usual care in two US cities (n=1467) using the nine-item Patient Health Questionnaire (PHQ-9) from the PRIME-MD. The PHQ-9 had curvilinear scaling properties and varying levels of measurement precision along the continuum of depression measured by the instrument. In our cohort, the scale showed a prominent floor effect and a distribution of scores across depression severity levels. Three items had differential item functioning (DIF) with respect to race (African-American vs. white); two had DIF with respect to sex; and one had DIF with respect to age. There was minimal individual-level DIF impact. Twenty percent of the difference in mean depression levels between African-Americans and whites was due to DIF. While standard scores for the PHQ-9 may be appropriate for use with individual HIV-infected patients in cross-sectional settings, these results suggest that investigations of depression across groups and within patients across time may require a more sophisticated analytic framework.

Observation of eta' decays to pi+pi-pi0 and pi+pi-e+e-.

Using psi(2S)-->pi;{+}pi;{-}J/psi, J/psi-->gammaeta;{'} events acquired with the CLEO-c detector at the CESR e;{+}e;{-} collider, we make the first observations of the decays eta;{'}-->pi;{+}pi;{-}pi;{0} and eta;{'}-->pi;{+}pi;{-}e;{+}e;{-}, measuring absolute branching fractions (37_{-9};{+11}+/-4)x10;{-4} and (25_{-9};{+12}+/-5)x10;{-4}, respectively. For eta;{'}-->pi;{+}pi;{-}pi;{0}, this result probes the mechanism of isospin violation and the roles of pi;{0}/eta/eta;{'}-mixing and final state rescattering in strong decays. We also set upper limits on branching fractions for eta;{'} decays to pi;{+}pi;{-}micro;{+}micro;{-}, 2(pi;{+}pi;{-}), pi;{+}pi;{-}2pi;{0}, 2(pi;{+}pi;{-})pi;{0}, 3(pi;{+}pi;{-}), and invisible final states.