Making informed choices on incorporating chemoprevention into carE (MiCHOICE, SWOG 1904): Design and methods of a cluster randomized controlled trial.

INTRODUCTION: Women with atypical hyperplasia (AH) or lobular carcinoma in situ (LCIS) have a significantly increased risk of breast cancer, which can be substantially reduced with antiestrogen therapy for chemoprevention. However, antiestrogen therapy for breast cancer risk reduction remains underutilized. Improving knowledge about breast cancer risk and chemoprevention among high-risk patients and their healthcare providers may enhance informed decision-making about this critical breast cancer risk reduction strategy. METHODS/DESIGN: We are conducting a cluster randomized controlled trial to evaluate the effectiveness and implementation of patient and provider decision support tools to improve informed choice about chemoprevention among women with AH or LCIS. We have cluster randomized 26 sites across the U.S. through the SWOG Cancer Research Network. A total of 415 patients and 200 healthcare providers are being recruited. They are assigned to standard educational materials alone or combined with the web-based decision support tools. Patient-reported and clinical outcomes are assessed at baseline, after a follow-up visit at 6 months, and yearly for 5 years. The primary outcome is chemoprevention informed choice after the follow-up visit. Secondary endpoints include other patient-reported outcomes, such as chemoprevention knowledge, decision conflict and regret, and self-reported chemoprevention usage. Barriers and facilitators to implementing decision support into clinic workflow are assessed through patient and provider interviews at baseline and mid-implementation. RESULTS/DISCUSSION: With this hybrid effectiveness/implementation study, we seek to evaluate if a multi-level intervention effectively promotes informed decision-making about chemoprevention and provide valuable insights on how the intervention is implemented in U.S. TRIAL REGISTRATION: NCT04496739.

Size And Locomotor Ecology Have Differing Effects on the External and Internal Morphologies of Squirrel (Rodentia: Sciuridae) Limb Bones.

Mammals exhibit a diverse range of limb morphologies that are associated with different locomotor ecologies and structural mechanics. Much remains to be investigated, however, about the combined effects of locomotor modes and scaling on the external shape and structural properties of limb bones. Here, we used squirrels (Sciuridae) as a model clade to examine the effects of locomotor mode and scaling on the external shape and structure of the two major limb bones, the humerus and femur. We quantified humeral and femoral morphologies using 3D geometric morphometrics and bone structure analyses on a sample of 76 squirrel species across their four major ecotypes. We then used phylogenetic generalized linear models to test how locomotor ecology, size, and their interaction influenced morphological traits. We found that size and locomotor mode exhibit different relationships with the external shape and structure of the limb bones, and that these relationships differ between the humerus and femur. External shapes of the humerus and, to a lesser extent, the femur are best explained by locomotor ecology rather than by size, whereas structures of both bones are best explained by interactions between locomotor ecology and scaling. Interestingly, the statistical relationships between limb morphologies and ecotype were lost when accounting for phylogenetic relationships among species under Brownian motion. That assuming Brownian motion confounded these relationships is not surprising considering squirrel ecotypes are phylogenetically clustered; our results suggest that humeral and femoral variation partitioned early between clades and their ecomorphologies were maintained to the present. Overall, our results show how mechanical constraints, locomotor ecology, and evolutionary history may enact different pressures on the shape and structure of limb bones in mammals.

EspañolLos mamíferos exhiben una amplia gama de morfologías de las extremidades, las cuales están asociadas con diferentes ecologías de locomoción y mecánicas estructurales. Sin embargo, aún queda mucho por investigar sobre cómo los tipos de locomoción y el tamaño corporal han afectado conjuntamente la forma externa y las propiedades estructurales de los huesos de las extremidades. En este estudio, usamos al clado de las ardillas (Sciuridae) como un modelo para examinar los efectos del tipo de locomoción y el tamaño en la forma externa y la estructura de los dos huesos principales de las extremidades, el húmero y el fémur. Utilizando morfometría geométrica en 3D y análisis de estructura ósea, cuantificamos la morfología humeral y femoral en una muestra de 76 especies de ardillas que abarcan sus cuatro ecotipos principales. Posteriormente, usamos modelos filogenéticos generalizados lineales para investigar cómo la ecología locomotora, el tamaño, y la interacción entre estos factores influencian los rasgos morfológicos. Encontramos que el tamaño y el tipo de locomoción exhiben diferentes relaciones con la forma externa y la estructura de los huesos de las extremidades, y que estas relaciones difieren entre el húmero y el fémur. La variación de la forma externa del húmero y, en menor medida, del fémur está más relacionada con la ecología locomotora que con el tamaño. Por otro lado, las diferencias en la estructura de ambos huesos se explican mejor por una combinación de efectos de la ecología locomotora y el tamaño. Curiosamente, las relaciones estadísticas entre la morfología de las extremidades y el ecotipo se pierden al incorporar las relaciones filogenéticas entre las especies bajo un modelo de movimiento browniano. El hecho de que asumir un modelo de movimiento browniano modifique estas relaciones no es sorprendente, considerando que los ecotipos de ardillas están agrupados filogenéticamente. Nuestros resultados además sugieren que la variación en morfología humeral y femoral se dividieron tempranamente entre clados y estas ecomorfologías se mantuvieron hasta el presente.En general, nuestros resultados demuestran cómo las restricciones mecánicas, la ecología locomotora y la historia evolutiva pueden ejercer diferentes presiones sobre la forma y la estructura de los huesos de las extremidades en los mamíferos.

Development of a prediction score (ThyroCOVID) for identifying abnormal thyroid function in COVID-19 patients.

PURPOSE: Thyroid dysfunction in COVID-19 carries clinical and prognostic implications. In this study, we developed a prediction score (ThyroCOVID) for abnormal thyroid function (TFT) on admission amongst COVID-19 patients. METHODS: Consecutive COVID-19 patients admitted to Queen Mary Hospital were prospectively recruited during July 2020-May 2021. Thyroid-stimulating hormone (TSH), free thyroxine (fT4) and free triiodothyronine (fT3) were measured on admission. Multivariable logistic regression analysis was performed to identify independent determinants of abnormal TFTs. ThyroCOVID was developed based on a clinical model with the lowest Akaike information criteria. RESULTS: Five hundred and forty six COVID-19 patients were recruited (median age 50 years, 45.4% men, 72.9% mild disease on admission). 84 patients (15.4%) had abnormal TFTs on admission. Patients with abnormal TFTs were more likely to be older, have more comorbidities, symptomatic, have worse COVID-19 severity, higher SARS-CoV-2 viral loads and more adverse profile of acute-phase reactants, haematological and biochemical parameters. ThyroCOVID consisted of five parameters: symptoms (malaise), comorbidities (ischaemic heart disease/congestive heart failure) and laboratory parameters (lymphocyte count, C-reactive protein, and SARS-CoV-2 cycle threshold values). It was able to identify abnormal TFT on admission with an AUROC of 0.73 (95% CI 0.67-0.79). The optimal cut-off of 0.15 had a sensitivity of 75.0%, specificity of 65.2%, negative predictive value of 93.5% and positive predictive value of 28.1% in identifying abnormal TFTs on admission amongst COVID-19 patients. CONCLUSION: ThyroCOVID, a prediction score to identify COVID-19 patients at risk of having abnormal TFT on admission, was developed based on a cohort of predominantly non-severe COVID-19 patients.

A repeating fast radio burst associated with a persistent radio source.

The dispersive sweep of fast radio bursts (FRBs) has been used to probe the ionized baryon content of the intergalactic medium1, which is assumed to dominate the total extragalactic dispersion. Although the host-galaxy contributions to the dispersion measure appear to be small for most FRBs2, in at least one case there is evidence for an extreme magneto-ionic local environment3,4 and a compact persistent radio source5. Here we report the detection and localization of the repeating FRB 20190520B, which is co-located with a compact, persistent radio source and associated with a dwarf host galaxy of high specific-star-formation rate at a redshift of 0.241 ± 0.001. The estimated host-galaxy dispersion measure of approximately [Formula: see text] parsecs per cubic centimetre, which is nearly an order of magnitude higher than the average of FRB host galaxies2,6, far exceeds the dispersion-measure contribution of the intergalactic medium. Caution is thus warranted in inferring redshifts for FRBs without accurate host-galaxy identifications.

Avelumab in unresectable/metastatic, progressive, grade 2-3 neuroendocrine neoplasms (NENs): Combined results from NET-001 and NET-002 trials.

BACKGROUND: Higher grade neuroendocrine neoplasm (NENs) continues to pose a treatment dilemma, with the optimal treatment undefined. Although immunotherapy has revolutionised the treatment of many cancers, its role in NENs remains unclear. We aimed to investigate the efficacy and safety of avelumab, a PD-L1-directed antibody, in patients with advanced unresectable/metastatic higher grade NENs. METHODS: NET001 and NET002 are phase II studies investigating avelumab (NCT03278405 and NCT03278379). Eligible patients had unresectable and/or metastatic WHO G2-3 NENs from a gastroenteropancreatic (GEP) source or a bronchial primary (excluding typical carcinoid) and 0-2 prior lines of systemic therapy (excluding SSAs). Patients were treated with avelumab 10 mg/kg intravenously every two weeks for 26 cycles. NET001 investigated G3 poorly differentiated GEP neuroendocrine carcinomas (NECs) and bronchial small/large cell NEC, whereas NET002 investigated G2-3 well-differentiated GEPNETs and bronchial atypical carcinoids. The primary endpoint in both trials was overall response rate (ORR) by RECIST v1.1; secondary endpoints included progression-free survival, overall survival, disease control rate at six months and toxicity. RESULTS: Twenty-seven patients were enrolled (21 GEP, 6 lung; 10 in NET-001, 17 in NET-002); median age 64 (range 37-80), 30% ECOG PS 1-2 and 78% received 1+ lines of prior therapy. The median Ki-67 index was 35% (range 10-100). Twelve of the twenty-seven patients had died at the time of data lock. The median time on treatment was 85 days (seven cycles). No objective responses were observed. Stable disease was achieved in 33% of patients, and the disease control rate at 6 mo was 21%. The median PFS was 3.3 months (range 1.2-24.6), and the median OS was 14.2 months. Treatment-related adverse events (all grades) occurred in 58% of patients. Three patients had treatment-related grade 3-4 AEs leading to treatment discontinuation (immune-related hepatitis n = 2 and infusion-related reaction n = 1). CONCLUSION: Single-agent PD-L1 blockade with avelumab showed limited antitumour activity in patients with G2-3 NENs. Correlative studies are underway. Further studies are needed to explore the role of dual immunotherapy and other combinations in this population with few treatment alternatives.

Update on the Recommendations on Breast Cancer Screening by the Cancer Expert Working Group on Cancer Prevention and Screening.

Breast cancer (BC) is the most common cancer among women in Hong Kong. The Food and Health Bureau commissioned The University of Hong Kong (HKU) to conduct the Hong Kong Breast Cancer Study (HKBCS) with the aim of identifying relevant risk factors for BC in Hong Kong and developing a locally validated BC risk assessment tool for Hong Kong Chinese women. After consideration of the most recent international and local scientific evidence including findings of the HKBCS, the Cancer Expert Working Group on Cancer Prevention and Screening (CEWG) has reviewed and updated its BC screening recommendations. Existing recommendations were preserved for women at high risk and slightly changed for women at moderate risk. The following major updates have been made concerning recommendations for other women in the general population: Women aged 44 to 69 with certain combinations of personalised risk factors (including presence of history of BC among first-degree relative, a prior diagnosis of benign breast disease, nulliparity and late age of first live birth, early age of menarche, high body mass index and physical inactivity) putting them at increased risk of BC are recommended to consider mammography screening every 2 years. They should discuss with their doctors on the potential benefits and harms before undergoing mammography screening. A risk assessment tool for local women (eg, one developed by HKU) is recommended to be used for estimating the risk of developing BC with regard to the personalised risk factors described above.

A repeating fast radio burst source in a globular cluster.

Fast radio bursts (FRBs) are flashes of unknown physical origin1. The majority of FRBs have been seen only once, although some are known to generate multiple flashes2,3. Many models invoke magnetically powered neutron stars (magnetars) as the source of the emission4,5. Recently, the discovery6 of another repeater (FRB 20200120E) was announced, in the direction of the nearby galaxy M81, with four potential counterparts at other wavelengths6. Here we report observations that localized the FRB to a globular cluster associated with M81, where it is 2 parsecs away from the optical centre of the cluster. Globular clusters host old stellar populations, challenging FRB models that invoke young magnetars formed in a core-collapse supernova. We propose instead that FRB 20200120E originates from a highly magnetized neutron star formed either through the accretion-induced collapse of a white dwarf, or the merger of compact stars in a binary system7. Compact binaries are efficiently formed inside globular clusters, so a model invoking them could also be responsible for the observed bursts.

A practical methodology to improve the dosimetric accuracy of MR-based radiotherapy simulation for brain tumors.

PURPOSE: To investigate the dosimetric accuracy of synthetic computed tomography (sCT) images generated by a clinically-ready voxel-based MRI simulation package, and to develop a simple and feasible method to improve the accuracy. METHODS: 20 patients with brain tumor were selected to undergo CT and MRI simulation. sCT images were generated by a clinical MRI simulation package. The discrepancy between planning CT and sCT in CT number and body contour were evaluated. To resolve the discrepancies, an sCT specific CT-relative electron density (RED) calibration curve was used, and a layer of pseudo-skin was created on the sCT. The dosimetric impact of these discrepancies, and the improvement brought about by the modifications, were evaluated by a planning study. Volumetric modulated arc therapy (VMAT) treatment plans for each patient were created and optimized on the planning CT, which were then transferred to the original sCT and the modified-sCT for dose re-calculation. Dosimetric comparisons and gamma analysis between the calculated doses in different images were performed. RESULTS: The average gamma passing rate with 1%/1 mm criteria was only 70.8% for the comparison of dose distribution between planning CT and original sCT. The mean dose difference between the planning CT and the original sCT were -1.2% for PTV D95 and -1.7% for PTV Dmax, while the mean dose difference was within 0.7 Gy for all relevant OARs. After applying the modifications on the sCT, the average gamma passing rate was increased to 92.2%. Mean dose difference in PTV D95 and Dmax were reduced to -0.1% and -0.3% respectively. The mean dose difference was within 0.2 Gy for all OAR structures and no statistically significant difference were found. CONCLUSIONS: The modified-sCT demonstrated improved dosimetric agreement with the planning CT. These results indicated the overall dosimetric accuracy and practicality of this improved MR-based treatment planning method.

Potential Efficacy of Pragmatic Exercise Program (SPRINT) during Hospitalization in Older Adults on Health Care and Physical Performance: A Pilot Study.

OBJECTIVES: Immobilization contribute to iatrogenic decline in hospitalized older adult. Implementing physical activity (PA) seems to be one of the best and easy solution. However, PA interventions are poorly integrated into usual care and those available are either non-specific, need supervision or requested human/material resources. Thus, we aimed to assess the effect of a pragmatic, unsupervised, and specific PA program (SPRINT) on health care practice and functional capacities in hospitalized older patients. DESIGN: Single arm interventional pragmatic pilot study. SETTING: Geriatric Assessment Unit (GAU). PARTICIPANTS: Of the 39 patients (> 65 years) hospitalized in a GAU and eligible, 19 agreed to participate (AP) and 20 declined (N-AP). INTERVENTION: One of the 4 PA programs, developed by our team, was allocated according to mobility profile. Individual functional capacities (i.e. balance, walking speed, functional mobility profile (PFMP)), active time (METS> 1.5: min), length of hospitalization (LOS), discharge orientation were assessed at admission and discharge of GAU. RESULTS: Baseline characteristics of the 2 groups were comparable. At discharge, the AP group improved more on walking speed (0.57 ± 0.21 vs. 0.64 ± 0.19; p = 0.013), Berg balance scale (41.8 ± 13.7 vs. 45.1 ± 9.7; p = 0.017) and PFMP (54.0 ± 7.1 vs 55.1 ± 5.5; p = 0.042) than the N-AP group. The LOS was significantly shorter in AP group compared to the N-AP group (5 vs. 36 days; p = 0.026) and more subjects in the AP group were oriented at home without health or social services (89.5 vs. 60%; p=0.065). CONCLUSION: SPRINT appears effective to counteract iatrogenic decline and decreased the LOS. Moreover, this simple pragmatic PA tool seems to improve the life trajectory and healthcare practice in aging population. Further researches are needed to confirm these promising pragmatic results.

Prevalence and associations of larger burden of intra-anal high-grade squamous intraepithelial lesions at baseline in an Australian cohort of gay and bisexual men: The Study of the Prevention of Anal Cancer.

OBJECTIVES: To investigate factors associated with larger burden of intra-anal high-grade squamous intraepithelial lesions (HSIL) in a natural history study of HSIL. METHODS: 617 gay and bisexual men (GBM) attended a baseline visit. High-resolution anoscopy-directed biopsy was performed of suspected HSIL. GBM with biopsy-confirmed HSIL (bHSIL) affecting a single-octant were compared with those who had bHSIL affecting a larger area. RESULTS: Of 196 men with bHSIL at baseline, 73 (37.2 %) had larger bHSIL burden. Larger burden was independently associated with anal HPV16 detection (aOR 2.06, 95 % CI 1.09-3.89, p = 0.026) and infection with a greater number of high-risk HPV types (aOR per type increase 1.25, 95 % CI 1.05-1.49, p-trend = 0.010). CONCLUSION: The observation that men with a larger burden of HSIL also had more risk factors for anal cancer suggests this group may warrant closer observation to ensure earlier detection, and thus improved prognosis, of individuals whose HSIL may progress to anal cancer.

A repeating fast radio burst source localized to a nearby spiral galaxy.

Fast radio bursts (FRBs) are brief, bright, extragalactic radio flashes1,2. Their physical origin remains unknown, but dozens of possible models have been postulated3. Some FRB sources exhibit repeat bursts4-7. Although over a hundred FRB sources have been discovered8, only four have been localized and associated with a host galaxy9-12, and just one of these four is known to emit repeating FRBs9. The properties of the host galaxies, and the local environments of FRBs, could provide important clues about their physical origins. The first known repeating FRB, however, was localized to a low-metallicity, irregular dwarf galaxy, and the apparently non-repeating sources were localized to higher-metallicity, massive elliptical or star-forming galaxies, suggesting that perhaps the repeating and apparently non-repeating sources could have distinct physical origins. Here we report the precise localization of a second repeating FRB source6, FRB 180916.J0158+65, to a star-forming region in a nearby (redshift 0.0337 ± 0.0002) massive spiral galaxy, whose properties and proximity distinguish it from all known hosts. The lack of both a comparably luminous persistent radio counterpart and a high Faraday rotation measure6 further distinguish the local environment of FRB 180916.J0158+65 from that of the single previously localized repeating FRB source, FRB 121102. This suggests that repeating FRBs may have a wide range of luminosities, and originate from diverse host galaxies and local environments.

Modulation of Macrophages Differentiation by Nanoscale-Engineered Geometric and Chemical Features.

Macrophage differentiation into M1 (inflammatory) and M2 (healing) phenotypes plays a vital role in determining the fate of biomaterials. The biophysical properties of the extracellular matrix are known to affect macrophage behavior. Mimicking these special biophysical properties of the extracellular matrix has led to increasing interest in biomaterial constructs with tailor-engineered surface nanotopographical and chemical properties. However, a significant gap of knowledge exists in the role played by the combinational effect of surface nanotopography and chemistry. To address this gap, we have fabricated nanoporous surfaces of controlled pore size (30, 65, and 200 nm) and lateral spacing with uniform outermost surface chemistry tailored with amines (NH2), carboxyl (COOH-) and hydrocarbon (CH3-) functionalities. We show that the combinatory effects of surface properties can direct the differentiation of macrophages to the pro-healing M2 phenotype. This is most evident on the surface featuring nanopores of 200 nm and -COOH functionality. Overall, the concentration of pro-inflammatory cytokines significantly decreases, while the concentration of anti-inflammatory cytokines increases many folds on nanotopographically, and chemically, modified surfaces compared to their planar counterparts. Our data provide pioneering knowledge that could provide pathways to tuning inflammatory and foreign body responses and instruct the design of tailor-engineered biomaterial implants to enable better clinical outcomes.

Implementation of a clinical guideline to decrease laboratory tests in newborns evaluated for early onset sepsis.

BACKGROUND: Creation of a clinical guideline to reduce the number of complete blood counts (CBCs) obtained on healthy term infants for early onset sepsis (EOS) evaluation secondary to maternal chorioamnionitis. METHODS: A clinical guideline was introduced at four neonatal intensive care units (NICU) to reduce laboratory tests during EOS evaluation. Measures include frequency and timing of CBCs, culture negative sepsis, length of stay, and readmission rate. RESULTS: Mean number of CBCs per patient significantly decreased (2.31±0.62 versus 1.52±0.65) without increasing trends for patients with culture negative sepsis, length of stay, or re-admission. CONCLUSION: The clinical guideline demonstrated a significant reduction in the number of CBCs obtained in well-appearing infants admitted to the NICU secondary to maternal chorioamnionitis.