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Heavy alcohol use, cumulative marijuana use, and cumulative tobacco use were associated with a higher frequency of vasomotor symptoms. Heavy alcohol use and opioid use were associated with mood symptoms of menopause and opioid use was associated with musculoskeletal symptoms of menopause.

The frequency of wildfires has significantly increased in recent years, posing concerns for many grapegrowers and winemakers. Exposure of grapes to smoke can result in wines with notable smoky notes, which in severe cases are described as “smoke tainted”. However, smoky aromas in wine are not a prioriquality defects but may be considered desirable in some styles of wines, as also widely found and appreciated in many spirits. In this perspective, we summarize recent research on sources and assessment of smoky sensory attributes in wine and provide an outlook on opportunities for managing excessive smoky characters.

ABSTRACTBehavioral problems are commonly observed in primary school children, yet the educational contexts in which children’s behaviors occur vary across regions of the world. Thus, culturally adapted and context-specific behavioral assessments are needed to successfully identify and support children at risk for severe behavior problems. This study examines behavior problems in a nationally representative sample (N= 700) of primary school students in Trinidad and Tobago using the Adjustment Scales for Children and Adolescents, a contextually-based assessment that has been adapted and standardized for use with this population. We applied latent profile analysis, a person-centered approach, to identify distinct patterns of behavior problems and contexts in which behaviors occurred. The resultant 6-profile model consisted of two profiles of adjusted children making up 60% of the sample and four profiles of at-risk children with elevated underactive and/or overactive behavior problems associated with different classroom contexts. Profiles were differentially associated with classroom learning behaviors and reading ability. The most vulnerable subgroup of primary school students showed high levels of under- and overactive behaviors in peer, learning, and teacher contexts, deficits in reading fluency, problem-solving, and motivation.

While technology-based interventions enhance instruction and improve outcomes for students with disabilities, implementing and integrating technology in authentic learning environments continues to be a challenge. Based on the experiences of a variety of Stepping-Up Technology Implementation projects funded by the U.S. Department of Education, Office of Special Education Programs, this mixed-methods study explored the essential factors for the successful implementation of technology-based interventions in K-12 schools and early childhood programs. Based on the qualitative analysis of projects’ implementation reports and responses to the follow-up questionnaire, four major themes emerged. The barriers and facilitators to technology implementation were reported across such areas as (a) developing and sustaining buy-in, (b) ensuring implementation fidelity to support the intervention, (c) research-to-practice dilemmas, and (d) data serving multiple purposes. The discussion and practical implications for supporting technology implementation are provided.

The federal judicial system is a hierarchy with district courts at the bottom, courts of appeals in the middle, and the Supreme Court at the top. A second, less visible, judicial hierarchy exists within district courts, with magistrate judges situated below district judges. Existing scholarship largely ignores magistrate judges, assuming they are agents tasked with procedural matters with little independent effect on federal courts adjudication. Using a combination of national administrative data (2000–2016) and original case-level data from nine district courts (1997–2014), we find that district courts not only grant meaningful responsibility and discretion to magistrate judges but do so in ways that vary substantially across and within districts. The effects of this judicial delegation extend from procedural rulings to substantive outcomes. Our findings provide evidence that a complete understanding of federal judicial decision making accounts for the roles—procedural and substantive—that magistrate judges perform.

Antimicrobial resistance (AMR) poses a major threat to human health around the world. Previous publications have estimated the effect of AMR on incidence, deaths, hospital length of stay, and health-care costs for specific pathogen–drug combinations in select locations. To our knowledge, this study presents the most comprehensive estimates of AMR burden to date.

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Objective In the United States, guidelines indicate all pregnant women should be screened for and counseled on alcohol use to prevent adverse perinatal outcomes due to alcohol consumption. The objective of this study was to describe sociodemographic factors associated with receipt of prenatal alcohol counseling and perinatal alcohol use among US women.Methods State health departments collected data for the Pregnancy Risk Assessment Monitoring System Phase 7 during 2012-2015, and we restricted the sample to a complete case analysis (N = 135 111). The 3 dichotomous outcomes were preconception alcohol use (3 months before pregnancy), prenatal alcohol use (during last 3 months of pregnancy), and prenatal alcohol counseling. Predictor variables were age, race, Hispanic ethnicity, education, marital status, health insurance status, and previous live births. We estimated survey-weighted logistic regression models for each outcome.Results Half (56.0%) of pregnant women reported preconception alcohol use, 70.5% received prenatal alcohol counseling, and 7.7% reported prenatal alcohol use during the last 3 months of pregnancy. Black women were significantly less likely than White women (odds ratio [OR] = 0.49; 95% CI, 0.46-0.52) and Hispanic women were significantly less likely than non-Hispanic women (OR = 0.62; 95% CI, 0.58-0.66) to report preconception alcohol use. We found similar patterns for prenatal alcohol use among Black women. Black women were significantly more likely than White women (OR = 1.66; 95% CI, 1.55-1.77) and Hispanic women were significantly more likely than non-Hispanic women (OR = 1.51; 95% CI, 1.40-1.61) to receive prenatal alcohol counseling. We found similar patterns for age, education, and health insurance status.Conclusion Disparities in alcohol counseling occurred despite the national recommendation for universal screening and counseling prenatally. Continued integration of universal screening for alcohol use during pregnancy is needed.

Novel toxicity metrics that account for all adverse event (AE) grades and the frequency of may enhance toxicity reporting in clinical trials. The Toxicity Index (TI) accounts for all AE grades and frequencies for categories of interest. We evaluate the feasibility of using the TI methodology in 2 prospective anal cancer trials and to evaluate whether more conformal radiation (using Intensity Modulated Radiation Therapy) results in improved toxicity as measured by the TI. Patients enrolled on NRG/RTOG 0529 or nonconformal RT enrolled on the 5-Fluorouracil/Mitomycin arm of NRG/RTOG 9811 were compared using the TI. Patients treated on NRG/RTOG 0529 had lower median TI compared with patients treated with nonconformal RT on NRG/RTOG 9811 for combined GI/GU/Heme/Derm events (3.935 vs 3.996, P=0.014). The TI methodology is a feasible method to assess all AEs of interest and may be useful as a composite metric for future efforts aimed at treatment de-escalation or escalation

AbstractObjectivesDistress screening has now become part of the culture of cancer care, with clinical practice guidelines set forth by the National Comprehensive Cancer Network (NCCN) and requirements by the Commission on Cancer (CoC). Because interdisciplinary teams are specialists in treating certain disease sites, it is important to develop distress screening guidelines that best serve that patient population and their treatment.MethodsA retrospective review of patients with surgically resectable esophageal cancer who were treated at a single institution was performed. Patients voluntarily undergoing the prehabilitation program (n = 11) received a structured protocol intervention in several clinical domains, including psychosocial distress screening.ResultsDespite having a protocol, variations in the number of times patients were screened for distress (range, 1-9 times; mean = 4.73) suggests that the protocol was not accomplished. Elapsed time between first and final distress screens ranged from 0 to 68 days (mean = 40.27), and time from final distress screen to surgery ranged from 50 to 122 days, with a mean of 76.45 days.Significance of ResultsThe pilot prehabilitation program demonstrated difficulties with the distress screening protocol. Subsequently, a more comprehensive distress screening program is recommended in this highly vulnerable patient population by aligning the NCCN distress management screening guidelines with the clinical pathway for treating surgically resectable esophageal cancer. With the difficult prognosis and treatment known for patients with esophageal cancer, tailored distress screening protocols should be implemented throughout the duration of treatment.

IMPORTANCE: Total neoadjuvant therapy (TNT) is often used to downstage locally advanced rectal cancer (LARC) and decrease locoregional relapse; however, more than one-third of patients develop recurrent metastatic disease. As such, novel combinations are needed. OBJECTIVE: To assess whether the addition of pembrolizumab during and after neoadjuvant chemoradiotherapy can lead to an improvement in the neoadjuvant rectal (NAR) score compared with treatment with FOLFOX (5-fluorouracil, leucovorin, and oxaliplatin) and chemoradiotherapy alone. DESIGN, SETTING, AND PARTICIPANTS: In this open-label, phase 2, randomized clinical trial (NRG-GI002), patients in academic and private practice settings were enrolled. Patients with stage II/III LARC with distal location (cT3-4 ≤ 5 cm from anal verge, any N), with bulky disease (any cT4 or tumor within 3 mm of mesorectal fascia), at high risk for metastatic disease (cN2), and/or who were not candidates for sphincter-sparing surgery (SSS) were stratified based on clinical tumor and nodal stages. Trial accrual opened on August 1, 2018, and ended on May 31, 2019. This intent-to-treat analysis is based on data as of August 2020. INTERVENTIONS: Patients were randomized (1:1) to neoadjuvant FOLFOX for 4 months and then underwent chemoradiotherapy (capecitabine with 50.4 Gy) with or without intravenous pembrolizumab administered at a dosage of 200 mg every 3 weeks for up to 6 doses before surgery. MAIN OUTCOMES AND MEASURES: The primary end point was the NAR score. Secondary end points included pathologic complete response (pCR) rate, SSS, disease-free survival, and overall survival. This report focuses on end points available after definitive surgery (NAR score, pCR, SSS, clinical complete response rate, margin involvement, and safety). RESULTS: A total of 185 patients (126 [68.1%] male; mean [SD] age, 55.7 [11.1] years) were randomized to the control arm (CA) (n = 95) or the pembrolizumab arm (PA) (n = 90). Of these patients, 137 were evaluable for NAR score (68 CA patients and 69 PA patients). The mean (SD) NAR score was 11.53 (12.43) for the PA patients (95% CI, 8.54-14.51) vs 14.08 (13.82) for the CA patients (95% CI, 10.74-17.43) (P = .26). The pCR rate was 31.9% in the PA vs 29.4% in the CA (P = .75). The clinical complete response rate was 13.9% in the PA vs 13.6% in the CA (P = .95). The percentage of patients who underwent SSS was 59.4% in the PA vs 71.0% in the CA (P = .15). Grade 3 to 4 adverse events were slightly increased in the PA (48.2%) vs the CA (37.3%) during chemoradiotherapy. Two deaths occurred during FOLFOX: sepsis (CA) and pneumonia (PA). No differences in radiotherapy fractions, FOLFOX, or capecitabine doses were found. CONCLUSIONS AND RELEVANCE: Pembrolizumab added to chemoradiotherapy as part of total neoadjuvant therapy was suggested to be safe; however, the NAR score difference does not support further study. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02921256

Fetal RHD screening for targeted routine antenatal anti-D prophylaxis has been implemented in many countries, including Finland, since the 2010s. Comprehensive knowledge of the RHD polymorphism in the population is essential for the performance and safety of the anti-D prophylaxis program. During the first 3 years of the national screening program in Finland, over 16 000 samples from RhD− women were screened for fetal RHD; among them, 79 samples (0.5%) containing a maternal variant allele were detected. Of the detected maternal variants, 35 cases remained inconclusive using the traditional genotyping methods and required further analysis by next-generation sequencing (NGS) of the whole RHD gene to uncover the variant allele. In addition to the 13 RHD variants that have been previously reported in different populations, 8 novel variants were also detected, indicating that there is more variation of RHD in the RhD− Finnish population than has been previously known. Three of the novel alleles were identified in multiple samples; thus, they are likely specific to the original Finnish population. National screening has thus provided new information about the diversity of RHD variants in the Finnish population. The results show that NGS is a powerful method for genotyping the highly polymorphic RHD gene compared with traditional methods that rely on the detection of specific nucleotides by polymerase chain reaction amplification.

Fetal RHDscreening for targeted routine antenatal anti-D prophylaxis has been implemented in many countries, including Finland, since the 2010s. Comprehensive knowledge of the RHDpolymorphism in the population is essential for the performance and safety of the anti-D prophylaxis program. During the first 3 years of the national screening program in Finland, over 16 000 samples from RhD−women were screened for fetal RHD; among them, 79 samples (0.5%) containing a maternal variant allele were detected. Of the detected maternal variants, 35 cases remained inconclusive using the traditional genotyping methods and required further analysis by next-generation sequencing (NGS) of the whole RHDgene to uncover the variant allele. In addition to the 13 RHDvariants that have been previously reported in different populations, 8 novel variants were also detected, indicating that there is more variation of RHDin the RhD−Finnish population than has been previously known. Three of the novel alleles were identified in multiple samples; thus, they are likely specific to the original Finnish population. National screening has thus provided new information about the diversity of RHDvariants in the Finnish population. The results show that NGS is a powerful method for genotyping the highly polymorphic RHDgene compared with traditional methods that rely on the detection of specific nucleotides by polymerase chain reaction amplification.

miR-140 is selectively expressed in cartilage. Deletion of the entire Mir140locus in mice results in growth retardation and early-onset osteoarthritis-like pathology; however, the relative contribution of miR-140-5p or miR-140-3p to the phenotype remains to be determined. An unbiased small RNA sequencing approach identified miR-140-3p as significantly more abundant (>10-fold) than miR-140-5p in human cartilage. Analysis of these data identified multiple miR-140-3p isomiRs differing from the miRBase annotation at both the 5′ and 3′ end, with >99% having one of two seed sequences (5′ bases 2–8). Canonical (miR-140-3p.2) and shifted (miR-140-3p.1) seed isomiRs were overexpressed in chondrocytes and transcriptomics performed to identify targets. miR-140-3p.1 and miR-140-3p.2 significantly down-regulated 694 and 238 genes, respectively, of which only 162 genes were commonly down-regulated. IsomiR targets were validated using 3′UTR luciferase assays. miR-140-3p.1 targets were enriched within up-regulated genes in rib chondrocytes of Mir140-null mice and within down-regulated genes during human chondrogenesis. Finally, through imputing the expression of miR-140 from the expression of the host gene WWP2in 124 previously published data sets, an inverse correlation with miR-140-3p.1 predicted targets was identified. Together these data suggest the novel seed containing isomiR miR-140-3p.1 is more functional than original consensus miR-140-3p seed containing isomiR.

As referenced in the Every Student Succeeds Act and the National Educational Technology Plan, personalized learning is the new focus in many K–12 learning environments. Nonetheless, few people understand what personalized learning really means and even fewer can design and implement a personalized learning environment appropriate for all learners, especially learners with disabilities. This 18-month descriptive research study focused on identifying the design characteristics of personalized learning environments and the initial results of these environments. Findings indicate that personalized learning environments require more than technology, that the technology itself is simply a tool to support implementation. These personalized learning environments were highly learner self-regulated, had transparent and actionable near-real-time data, provided various structures for student voice and feedback, and integrated purposeful supports for embedding the principles of Universal Design for Learning at the cornerstone of practice. Personalized learning requires a shift in instructional practice on behalf of both the teacher and the learners. Implications for further research and practice are discussed.

Conducting focus groups with target audiences to assess user needs is a critical step in the process of designing and developing a web-based writing environment. This descriptive study examined focus group data gathered to address two questions: First, do data from focus groups affirm and expand our understanding of writing and writing development among middle school students? And second, do data from focus groups provide information helpful to the use of digital technology for enhancing writing instruction, production, and engagement? Analysis of students’ writing experiences across grade levels revealed that sixth graders placed more emphasis on procedural knowledge such as format, editing, and timelines, whereas seventh and eighth graders placed more emphasis on substantive processes such as plan, draft, and revise. Students’ writing experiences also showed a disconnect between writing behaviors they engaged in on their own (texting, social media, and email) and writings they learned in school. Future research and instructional practice implications are discussed, including providing ongoing supports when writing and use of digital technology to enhance instruction and engagement.

Genotoxic DNA double-strand breaks (DSBs) can be repaired by error-free homologous recombination (HR) or mutagenic non-homologous end-joining1. HR supresses tumorigenesis1, but is restricted to the S and G2 phases of the cell cycle when a sister chromatid is present2. Breast cancer type 1 susceptibility protein (BRCA1) promotes HR by antagonizing the anti-resection factor TP53-binding protein 1(53BP1) (refs. 2, 3, 4–5), but it remains unknown how BRCA1 function is limited to the S and G2 phases. We show that BRCA1 recruitment requires recognition of histone H4 unmethylated at lysine 20 (H4K20me0), linking DSB repair pathway choice directly to sister chromatid availability. We identify the ankyrin repeat domain of BRCA1-associated RING domain protein 1 (BARD1)—the obligate BRCA1 binding partner3—as a reader of H4K20me0 present on new histones in post-replicative chromatin6. BARD1 ankyrin repeat domain mutations disabling H4K20me0 recognition abrogate accumulation of BRCA1 at DSBs, causing aberrant build-up of 53BP1, and allowing anti-resection activity to prevail in S and G2. Consequently, BARD1 recognition of H4K20me0 is required for HR and resistance to poly (ADP-ribose) polymerase inhibitors. Collectively, this reveals that BRCA1–BARD1 monitors the replicative state of the genome to oppose 53BP1 function, routing only DSBs within sister chromatids to HR.

The Rh blood group system (ISBT004) is the second most important blood group after ABO and is the most polymorphic one, with 55 antigens encoded by 2 genes, RHDand RHCE. This research uses next-generation sequencing (NGS) to sequence the complete RHDgene by amplifying the whole gene using overlapping long-range polymerase chain reaction (LR-PCR) amplicons. The aim was to study different RHDalleles present in the population to establish reference RHDallele sequences by using the analysis of intronic single-nucleotide polymorphisms (SNPs) and their correlation to a specific Rh haplotype. Genomic DNA samples (n = 69) from blood donors of different serologically predicted genotypes including R1R1(DCe/DCe), R2R2(DcE/DcE), R1R2(DCe/DcE), R2RZ(DcE/DCE), R1r (DCe/dce), R2r (DcE/dce), and R0r (Dce/dce) were sequenced and data were then mapped to the human genome reference sequence hg38. We focused on the analysis of hemizygous samples, as these by definition will only have a single copy of RHD. For the 69 samples sequenced, different exonic SNPs were detected that correlate with known variants. Multiple intronic SNPs were found in all samples: 21 intronic SNPs were present in all samples indicating their specificity to the RHD*DAU0 (RHD*10.00)haplotype which the hg38 reference sequence encodes. Twenty-three intronic SNPs were found to be R2haplotype specific, and 15 were linked to R1, R0, and RZhaplotypes. In conclusion, intronic SNPs may represent a novel diagnostic approach to investigate known and novel variants of the RHDand RHCEgenes, while being a useful approach to establish reference RHDallele sequences.

The Rh blood group system (ISBT004) is the second most important blood group after ABO and is the most polymorphic one, with 55 antigens encoded by 2 genes, RHD and RHCE. This research uses next-generation sequencing (NGS) to sequence the complete RHD gene by amplifying the whole gene using overlapping long-range polymerase chain reaction (LR-PCR) amplicons. The aim was to study different RHD alleles present in the population to establish reference RHD allele sequences by using the analysis of intronic single-nucleotide polymorphisms (SNPs) and their correlation to a specific Rh haplotype. Genomic DNA samples (n = 69) from blood donors of different serologically predicted genotypes including R1R1 (DCe/DCe), R2R2 (DcE/DcE), R1R2 (DCe/DcE), R2RZ (DcE/DCE), R1r (DCe/dce), R2r (DcE/dce), and R0r (Dce/dce) were sequenced and data were then mapped to the human genome reference sequence hg38. We focused on the analysis of hemizygous samples, as these by definition will only have a single copy of RHD. For the 69 samples sequenced, different exonic SNPs were detected that correlate with known variants. Multiple intronic SNPs were found in all samples: 21 intronic SNPs were present in all samples indicating their specificity to the RHD*DAU0 (RHD*10.00) haplotype which the hg38 reference sequence encodes. Twenty-three intronic SNPs were found to be R2 haplotype specific, and 15 were linked to R1, R0, and RZ haplotypes. In conclusion, intronic SNPs may represent a novel diagnostic approach to investigate known and novel variants of the RHD and RHCE genes, while being a useful approach to establish reference RHD allele sequences.

Few data exist for the genetic variants underlying the risk for steroid-sensitive nephrotic syndrome (SSNS) in children. The objectives of this study were to evaluate HLA-DQA1and APOL1variants as risk factors for SSNS in African American children and use classic HLA antigen types and amino acid inference to refine the HLA-DQA1association.

This study reports on the national standardization and validation of the Learning Behaviors Scale (LBS) for use in Trinidad and Tobago. The LBS is a teacher rating scale centering on observable behaviors relevant to identifying childhood approaches to classroom learning. Teachers observed a stratified sample of 900 students across the islands' schools nationwide. Exploratory and confirmatory factor analyses yielded two reliable dimensions: Competence Motivation and Strategy/Flexibility. Scales were developed using IRT and Bayesian scoring methods and scores were used in HLM models to investigate variance accounted for in measures of academic achievement and psychopathology.

Hemostasis in vertebrates involves both a cellular and a protein component. Previous studies in jawless vertebrates (cyclostomes) suggest that the protein response, which involves thrombin-catalyzed conversion of a soluble plasma protein, fibrinogen, into a polymeric fibrin clot, is conserved in all vertebrates. However, similar data are lacking for the cellular response, which in gnathostomes is regulated by von Willebrand factor (VWF), a glycoprotein that mediates the adhesion of platelets to the subendothelial matrix of injured blood vessels. To gain evolutionary insights into the cellular phase of coagulation, we asked whether a functional vwfgene is present in the Atlantic hagfish, Myxine glutinosa. We found a single vwftranscript that encodes a simpler protein compared with higher vertebrates, the most striking difference being the absence of an A3 domain, which otherwise binds collagen under high-flow conditions. Immunohistochemical analyses of hagfish tissues and blood revealed Vwf expression in endothelial cells and thrombocytes. Electron microscopic studies of hagfish tissues demonstrated the presence of Weibel-Palade bodies in the endothelium. Hagfish Vwf formed high-molecular-weight multimers in hagfish plasma and in stably transfected CHO cells. In functional assays, botrocetin promoted VWF-dependent thrombocyte aggregation. A search for vwfsequences in the genome of sea squirts, the closest invertebrate relatives of hagfish, failed to reveal evidence of an intact vwfgene. Together, our findings suggest that VWF evolved in the ancestral vertebrate following the divergence of the urochordates some 500 million years ago and that it acquired increasing complexity though sequential insertion of functional modules.

Hemostasis in vertebrates involves both a cellular and a protein component. Previous studies in jawless vertebrates (cyclostomes) suggest that the protein response, which involves thrombin-catalyzed conversion of a soluble plasma protein, fibrinogen, into a polymeric fibrin clot, is conserved in all vertebrates. However, similar data are lacking for the cellular response, which in gnathostomes is regulated by von Willebrand factor (VWF), a glycoprotein that mediates the adhesion of platelets to the subendothelial matrix of injured blood vessels. To gain evolutionary insights into the cellular phase of coagulation, we asked whether a functional vwf gene is present in the Atlantic hagfish, Myxine glutinosa. We found a single vwf transcript that encodes a simpler protein compared with higher vertebrates, the most striking difference being the absence of an A3 domain, which otherwise binds collagen under high-flow conditions. Immunohistochemical analyses of hagfish tissues and blood revealed Vwf expression in endothelial cells and thrombocytes. Electron microscopic studies of hagfish tissues demonstrated the presence of Weibel-Palade bodies in the endothelium. Hagfish Vwf formed high-molecular-weight multimers in hagfish plasma and in stably transfected CHO cells. In functional assays, botrocetin promoted VWF-dependent thrombocyte aggregation. A search for vwf sequences in the genome of sea squirts, the closest invertebrate relatives of hagfish, failed to reveal evidence of an intact vwf gene. Together, our findings suggest that VWF evolved in the ancestral vertebrate following the divergence of the urochordates some 500 million years ago and that it acquired increasing complexity though sequential insertion of functional modules.