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Nature Methods Jul 2020The Rosetta software for macromolecular modeling, docking and design is extensively used in laboratories worldwide. During two decades of development by a community of... (Review)
Review
The Rosetta software for macromolecular modeling, docking and design is extensively used in laboratories worldwide. During two decades of development by a community of laboratories at more than 60 institutions, Rosetta has been continuously refactored and extended. Its advantages are its performance and interoperability between broad modeling capabilities. Here we review tools developed in the last 5 years, including over 80 methods. We discuss improvements to the score function, user interfaces and usability. Rosetta is available at http://www.rosettacommons.org.
Topics: Macromolecular Substances; Models, Molecular; Molecular Docking Simulation; Peptidomimetics; Protein Conformation; Proteins; Software
PubMed: 32483333
DOI: 10.1038/s41592-020-0848-2 -
The Lancet. Oncology Feb 2023Poly(ADP-ribose) polymerase (PARP) inhibitors are effective in germline BRCA1 or BRCA2 (BRCA1/2) mutation-associated metastatic breast cancer. However, studies... (Randomized Controlled Trial)
Randomized Controlled Trial
Cisplatin with veliparib or placebo in metastatic triple-negative breast cancer and BRCA mutation-associated breast cancer (S1416): a randomised, double-blind, placebo-controlled, phase 2 trial.
BACKGROUND
Poly(ADP-ribose) polymerase (PARP) inhibitors are effective in germline BRCA1 or BRCA2 (BRCA1/2) mutation-associated metastatic breast cancer. However, studies evaluating PARP inhibitors plus platinum-based chemotherapy in germline BRCA1/2-wildtype triple-negative breast cancer are scarce. A large proportion of germline BRCA1/2-wildtype triple-negative breast cancer shows homologous recombination deficiency (HRD), resulting in a BRCA-like phenotype that might render sensitivity to PARP inhibitors. The S1416 trial assessed the efficacy of cisplatin combined with the PARP inhibitor veliparib in three predefined groups of metastatic breast cancer: germline BRCA1/2-mutated, BRCA-like, and non-BRCA-like.
METHODS
S1416 was a randomised, double-blind, placebo-controlled, phase 2 trial conducted at 154 community and academic clinical sites across the USA. Eligible patients aged 18 years or older had metastatic or recurrent triple-negative breast cancer or germline BRCA1/2-associated metastatic or recurrent breast cancer, an Eastern Cooperative Oncology Group performance status of 0-2, and had received up to one line of chemotherapy for metastatic disease. Patients were randomly assigned (1:1) via the National Clinical Trials Network open interactive system with dynamic balancing on number of previous cytotoxic regimens for metastatic disease to receive intravenous cisplatin (75 mg/m, day 1) combined with either veliparib or matching placebo (300 mg orally twice a day, days 1-14) on a 21-day cycle. Investigators, patients, and the sponsors were masked to treatment assignment; the study statisticians were unmasked. Central testing after ran domisation classified patients as having mutated or wildtype germline BRCA1/2. A biomarker panel established a priori was used to classify patients with wildtype germline BRCA1/2 into BRCA-like and non-BRCA-like phenotype groups, with BRCA-like status based on at least one of the biomarkers: genomic instability score (≥42), somatic BRCA1/2 mutations, BRCA1 promoter methylation, or non-BRCA1/2 homologous recombination repair germline mutations. The primary endpoint was investigator-assessed progression-free survival, analysed separately for the three predefined biomarker groups with a prespecified α value for each analysis. Efficacy analyses were done by intention to treat and included all eligible patients. Safety analyses of toxicities attributed to treatment included all patients who received at least one dose of veliparib or placebo. The study is ongoing and registered with ClinicalTrials.gov, NCT02595905.
FINDINGS
Between July 7, 2016, and June 15, 2019, 335 patients were enrolled and randomly assigned. 320 patients (n=162 to cisplatin plus veliparib, all women; and n=158 to cisplatin plus placebo, 157 women and one man) were eligible for efficacy evaluation. 247 patients were classified into the three biomarker groups: germline BRCA1/2-mutated (n=37), BRCA-like (n=101), and non-BRCA-like (n=109). 73 patients could not be classified due to missing biomarker information. Median follow-up was 11·1 months (IQR 5·6-20·8). In the germline BRCA1/2-mutated group, median progression-free survival was 6·2 months (95% CI 2·3-9·2) in the cisplatin plus veliparib group and 6·4 months (4·3-8·2) in the cisplatin plus placebo group (HR 0·79 [95% CI 0·38-1·67]; log-rank p=0·54). In the BRCA-like group, median progression-free survival was 5·9 months (95% CI 4·3-7·8) in the cisplatin plus veliparib group versus 4·2 months (2·3-5·0) in the cisplatin plus placebo group (HR 0·57 [95% CI 0·37-0·88]; p=0·010). In the non-BRCA-like group, median progression-free survival was 4·0 months (95% CI 2·5-4·7) in the cisplatin plus veliparib group versus 3·0 months (2·2-4·4) in the cisplatin plus placebo group (HR 0·89 [95% CI 0·60-1·33]; p=0·57). The most common grade 3 or worse adverse events attributed to treatment were neutropenia (71 [46%] of 155 patients in the cisplatin plus veliparib group vs 29 [20%] of 147 in the cisplatin plus placebo group), leukopenia (42 [27%] vs 11 [7%]), anaemia (35 [23%] vs 12 [8%]), and thrombocytopenia (29 [19%] vs four [3%]). Serious adverse events attributed to treatment occurred in 48 (31%) patients in the cisplatin plus veliparib group and 53 (36%) patients in the cisplatin plus placebo group. Treatment-related adverse events led to death in one patient in the cisplatin plus veliparib group (sepsis) and one patient in the cisplatin plus placebo group (acute kidney injury due to cisplatin plus heart failure from previous doxorubicin exposure).
INTERPRETATION
The addition of veliparib to cisplatin significantly improved progression-free survival in patients with BRCA-like metastatic triple-negative breast cancer, but not in patients with non-BRCA-like metastatic breast cancer. PARP inhibitors combined with platinum-based chemotherapy should be explored further in BRCA-like triple-negative breast cancer.
FUNDING
National Cancer Institute and National Institute of General Medical Sciences (US National Institutes of Health); AbbVie; Myriad Genetics; the Biomarker, Imaging, and Quality of Life Studies Funding Program (awarded by the National Cancer Institute); and The University of Kansas Cancer Center.
Topics: Female; Humans; Cisplatin; Triple Negative Breast Neoplasms; Poly(ADP-ribose) Polymerase Inhibitors; Quality of Life; Neoplasm Recurrence, Local; Antineoplastic Agents; Mutation; Antineoplastic Combined Chemotherapy Protocols; Double-Blind Method
PubMed: 36623515
DOI: 10.1016/S1470-2045(22)00739-2 -
BMJ (Clinical Research Ed.) Sep 2022To determine the effect of population level implementation of a test-and-treat approach to correction of suboptimal vitamin D status (25-hydroxyvitamin D (25(OH)D) <75... (Randomized Controlled Trial)
Randomized Controlled Trial
Effect of a test-and-treat approach to vitamin D supplementation on risk of all cause acute respiratory tract infection and covid-19: phase 3 randomised controlled trial (CORONAVIT).
OBJECTIVE
To determine the effect of population level implementation of a test-and-treat approach to correction of suboptimal vitamin D status (25-hydroxyvitamin D (25(OH)D) <75 nmol/L) on risk of all cause acute respiratory tract infection and covid 19.
DESIGN
Phase 3 open label randomised controlled trial.
SETTING
United Kingdom.
PARTICIPANTS
6200 people aged ≥16 years who were not taking vitamin D supplements at baseline.
INTERVENTIONS
Offer of a postal finger prick test of blood 25(OH)D concentration with provision of a six month supply of lower dose vitamin D (800 IU/day, n=1550) or higher dose vitamin D (3200 IU/day, n=1550) to those with blood 25(OH)D concentration <75 nmol/L, compared with no offer of testing or supplementation (n=3100). Follow-up was for six months.
MAIN OUTCOME MEASURES
The primary outcome was the proportion of participants with at least one swab test or doctor confirmed acute respiratory tract infection of any cause. A secondary outcome was the proportion of participants with swab test confirmed covid-19. Logistic regression was used to calculate odds ratios and associated 95% confidence intervals. The primary analysis was conducted by intention to treat.
RESULTS
Of 3100 participants offered a vitamin D test, 2958 (95.4%) accepted and 2674 (86.3%) had 25(OH)D concentrations <75 nmol/L and received vitamin D supplements (n=1328 lower dose, n=1346 higher dose). Compared with 136/2949 (4.6%) participants in the no offer group, at least one acute respiratory tract infection of any cause occurred in 87/1515 (5.7%) in the lower dose group (odds ratio 1.26, 95% confidence interval 0.96 to 1.66) and 76/1515 (5.0%) in the higher dose group (1.09, 0.82 to 1.46). Compared with 78/2949 (2.6%) participants in the no offer group, 55/1515 (3.6%) developed covid-19 in the lower dose group (1.39, 0.98 to 1.97) and 45/1515 (3.0%) in the higher dose group (1.13, 0.78 to 1.63).
CONCLUSIONS
Among people aged 16 years and older with a high baseline prevalence of suboptimal vitamin D status, implementation of a population level test-and-treat approach to vitamin D supplementation was not associated with a reduction in risk of all cause acute respiratory tract infection or covid-19.
TRIAL REGISTRATION
ClinicalTrials.gov NCT04579640.
Topics: COVID-19; Cholecalciferol; Dietary Supplements; Double-Blind Method; Humans; Respiratory Tract Infections; Vitamin D; Vitamin D Deficiency; Vitamins
PubMed: 36215226
DOI: 10.1136/bmj-2022-071230 -
American Journal of Obstetrics and... Nov 2022The CovidSurg-Cancer Consortium aimed to explore the impact of COVID-19 in surgical patients and services for solid cancers at the start of the pandemic. The...
BACKGROUND
The CovidSurg-Cancer Consortium aimed to explore the impact of COVID-19 in surgical patients and services for solid cancers at the start of the pandemic. The CovidSurg-Gynecologic Oncology Cancer subgroup was particularly concerned about the magnitude of adverse outcomes caused by the disrupted surgical gynecologic cancer care during the COVID-19 pandemic, which are currently unclear.
OBJECTIVE
This study aimed to evaluate the changes in care and short-term outcomes of surgical patients with gynecologic cancers during the COVID-19 pandemic. We hypothesized that the COVID-19 pandemic had led to a delay in surgical cancer care, especially in patients who required more extensive surgery, and such delay had an impact on cancer outcomes.
STUDY DESIGN
This was a multicenter, international, prospective cohort study. Consecutive patients with gynecologic cancers who were initially planned for nonpalliative surgery, were recruited from the date of first COVID-19-related admission in each participating center for 3 months. The follow-up period was 3 months from the time of the multidisciplinary tumor board decision to operate. The primary outcome of this analysis is the incidence of pandemic-related changes in care. The secondary outcomes included 30-day perioperative mortality and morbidity and a composite outcome of unresectable disease or disease progression, emergency surgery, and death.
RESULTS
We included 3973 patients (3784 operated and 189 nonoperated) from 227 centers in 52 countries and 7 world regions who were initially planned to have cancer surgery. In 20.7% (823/3973) of the patients, the standard of care was adjusted. A significant delay (>8 weeks) was observed in 11.2% (424/3784) of patients, particularly in those with ovarian cancer (213/1355; 15.7%; P<.0001). This delay was associated with a composite of adverse outcomes, including disease progression and death (95/424; 22.4% vs 601/3360; 17.9%; P=.024) compared with those who had operations within 8 weeks of tumor board decisions. One in 13 (189/2430; 7.9%) did not receive their planned operations, in whom 1 in 20 (5/189; 2.7%) died and 1 in 5 (34/189; 18%) experienced disease progression or death within 3 months of multidisciplinary team board decision for surgery. Only 22 of the 3778 surgical patients (0.6%) acquired perioperative SARS-CoV-2 infections; they had a longer postoperative stay (median 8.5 vs 4 days; P<.0001), higher predefined surgical morbidity (14/22; 63.6% vs 717/3762; 19.1%; P<.0001) and mortality (4/22; 18.2% vs 26/3762; 0.7%; P<.0001) rates than the uninfected cohort.
CONCLUSION
One in 5 surgical patients with gynecologic cancer worldwide experienced management modifications during the COVID-19 pandemic. Significant adverse outcomes were observed in those with delayed or cancelled operations, and coordinated mitigating strategies are urgently needed.
Topics: Humans; Female; COVID-19; Genital Neoplasms, Female; Prospective Studies; Pandemics; SARS-CoV-2
PubMed: 35779589
DOI: 10.1016/j.ajog.2022.06.052 -
Developmental Medicine and Child... Dec 2022To describe the development of cognitive empathy across the lifespan from a very large cohort using a standardized measure of cognitive empathy ability.
AIM
To describe the development of cognitive empathy across the lifespan from a very large cohort using a standardized measure of cognitive empathy ability.
METHOD
Participants (n=4545, age bands <5y to >75y, 60% female) were a convenience sample recruited voluntarily from visitors to the Glasgow Science Centre in the UK, who completed the Reading the Mind in the Eyes Test.
RESULTS
When compared to preceding age groups, we found significant developmental gains in empathy ability in children aged 6 to 7 years (p=0.048, d=0.45) and again at 10 to 12 years (p=0.042, d=0.23), followed by a slight reduction in ability during adolescence (p=0.087, d=-0.18), and functional maturity in those aged 19 to 25 years (p=0.001, d=0.76). Cognitive empathy abilities remained relatively stable across adulthood but gradually declined in people over 65 years, with notable decline in males over 75 years (p=0.001, d=-0.98). Females performed better than males at all ages.
INTERPRETATION
Understanding developmental issues in cognitive empathy could influence approaches to moral and social education for children, and health and social care support for older people. Standardized cognitive empathy tests could also provide novel approaches in the early detection of developmental vulnerabilities in a range of neurological conditions, and within neuropsychiatric and neurodegenerative disorders in which cognitive empathy is known to be impaired.
WHAT THIS PAPER ADDS
Cognitive empathy is a late-developing ability and changes across the lifespan. Cognitive empathy increases during childhood but with potentially altered abilities during adolescence. Cognitive empathy matures during early adulthood and gradually declines in older age. There is a female advantage in cognitive empathy abilities.
Topics: Adolescent; Male; Child; Humans; Female; Aged; Adult; Empathy; Longevity; Cognition
PubMed: 35594529
DOI: 10.1111/dmcn.15263 -
Globalization and Health Jan 2022The COVID-19 pandemic has led to an avalanche of scientific studies, drawing on many different types of data. However, studies addressing the effectiveness of government... (Review)
Review
BACKGROUND
The COVID-19 pandemic has led to an avalanche of scientific studies, drawing on many different types of data. However, studies addressing the effectiveness of government actions against COVID-19, especially non-pharmaceutical interventions, often exhibit data problems that threaten the validity of their results. This review is thus intended to help epidemiologists and other researchers identify a set of data issues that, in our view, must be addressed in order for their work to be credible. We further intend to help journal editors and peer reviewers when evaluating studies, to apprise policy-makers, journalists, and other research consumers about the strengths and weaknesses of published studies, and to inform the wider debate about the scientific quality of COVID-19 research.
RESULTS
To this end, we describe common challenges in the collection, reporting, and use of epidemiologic, policy, and other data, including completeness and representativeness of outcomes data; their comparability over time and among jurisdictions; the adequacy of policy variables and data on intermediate outcomes such as mobility and mask use; and a mismatch between level of intervention and outcome variables. We urge researchers to think critically about potential problems with the COVID-19 data sources over the specific time periods and particular locations they have chosen to analyze, and to choose not only appropriate study designs but also to conduct appropriate checks and sensitivity analyses to investigate the impact(s) of potential threats on study findings.
CONCLUSIONS
In an effort to encourage high quality research, we provide recommendations on how to address the issues we identify. Our first recommendation is for researchers to choose an appropriate design (and the data it requires). This review describes considerations and issues in order to identify the strongest analytical designs and demonstrates how interrupted time-series and comparative longitudinal studies can be particularly useful. Furthermore, we recommend that researchers conduct checks or sensitivity analyses of the results to data source and design choices, which we illustrate. Regardless of the approaches taken, researchers should be explicit about the kind of data problems or other biases that the design choice and sensitivity analyses are addressing.
Topics: COVID-19; Humans; Pandemics; Research Design; Research Personnel; SARS-CoV-2
PubMed: 34991622
DOI: 10.1186/s12992-021-00795-0 -
Frontiers in Surgery 2022Hip ultrasound screening for DDH provides better sensitivity compared to physical examination. Due to a lower prevalence and limited resources, selective hip ultrasound...
BACKGROUND
Hip ultrasound screening for DDH provides better sensitivity compared to physical examination. Due to a lower prevalence and limited resources, selective hip ultrasound in newborns at risk could be considered a proper screening protocol in Thailand and Asian countries.
OBJECTIVE
This study was aimed to evaluate risk factors and define criteria for selective screening.
METHODS
A case-control study was conducted in 2020. All newborns with hip ultrasound screening were included. Cases were defined as newborns with abnormal hip ultrasounds, while controls were those with normal studies. Inter and intra-rater reliability were evaluated. All factors were analyzed using univariate and multivariate logistic regression. The model performance was tested by Hosmer-Lemeshow goodness of fit. Internal validity was performed by the split data method. Area under the receiver operating characteristic (ROC) curve was estimated.
RESULTS
Ninety-five newborns (29 cases and 66 controls) were included. Eighty percent of cases and 58% of controls were female. The gestational age was 36.6 and 37.7 weeks in case and control, respectively. Female, breech presentation, positive Ortolani test, positive Barlow test, and limited hip abduction were significant factors with odds ratio of 2.82, 5.12, 34.21, 69.64, and 5.48, respectively. The final model included breech presentation, positive Ortolani test, and positive Barlow test. The model cut-off value 15.02 provided sensitivity (93.10%) and specificity were (80.30%). The area under the ROC curve was 0.9308. The split data remained significant internal validity for all factors with -value < 0.05.
CONCLUSION
Careful history taking and physical examination are essential to identify the risk factors for DDH. Newborns with breech presentation, positive Ortolani test and positive Barlow test should be screened by hip ultrasound.
PubMed: 36353611
DOI: 10.3389/fsurg.2022.1038066 -
The Archives of Bone and Joint Surgery May 2022Developmental dysplasia of the hip (DDH) is a spectrum of diseases involving the femoroacetabular joint. Due to the controversies over the value of different strategies... (Review)
Review
BACKGROUND
Developmental dysplasia of the hip (DDH) is a spectrum of diseases involving the femoroacetabular joint. Due to the controversies over the value of different strategies used for DDH screening, this systematic review and meta-analysis aimed to assess the diagnostic performance of standard physical examination maneuvers on the diagnosis of DDH, compared to the Graf ultrasonography (US) method.
METHODS
PubMed, Web of Science, and SCOPUS databases were searched until the end of October 2020. Studies that (i) used the Ortolani test, Barlow test, or limited hip abduction (LHA) test to assess the risk of DDH in physical examination, (ii)used the Graf US method to examine DDH in sonography, and (iii) provided adequate data to extract the diagnostic performance were included. Pooled sensitivity and specificity were calculated for clinical examinations.
RESULTS
A total of 25 studies (72,079 patients in total) were considered eligible to enter the present study. The pooled data of the Ortolani-Barlow test demonstrated a sensitivity of 36% (95% CI:0.25-0.48) and specificity of 98% (95% CI:0.93-0.99). Calculated pooled sensitivity and specificity for the limited hip abduction exam were obtained at 45% (95% CI:0.24-0.69) and 78% (95% CI:0.62-0.88) respectively. A separate analysis of the studies using both exams revealed a sensitivity of 57% (95% CI:0.30-0.82) and a specificity of 95% (95% CI:0.68-0.99).
CONCLUSION
Based on the results, the investigated clinical examinations have high specificity but low sensitivity to detect the DDH; therefore, they have limited application as a screening test. If obliged to rely on clinical examinations for screening, the combination of Ortolani-Barlow and LHA tests can provide more sensitivity than either of these tests performed independently.
PubMed: 35755788
DOI: 10.22038/ABJS.2021.60504.2984 -
BMC Health Services Research Apr 2021Process mapping (PM) supports better understanding of complex systems and adaptation of improvement interventions to their local context. However, there is little...
INTRODUCTION
Process mapping (PM) supports better understanding of complex systems and adaptation of improvement interventions to their local context. However, there is little research on its use in healthcare. This study (i) proposes a conceptual framework outlining quality criteria to guide the effective implementation, evaluation and reporting of PM in healthcare; (ii) reviews published PM cases to identify context and quality of PM application, and the reported benefits of using PM in healthcare.
METHODS
We developed the conceptual framework by reviewing methodological guidance on PM and empirical literature on its use in healthcare improvement interventions. We conducted a systematic review of empirical literature using PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) methodology. Inclusion criteria were: full text empirical study; describing the process through which PM has been applied in a healthcare setting; published in English. Databases searched are: Medline, Embase, HMIC-Health Management Information Consortium, CINAHL-Cumulative Index to Nursing and Allied Health Literature, Scopus. Two independent reviewers extracted and analysed data. Each manuscript underwent line by line coding. The conceptual framework was used to evaluate adherence of empirical studies to the identified PM quality criteria. Context in which PM is used and benefits of using PM were coded using an inductive thematic analysis approach.
RESULTS
The framework outlines quality criteria for each PM phase: (i) preparation, planning and process identification, (ii) data and information gathering, (iii) process map generation, (iv) analysis, (v) taking it forward. PM is used in a variety of settings and approaches to improvement. None of the reviewed studies (N = 105) met all ten quality criteria; 7% were compliant with 8/10 or 9/10 criteria. 45% of studies reported that PM was generated through multi-professional meetings and 15% reported patient involvement. Studies highlighted the value of PM in navigating the complexity characterising healthcare improvement interventions.
CONCLUSION
The full potential of PM is inhibited by variance in reporting and poor adherence to underpinning principles. Greater rigour in the application of the method is required. We encourage the use and further development of the proposed framework to support training, application and reporting of PM.
TRIAL REGISTRATION
Prospero ID: CRD42017082140.
Topics: Delivery of Health Care; Health Facilities; Humans; Research Design
PubMed: 33853610
DOI: 10.1186/s12913-021-06254-1 -
Prevention Science : the Official... May 2023As commissioned by the Society for Prevention Research, this paper describes and illustrates strategic approaches for reducing health inequities and advancing health... (Review)
Review
As commissioned by the Society for Prevention Research, this paper describes and illustrates strategic approaches for reducing health inequities and advancing health equity when adopting an equity-focused approach for applying prevention science evidence-based theory, methodologies, and practices. We introduce an ecosystemic framework as a guide for analyzing, designing, and planning innovative equity-focused evidence-based preventive interventions designed to attain intended health equity outcomes. To advance this process, we introduce a health equity statement for conducting integrative analyses of ecosystemic framework pathways, by describing the role of social determinants, mechanisms, and interventions as factors directly linked to specific health equity outcomes. As background, we present health equity constructs, theories, and research evidence which can inform the design and development of equity-focused intervention approaches. We also describe multi-level interventions that when coordinated can produce synergistic intervention effects across macro, meso, and micro ecological levels. Under this approach, we encourage prevention and implementation scientists to apply and extend these strategic directions in future research to increase our evidence-based knowledge and theory building. A general goal is to apply prevention science knowledge to design, widely disseminate, and implement culturally grounded interventions that incrementally attain specific HE outcomes and an intended HE goal. We conclude with recommendations for conducting equity-focused prevention science research, interventions, and training.
Topics: Humans; Health Equity; Knowledge
PubMed: 36469162
DOI: 10.1007/s11121-022-01462-5