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Asparagine (Asn) deamidation and aspartic acid (Asp) isomerization are common degradation pathways that affect the stability of therapeutic antibodies. These modifications can pose a significant challenge in the development of biopharmaceuticals. As such, the early engineering and selection of chemically stable monoclonal antibodies (mAbs) can substantially mitigate the risk of subsequent failure. In this study, we introduce a novel in silico approach for predicting deamidation and isomerization sites in therapeutic antibodies by analyzing the structural environment surrounding asparagine and aspartate residues. The resulting quantitative structure-activity relationship (QSAR) model was trained using previously published forced degradation data from 57 clinical-stage mAbs. The predictive accuracy of the model was evaluated for four different states of the protein structure: (1) static homology models, (2) enhancing low-frequency vibrational modes during short molecular dynamics (MD) runs, (3) a combination of (2) with a protonation state reassignment, and (4) conventional full-atomistic MD simulations. The most effective QSAR model considered the accessible surface area (ASA) of the residue, the pKa value of the backbone amide, and the root mean square deviations of both the alpha carbon and the side chain. The accuracy was further enhanced by incorporating the QSAR model into a decision tree, which also includes empirical information about the sequential successor and the position in the protein. The resulting model has been implemented as a plugin named "Forecasting Reactivity of Isomerization and Deamidation in Antibodies" in MOE software, completed with a user-friendly graphical interface to facilitate its use.
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Anticorpos Monoclonais , Asparagina , Isomerismo , Asparagina/química , Anticorpos Monoclonais/química , Amidas/química , SoftwareRESUMO
BACKGROUND: Older adults were more likely to be socially isolated during the COVID-19 pandemic, with increased risk of depression and loneliness. We aimed to investigate whether a behavioural activation intervention delivered via telephone could mitigate depression and loneliness in at-risk older people during the COVID-19 pandemic. METHODS: BASIL+ (Behavioural Activation in Social Isolation) was a pragmatic randomised controlled trial conducted among patients recruited from general practices in England and Wales, and was designed to assess the effectiveness of behavioural activation in mitigating depression and loneliness among older people during the COVID-19 pandemic. Eligible participants were aged 65 years and older, socially isolated, with a score of 5 or higher on the Patient Health Questionnaire-9 (PHQ-9), and had multiple long-term conditions. Participants were allocated in a 1:1 ratio to the intervention (behavioural activation) or control groups by use of simple randomisation without stratification. Behavioural activation was delivered by telephone; participants were offered up to eight weekly sessions with trained BASIL+ Support Workers. Behavioural activation was adapted to maintain social connections and encourage socially reinforcing activities. Participants in the control group received usual care with existing COVID-19 wellbeing resources. The primary clinical outcome was self-reported depression severity, assessed by the PHQ-9, at 3 months. Outcomes were assessed masked to allocation and analysis was by treatment allocation. This trial is registered with the ISRCTN registry (ISRCTN63034289). FINDINGS: Between Feb 8, 2021, and Feb 28, 2022, 449 eligible participants were identified and 435 from 26 general practices were recruited and randomly assigned (1:1) to the behavioural activation intervention (n=218) or to the control group (usual care with signposting; n=217). The mean age of participants was 75·7 years (SD 6·7); 270 (62·1%) of 435 participants were female, and 418 (96·1%) were White. Participants in the intervention group attended an average of 5·2 (SD 2·9) of eight remote behavioural activation sessions. The adjusted mean difference in PHQ-9 scores between the control and intervention groups at 3 months was -1·65 (95% CI -2·54 to -0·75, p=0·0003). No adverse events were reported that were attributable to the behavioural activation intervention. INTERPRETATION: Behavioural activation is an effective and potentially scalable intervention that can reduce symptoms of depression and emotional loneliness in at-risk groups in the short term. The findings of this trial add to the range of strategies to improve the mental health of older adults with multiple long-term conditions. These results can be helpful to policy makers beyond the pandemic in reducing the global burden of depression and addressing the health impacts of loneliness, particularly in at-risk groups. FUNDING: UK National Institute for Health and Care Research.
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COVID-19 , Ocimum basilicum , Humanos , Feminino , Idoso , Masculino , País de Gales/epidemiologia , Pandemias/prevenção & controle , COVID-19/epidemiologia , COVID-19/prevenção & controle , Inglaterra/epidemiologiaRESUMO
Various applications of bis(catecholato)germanes in catalysis were examined. The hydrosilylation of benzaldehydes, hydroboration of phenylacetylene derivatives, and Friedel-Crafts alkylation using arylalkenes and either diphenylamine or anisole was achieved. Furthermore, the recently reported oligomerization of α-methylstyrene catalyzed by bis(catecholato)germanes with weak donor ligands was examined further. The formation of a trimer species was observed in DCM. VTNA and Hammett analyses of the oligomerization reaction were conducted and an updated mechanism for bis(catecholato)germane catalysis is proposed.
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OBJECTIVE: To evaluate the readmission rate after orthognathic surgery and identify associated risk factors. STUDY DESIGN: Retrospective analysis of patients who underwent orthognathic surgery and had an unexpected hospital admission, with or without return to the operating room (OR), within the first postoperative year. Study variables included sex, age, American Society of Anesthesiologists (ASA) status, type of surgery, concomitant third molar extraction, concomitant genioplasty, duration of surgery, first assistant experience, and duration of hospitalization. Bivariate associations were calculated between variables and readmission status. Chi-square and Fisher's Exact tests were used to compare categorical variables, and a 2-sample t test was used to compare continuous variables. RESULTS: There were 701 patients included in the study. The readmission rate was 9.70%. Twelve patients were managed non-surgically, and 56 patients required an OR procedure. The most common reason for readmission without return to the OR was an infection, and for reoperation was hardware removal. Age, sex, type of surgery, third molar extraction, genioplasty, duration of surgery, and experience of first assistant were not found to be predictors for readmission. CONCLUSIONS: Only ASA classification and duration of initial hospitalization were significant risk factors for readmission of patients within the first postoperative year after orthognathic surgery.
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Cirurgia Ortognática , Humanos , Estudos Retrospectivos , Readmissão do Paciente , Mentoplastia/efeitos adversos , Mentoplastia/métodos , Complicações Pós-Operatórias , Fatores de Risco , Reoperação/efeitos adversosRESUMO
OBJECTIVES: The COVID-19 pandemic heightened the need to address loneliness, social isolation and associated incidence of depression among older adults. Between June and October 2020, the Behavioural Activation in Social IsoLation (BASIL) pilot study investigated the acceptability and feasibility of a remotely delivered brief psychological intervention (behavioural cctivation) to prevent and reduce loneliness and depression in older people with long-term conditions during the COVID-19 pandemic. DESIGN: An embedded qualitative study was conducted. Semi-structured interviews generated data that was analysed inductively using thematic analysis and then deductively using the theoretical framework of acceptability (TFA). SETTING: NHS and third sector organisations in England. PARTICIPANTS: Sixteen older adults and nine support workers participating in the BASIL pilot study. RESULTS: Acceptability of the intervention was high across all constructs of the TFA: Older adults and BASIL Support Workers described a positive Affective Attitude towards the intervention linked to altruism, however the activity planning aspect of the intervention was limited due to COVID-19 restrictions. A manageable Burden was involved with delivering and participating in the intervention. For Ethicality, older adults valued social contact and making changes, support workers valued being able to observe those changes. The intervention was understood by older adults and support workers, although less understanding in older adults without low mood (Intervention Coherence). Opportunity Cost was low for support workers and older adults. Behavioural Activation was perceived to be useful in the pandemic and likely to achieve its aims (Perceived Effectiveness), especially if tailored to people with both low mood and long-term conditions. Self-efficacy developed over time and with experience for both support workers and older adults. CONCLUSIONS: Overall, BASIL pilot study processes and the intervention were acceptable. Use of the TFA provided valuable insights into how the intervention was experienced and how the acceptability of study processes and the intervention could be enhanced ahead of the larger definitive trial (BASIL+).
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COVID-19 , Humanos , Idoso , COVID-19/prevenção & controle , Pandemias/prevenção & controle , Projetos Piloto , Depressão/etiologia , Terapia ComportamentalRESUMO
BACKGROUND: Behavioural and cognitive interventions remain credible approaches in addressing loneliness and depression. There was a need to rapidly generate and assimilate trial-based data during COVID-19. OBJECTIVES: We undertook a parallel pilot RCT of behavioural activation (a brief behavioural intervention) for depression and loneliness (Behavioural Activation in Social Isolation, the BASIL-C19 trial ISRCTN94091479). We also assimilate these data in a living systematic review (PROSPERO CRD42021298788) of cognitive and/or behavioural interventions. METHODS: Participants (≥65 years) with long-term conditions were computer randomised to behavioural activation (n=47) versus care as usual (n=49). Primary outcome was PHQ-9. Secondary outcomes included loneliness (De Jong Scale). Data from the BASIL-C19 trial were included in a metanalysis of depression and loneliness. FINDINGS: The 12 months adjusted mean difference for PHQ-9 was -0.70 (95% CI -2.61 to 1.20) and for loneliness was -0.39 (95% CI -1.43 to 0.65).The BASIL-C19 living systematic review (12 trials) found short-term reductions in depression (standardised mean difference (SMD)=-0.31, 95% CI -0.51 to -0.11) and loneliness (SMD=-0.48, 95% CI -0.70 to -0.27). There were few long-term trials, but there was evidence of some benefit (loneliness SMD=-0.20, 95% CI -0.40 to -0.01; depression SMD=-0.20, 95% CI -0.47 to 0.07). DISCUSSION: We delivered a pilot trial of a behavioural intervention targeting loneliness and depression; achieving long-term follow-up. Living meta-analysis provides strong evidence of short-term benefit for loneliness and depression for cognitive and/or behavioural approaches. A fully powered BASIL trial is underway. CLINICAL IMPLICATIONS: Scalable behavioural and cognitive approaches should be considered as population-level strategies for depression and loneliness on the basis of a living systematic review.
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COVID-19 , Ocimum basilicum , Humanos , Depressão , Projetos Piloto , Saúde Pública , Ensaios Clínicos Controlados Aleatórios como Assunto , Isolamento Social/psicologia , Reino UnidoRESUMO
Inflammatory arthritis presents a unique destructive process to the temporomandibular joint. This article provides information on the proper diagnosis, treatment planning, and surgical management aimed to provide patients with improvement in pain, function, stability and facial aesthetics. Additionally, it aims to provide a detailed insight on the joint reconstruction options including alloplastic joint replacement, autogenous joint replacement, orthognathic surgery and distraction osteogenesis.
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Fecal communities transplanted into individuals can eliminate recurrent Clostridioides difficile infection (CDI) with high efficacy. However, this treatment is only used once CDI becomes resistant to antibiotics or has recurred multiple times. We sought to investigate whether a fecal community transplant (FCT) pretreatment could be used to prevent CDI altogether. We treated male C57BL/6 mice with either clindamycin, cefoperazone, or streptomycin and then inoculated them with the microbial community from untreated mice before challenge with C. difficile. We measured colonization and sequenced the V4 region of the 16S rRNA gene to understand the dynamics of the murine fecal community in response to the FCT and C. difficile challenge. Clindamycin-treated mice became colonized with C. difficile but cleared it naturally and did not benefit from the FCT. Cefoperazone-treated mice became colonized by C. difficile, but the FCT enabled clearance of C. difficile. In streptomycin-treated mice, the FCT was able to prevent C. difficile from colonizing. We then diluted the FCT and repeated the experiments. Cefoperazone-treated mice no longer cleared C. difficile. However, streptomycin-treated mice colonized with 1:102 dilutions resisted C. difficile colonization. Streptomycin-treated mice that received an FCT diluted 1:103 became colonized with C. difficile but later cleared the infection. In streptomycin-treated mice, inhibition of C. difficile was associated with increased relative abundance of a group of bacteria related to Porphyromonadaceae and Lachnospiraceae. These data demonstrate that C. difficile colonization resistance can be restored to a susceptible community with an FCT as long as it complements the missing populations. IMPORTANCE Antibiotic use, ubiquitous with the health care environment, is a major risk factor for Clostridioides difficile infection (CDI), the most common nosocomial infection. When C. difficile becomes resistant to antibiotics, a fecal microbiota transplant from a healthy individual can effectively restore the gut bacterial community and eliminate the infection. While this relationship between the gut bacteria and CDI is well established, there are no therapies to treat a perturbed gut community to prevent CDI. This study explored the potential of restoring colonization resistance to antibiotic-induced susceptible gut communities. We described the effect that gut bacterial community variation has on the effectiveness of a fecal community transplant for inhibiting CDI. These data demonstrated that communities susceptible to CDI can be supplemented with fecal communities but that the effectiveness depended on the structure of the community following the perturbation. Thus, a reduced bacterial community may be able to recover colonization resistance in patients treated with antibiotics.
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Clostridioides difficile , Infecções por Clostridium , Microbioma Gastrointestinal , Animais , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Bactérias/genética , Cefoperazona/farmacologia , Clindamicina/farmacologia , Clindamicina/uso terapêutico , Clostridioides , Infecções por Clostridium/microbiologia , Infecções por Clostridium/prevenção & controle , Suscetibilidade a Doenças , Transplante de Microbiota Fecal , Fezes/microbiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , RNA Ribossômico 16S/genética , Estreptomicina/farmacologia , Estreptomicina/uso terapêuticoRESUMO
INTRODUCTION: Depression is a leading mental health problem worldwide. People with long-term conditions are at increased risk of experiencing depression. The COVID-19 pandemic led to strict social restrictions being imposed across the UK population. Social isolation can have negative consequences on the physical and mental wellbeing of older adults. In the Behavioural Activation in Social IsoLation (BASIL+) trial we will test whether a brief psychological intervention (based on Behavioural Activation), delivered remotely, can mitigate depression and loneliness in older adults with long-term conditions during isolation. METHODS: We will conduct a two-arm, parallel-group, randomised controlled trial across several research sites, to evaluate the clinical and cost-effectiveness of the BASIL+ intervention. Participants will be recruited via participating general practices across England and Wales. Participants must be aged ≥65 with two or more long-term conditions, or a condition that may indicate they are within a 'clinically extremely vulnerable' group in relation to COVID-19, and have scored ≥5 on the Patient Health Questionnaire (PHQ9), to be eligible for inclusion. Randomisation will be 1:1, stratified by research site. Intervention participants will receive up to eight intervention sessions delivered remotely by trained BASIL+ Support Workers and supported by a self-help booklet. Control participants will receive usual care, with additional signposting to reputable sources of self-help and information, including advice on keeping mentally and physically well. A qualitative process evaluation will also be undertaken to explore the acceptability of the BASIL+ intervention, as well as barriers and enablers to integrating the intervention into participants' existing health and care support, and the impact of the intervention on participants' mood and general wellbeing in the context of the COVID-19 restrictions. Semi-structured interviews will be conducted with intervention participants, participant's caregivers/supportive others and BASIL+ Support Workers. Outcome data will be collected at one, three, and 12 months post-randomisation. Clinical and cost-effectiveness will be evaluated. The primary outcome is depressive symptoms at the three-month follow up, measured by the PHQ9. Secondary outcomes include loneliness, social isolation, anxiety, quality of life, and a bespoke health services use questionnaire. DISCUSSION: This study is the first large-scale trial evaluating a brief Behavioural Activation intervention in this population, and builds upon the results of a successful external pilot trial. TRIAL REGISTRATION: ClinicalTrials.Gov identifier ISRCTN63034289, registered on 5th February 2021.
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COVID-19 , Ocimum basilicum , Idoso , Análise Custo-Benefício , Depressão/prevenção & controle , Humanos , Solidão , Pandemias , Qualidade de Vida , Ensaios Clínicos Controlados Aleatórios como Assunto , Isolamento SocialRESUMO
Tophaceous pseudogout is a rare variant of the calcium pyrophosphate dihydrate (CPPD) disorder, with predilection for the TMJ. It is characterized by calcific deposits composed of rhomboid- or rectangular-shaped crystals that exhibit birefringence when examined under polarized light. We hereby present a case of a 65-year-old man with left pre-auricular tenderness and malocclusion. CT imaging was notable for a left TMJ mineralized mass with erosion of the condylar head. Treatment involved excision of the mass with eminectomy, condylectomy, and a stock total TMJ reconstruction. In this report, important considerations for diagnosis, biopsy, and surgical treatment with emphasis on reconstruction for tophaceous pseudogout of the TMJ have been highlighted by the authors.
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Condrocalcinose , Idoso , Biópsia , Condrocalcinose/diagnóstico por imagem , Condrocalcinose/cirurgia , Humanos , Masculino , Articulação Temporomandibular/diagnóstico por imagem , Articulação Temporomandibular/patologia , Articulação Temporomandibular/cirurgiaRESUMO
PURPOSE: Patients with significant dentofacial deformities undergoing aesthetic and functional orthognathic surgery may often require genioplasty to advance the position of the pogonion relative to B point. No study to date has evaluated nationally registered data pertaining to addition of osseous genioplasty to bimaxillary orthognathic surgery and its associated clinical outcomes. METHODS: Data was extracted from the National Surgical Quality Improvement Program from 2010 to 2018 using current procedural terminology codes pertaining to Le Fort I osteotomy (LF), bilateral sagittal split osteotomy (BSSO), and osseous genioplasty (G) and divided into 2 cohorts: bimaxillary orthognathic surgery with and without osseous genioplasty. Thirty-day postoperative outcomes inherently recorded within National Surgical Quality Improvement Program were identified and recorded. Chi-squared analysis and unpaired 2-tail t tests were performed between the cohorts and their respective outcomes to determine significant relationships with significance set as Pâ<â0.05. RESULTS: There were 373 patients double- or triple-jaw patients identified from the years 2010 to 2018. The most common recorded indication for LF/BSSO was maxillary hypoplasia (27.3%) and mandibular hypoplasia (6.8%). The most common indications for LF/BSSO/G were maxillary hypoplasia (16.1%) and maxillary asymmetry (16.1%). In comparison to LF/BBSO only, LF/BSSO/GP was not associated with any differences in the rate of surgical (0.0% versus 0.31%, Pâ=â0.72) or medical complications (0.0% versus 0.63%, Pâ=â0.60), in addition to unplanned readmissions (0.0% versus 1.56% versus Pâ=â0.41) or reoperations (0.0% versus 1.25%, Pâ=â0.46). However, osseous genioplasty addition was associated with increased overall operating time (271.77 versus 231.75 minutes, Pâ=â0.04). CONCLUSIONS: Osseous genioplasty does not alter short-term, 30-day complication rate when performed with bimaxillary orthognathic surgery. As reoperation rates remained relatively unchanged, it can be inferred that immediate adverse events or patient dissatisfaction were not apparent within 30âdays. Although mean operating time is slightly longer, cardiopulmonary resuscitation without medical comorbidity was achieved at the conclusion of the procedure.
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Cirurgia Ortognática , Procedimentos Cirúrgicos Ortognáticos , Cirurgiões , Estética Dentária , Mentoplastia/métodos , Humanos , Procedimentos Cirúrgicos Ortognáticos/métodos , Osteotomia de Le Fort/métodos , Osteotomia Sagital do Ramo Mandibular , Melhoria de Qualidade , Estudos Retrospectivos , Fatores de RiscoAssuntos
COVID-19 , Internato e Residência , Cirurgia Bucal , Humanos , COVID-19/epidemiologia , PandemiasRESUMO
The synthesis of a variety of bis(catecholato)germanes is reported. The Lewis acidity of the bis(catecholato)germanes was assessed using the experimental Gutmann-Beckett method and computational FIA and GEI methods. The oligomerization of alkenes using bis(catecholato)germanes demonstrates the use of these complexes in catalysis. The use of donor additives in the dimerization of α-methylstyrene resulted in selectivity control comparable to transition metal catalyst systems.
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BACKGROUND: Older adults, including those with long-term conditions (LTCs), are vulnerable to social isolation. They are likely to have become more socially isolated during the Coronavirus Disease 2019 (COVID-19) pandemic, often due to advice to "shield" to protect them from infection. This places them at particular risk of depression and loneliness. There is a need for brief scalable psychosocial interventions to mitigate the psychological impacts of social isolation. Behavioural activation (BA) is a credible candidate intervention, but a trial is needed. METHODS AND FINDINGS: We undertook an external pilot parallel randomised trial (ISRCTN94091479) designed to test recruitment, retention and engagement with, and the acceptability and preliminary effects of the intervention. Participants aged ≥65 years with 2 or more LTCs were recruited in primary care and randomised by computer and with concealed allocation between June and October 2020. BA was offered to intervention participants (n = 47), and control participants received usual primary care (n = 49). Assessment of outcome was made blind to treatment allocation. The primary outcome was depression severity (measured using the Patient Health Questionnaire 9 (PHQ-9)). We also measured health-related quality of life (measured by the Short Form (SF)-12v2 mental component scale (MCS) and physical component scale (PCS)), anxiety (measured by the Generalised Anxiety Disorder 7 (GAD-7)), perceived social and emotional loneliness (measured by the De Jong Gierveld Scale: 11-item loneliness scale). Outcome was measured at 1 and 3 months. The mean age of participants was aged 74 years (standard deviation (SD) 5.5) and they were mostly White (n = 92, 95.8%), and approximately two-thirds of the sample were female (n = 59, 61.5%). Remote recruitment was possible, and 45/47 (95.7%) randomised to the intervention completed 1 or more sessions (median 6 sessions) out of 8. A total of 90 (93.8%) completed the 1-month follow-up, and 86 (89.6%) completed the 3-month follow-up, with similar rates for control (1 month: 45/49 and 3 months 44/49) and intervention (1 month: 45/47and 3 months: 42/47) follow-up. Between-group comparisons were made using a confidence interval (CI) approach, and by adjusting for the covariate of interest at baseline. At 1 month (the primary clinical outcome point), the median number of completed sessions for people receiving the BA intervention was 3, and almost all participants were still receiving the BA intervention. The between-group comparison for the primary clinical outcome at 1 month was an adjusted between-group mean difference of -0.50 PHQ-9 points (95% CI -2.01 to 1.01), but only a small number of participants had completed the intervention at this point. At 3 months, the PHQ-9 adjusted mean difference (AMD) was 0.19 (95% CI -1.36 to 1.75). When we examined loneliness, the adjusted between-group difference in the De Jong Gierveld Loneliness Scale at 1 month was 0.28 (95% CI -0.51 to 1.06) and at 3 months -0.87 (95% CI -1.56 to -0.18), suggesting evidence of benefit of the intervention at this time point. For anxiety, the GAD adjusted between-group difference at 1 month was 0.20 (-1.33, 1.73) and at 3 months 0.31 (-1.08, 1.70). For the SF-12 (physical component score), the adjusted between-group difference at 1 month was 0.34 (-4.17, 4.85) and at 3 months 0.11 (-4.46, 4.67). For the SF-12 (mental component score), the adjusted between-group difference at 1 month was 1.91 (-2.64, 5.15) and at 3 months 1.26 (-2.64, 5.15). Participants who withdrew had minimal depressive symptoms at entry. There were no adverse events. The Behavioural Activation in Social Isolation (BASIL) study had 2 main limitations. First, we found that the intervention was still being delivered at the prespecified primary outcome point, and this fed into the design of the main trial where a primary outcome of 3 months is now collected. Second, this was a pilot trial and was not designed to test between-group differences with high levels of statistical power. Type 2 errors are likely to have occurred, and a larger trial is now underway to test for robust effects and replicate signals of effectiveness in important secondary outcomes such as loneliness. CONCLUSIONS: In this study, we observed that BA is a credible intervention to mitigate the psychological impacts of COVID-19 isolation for older adults. We demonstrated that it is feasible to undertake a trial of BA. The intervention can be delivered remotely and at scale, but should be reserved for older adults with evidence of depressive symptoms. The significant reduction in loneliness is unlikely to be a chance finding, and replication will be explored in a fully powered randomised controlled trial (RCT). TRIAL REGISTRATION: ISRCTN94091479.
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COVID-19/psicologia , Depressão/prevenção & controle , Promoção da Saúde/métodos , Serviços de Saúde para Idosos , Solidão , Pandemias , Isolamento Social , Idoso , Exercício Físico , Feminino , Comportamentos Relacionados com a Saúde , Humanos , Internet , Masculino , Projetos Piloto , Avaliação de Programas e Projetos de Saúde , SARS-CoV-2 , Participação Social , Medicina Estatal , Reino UnidoRESUMO
Introduction: Intimate Partner Violence (IPV) is a global epidemic which 30% of women experience world-wide. Domestic violence has serious health consequences, with an estimated cost of 1.7 billion annually to the NHS. However, healthcare professionals remain uncertain on how to manage IPV. In 2007, the Identification and Referral to Improve Safety (IRIS) was introduced within primary care to address this shortcoming. The aim of this project is to analyse the impact of IRIS, whilst discussing the extension into secondary care. Materials and Methods: A literature review was conducted using PubMed, Cochrane Library and Google scholar. The official IRIS publication list for randomized controlled trial data. Results: General practices with IRIS displayed a threefold increase in the identification of IPV and sevenfold increase in referrals. IRIS is cost-effective and under the NICE threshold of GBP 20,000 per quality-adjusted life year gained. Additionally, a systematic review illustrated that one in six women presenting to the fracture clinic experienced IPV within the last year. Conclusions: The implementation of IRIS into general practice proved to be cost-effective. Orthopaedic fracture clinics are at the forefront of dealing with IPV, and therefore an adapted IRIS programme within this setting has potential in the prevention of IPV.
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Violência Doméstica , Medicina Geral , Violência por Parceiro Íntimo , Violência Doméstica/prevenção & controle , Feminino , Humanos , Violência por Parceiro Íntimo/prevenção & controle , Atenção Primária à Saúde , Encaminhamento e ConsultaRESUMO
OBJECTIVE: The coronavirus disease 2019 (COVID-19) pandemic has specific implications for oral and maxillofacial surgeons because of an increased risk of exposure to the virus during surgical procedures involving the aerodigestive tract. The objective of this survey was to evaluate how the COVID-19 pandemic affected oral and maxillofacial surgery (OMFS) training programs during the early phase of the pandemic. STUDY DESIGN: During the period April 3 to May 6, 2020, a cross-sectional survey was sent to the program directors of 95 of the 101 accredited OMFS training programs in the United States. The 35-question survey, designed by using Qualtrics software, aimed to elicit information about the impact of the COVID-19 pandemic on OMFS residency programs and the resulting specific modifications made to clinical care, PPE, and resident training/wellness. RESULTS: The survey response rate from OMFS program directors was 35% (33 of 95), with most responses from the states with a high incidence of COVID-19. All OMFS programs (100%) implemented guidelines to suspend elective and nonurgent surgical procedures and limited ambulatory clinic visits by third week of March, with the average date being March 16, 2020 (date range March 8-23). The programs used telemedicine (40%) and modified in-person visit (51%) protocols for dental and maxillofacial emergency triage to minimize the risk of exposure of HCP to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Shortage of personal protective equipment (PPE) was experienced by 51% of the programs. Almost two-thirds (63%) of the respondents recommended the use of a filtered respirator (i.e., N95 respirator) with full-face shield and stated that it was their preferred PPE, whereas 21% recommended the use of powered air-purifying respirators (PAPRs) during OMFS procedures. Only (73%) of the programs had resources for resident wellness and stress reduction. Virtual didactic training sessions conducted on digital platforms, most commonly Zoom, formed a major part of education for all programs. CONCLUSIONS: All programs promptly responded to the pandemic by making appropriate changes, including suspending elective surgery and limiting patient care to emergent and urgent services. OMFS training programs should give more consideration to providing residents with adequate stress reduction resources to maintain their well-being and training and to minimize exposure risk during an evolving global epidemic.
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COVID-19 , Cirurgia Bucal , Estudos Transversais , Humanos , Pandemias/prevenção & controle , SARS-CoV-2 , Inquéritos e Questionários , Estados Unidos/epidemiologiaRESUMO
Extending upon our previous publication [Drummond, M.; J. Chem. Inf. Model. 2019, 59, 1634-1644], two additional computational methods are presented to model PROTAC-mediated ternary complex structures, which are then used to predict the efficacy of any accompanying protein degradation. Method 4B, an extension to one of our previous approaches, incorporates a clustering procedure uniquely suited for considering ternary complexes. Method 4B yields the highest proportion to date of crystal-like poses in modeled ternary complex ensembles, nearing 100% in two cases and always giving a hit rate of at least 10%. Techniques to further improve this performance for particularly troublesome cases are suggested and validated. This demonstrated ability to reliably reproduce known crystallographic ternary complex structures is further established through modeling of a newly released crystal structure. Moreover, for the far more common scenario where the structure of the ternary complex intermediate is unknown, the methods detailed in this work nonetheless consistently yield results that reliably follow experimental protein degradation trends, as established through seven retrospective case studies. These various case studies cover challenging yet common modeling situations, such as when the precise orientation of the PROTAC binding moiety in one (or both) of the protein pockets has not been experimentally established. Successful results are presented for one PROTAC targeting many proteins, for different PROTACs targeting the same protein, and even for degradation effected by an E3 ligase that has not been structurally characterized in a ternary complex. Overall, the computational modeling approaches detailed in this work should greatly facilitate PROTAC screening and design efforts, so that the many advantages of a PROTAC-based degradation approach can be effectively utilized both rapidly and at reduced cost.
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Bibliotecas de Moléculas Pequenas , Simulação por Computador , Proteólise , Estudos RetrospectivosRESUMO
Several uncertainties exist regarding how we will conduct our clinical, didactic, business, and social activities as the coronavirus disease 2019 (COVID-19) global pandemic abates and social distancing guidelines are relaxed. We anticipate changes in how we interact with our patients and other providers, how patient workflow is designed, the methods used to conduct our teaching sessions, and how we perform procedures in different clinical settings. The objective of the present report is to review some of the changes to consider in the clinical and academic oral and maxillofacial surgery workflow and, allow for a smoother transition, with less risk to our patients and healthcare personnel. New infection control policies should be strictly enforced and monitored in all clinical and nonclinical settings, with an overall goal to decrease the risk of exposure and transmission. Screening for COVID-19 symptoms, testing when indicated, and establishing the epidemiologic linkage will be crucial to containing and preventing new COVID-19 cases until a vaccine or an alternate solution is available. Additionally, the shortage of essential supplies such as drugs and personal protective equipment, the design and ventilation of workspaces and waiting areas, the increase in overhead costs, and the possible absence of staff, if quarantine is necessary, must be considered. This shift in our workflow and patient care paths will likely continue in the short-term at least through 2021 or the next 12 to 24 months. Thus, we must prioritize surgery, balancing patient preferences and healthcare personnel risks. We have an opportunity now to make changes and embrace telemedicine and other collaborative virtual platforms for teaching and clinical care. It is crucial that we maintain COVID-19 awareness, proper surveillance in our microenvironments, good clinical judgment, and ethical values to continue to deliver high-quality, economical, and accessible patient care.
Assuntos
Infecções por Coronavirus/epidemiologia , Pneumonia Viral/epidemiologia , Cirurgia Bucal/organização & administração , Betacoronavirus , COVID-19 , Infecções por Coronavirus/prevenção & controle , Humanos , Exposição Ocupacional/prevenção & controle , Cirurgiões Bucomaxilofaciais , Pandemias/prevenção & controle , Equipamento de Proteção Individual , Pneumonia Viral/prevenção & controle , SARS-CoV-2 , Fluxo de TrabalhoRESUMO
Motivation: Bivalent ligands are increasingly important such as for targeting G protein-coupled receptor (GPCR) dimers or proteolysis targeting chimeras (PROTACs). They contain two pharmacophoric units that simultaneously bind in their corresponding binding sites, connected with a spacer chain. Here, we report a molecular modelling tool that links the pharmacophore units via the shortest pathway along the receptors van der Waals surface and then scores the solutions providing prioritization for the design of new bivalent ligands. Results: Bivalent ligands of known dimers of GPCRs, PROTACs and a model bivalent antibody/antigen system were analysed. The tool could rapidly assess the preferred linker length for the different systems and recapitulated the best reported results. In the case of GPCR dimers the results suggest that in some cases these ligands might bind to a secondary binding site at the extracellular entrance (vestibule or allosteric site) instead of the orthosteric binding site. Availability and implementation: Freely accessible from the Molecular Operating Environment svl exchange server (https://svl.chemcomp.com/). Supplementary information: Supplementary data are available at Bioinformatics online.