Peninsula Health

BACKGROUND: Misoprostol is effective for ulcers associated with the use of nonsteroidal antiinflammatory drugs (NSAIDs) but is often poorly tolerated because of diarrhea and abdominal pain. We compared the efficacy of omeprazole and misoprostol in healing and preventing ulcers associated with NSAIDs. METHODS: In a double-blind study, we randomly assigned 935 patients who required continuous NSAID therapy and who had ulcers or more than 10 erosions in the stomach or duodenum (or both) to receive 20 mg or 40 mg of omeprazole orally in the morning or 200 microg of misoprostol orally four times daily. Patients were treated for four weeks or, in the absence of healing, eight weeks. Treatment success was defined as the absence of ulcers and the presence of fewer than five erosions at each site and not more than mild dyspepsia. We then randomly reassigned 732 patients in whom treatment was successful to maintenance therapy with 20 mg of omeprazole daily, 200 microg of misoprostol twice daily, or placebo for six months. RESULTS: At eight weeks, treatment was successful in 76 percent of the patients given 20 mg of omeprazole (233 of 308), 75 percent of those given 40 mg of omeprazole (237 of 315), and 71 percent of those given misoprostol (212 of 298). The rates of gastric-ulcer healing were significantly higher with 20 mg of omeprazole (but not 40 mg of omeprazole) than with misoprostol. Healing rates among patients with duodenal ulcers were higher with either dose of omeprazole than with misoprostol, whereas healing rates among patients with erosions alone were higher with misoprostol. More patients remained in remission during maintenance treatment with omeprazole (61 percent) than with misoprostol (48 percent, P=0.001) and with either drug than with placebo (27 percent, P<0.001). There were more adverse events during the healing phase in the misoprostol group than in the groups given 20 mg and 40 mg of omeprazole (59 percent, 48 percent, and 46 percent, respectively). CONCLUSIONS: The overall rates of successful treatment of ulcers, erosions, and symptoms associated with NSAIDs were similar for the two doses of omeprazole and misoprostol. Maintenance therapy with omeprazole was associated with a lower rate of relapse than misoprostol. Omeprazole was better tolerated than misoprostol.

AIMS: The working group initiated by the ICS Standardisation Steering Committee has updated the International Continence Society Standard "Good Urodynamic Practice" published in 2002. METHODS: On the basis of the manuscript: "ICS standard to develop evidence-based standards," a new ICS Standard was developed in the period from December 2013 to December 2015. In July, a draft was posted on the ICS website for membership comments and discussed at the ICS 2015 annual meeting. The input of ICS membership was included in the final draft before ICS approval and subsequent peer review (for this journal). RESULTS: This evidence-based ICS-GUP2016 has newly or more precisely defined more than 30 terms and provides standards for the practice, quality control, interpretation, and reporting of urodynamics; cystometry and pressure-flow analysis. Furthermore, the working group has included recommendations for pre-testing information and for patient information and preparation. On the basis of earlier ICS standardisations and updating according to available evidence, the practice of uroflowmetry, cystometry, and pressure-flow studies are further detailed. CONCLUSION: ICS-GUP2016 updates and adds on to ICS-GUP2002 to improve urodynamic testing and reporting both for individual care and scientific purposes.

The emerging understanding of gut microbiota as 'metabolic machinery' influencing many aspects of physiology has gained substantial attention in the field of psychiatry. This is largely due to the many overlapping pathophysiological mechanisms associated with both the potential functionality of the gut microbiota and the biological mechanisms thought to be underpinning mental disorders. In this systematic review, we synthesised the current literature investigating differences in gut microbiota composition in people with the major psychiatric disorders, major depressive disorder (MDD), bipolar disorder (BD) and schizophrenia (SZ), compared to 'healthy' controls. We also explored gut microbiota composition across disorders in an attempt to elucidate potential commonalities in the microbial signatures associated with these mental disorders. Following the PRISMA guidelines, databases were searched from inception through to December 2021. We identified 44 studies (including a total of 2510 psychiatric cases and 2407 controls) that met inclusion criteria, of which 24 investigated gut microbiota composition in MDD, seven investigated gut microbiota composition in BD, and 15 investigated gut microbiota composition in SZ. Our syntheses provide no strong evidence for a difference in the number or distribution (α-diversity) of bacteria in those with a mental disorder compared to controls. However, studies were relatively consistent in reporting differences in overall community composition (β-diversity) in people with and without mental disorders. Our syntheses also identified specific bacterial taxa commonly associated with mental disorders, including lower levels of bacterial genera that produce short-chain fatty acids (e.g. butyrate), higher levels of lactic acid-producing bacteria, and higher levels of bacteria associated with glutamate and GABA metabolism. We also observed substantial heterogeneity across studies with regards to methodologies and reporting. Further prospective and experimental research using new tools and robust guidelines hold promise for improving our understanding of the role of the gut microbiota in mental and brain health and the development of interventions based on modification of gut microbiota.

BACKGROUND: In 1999, meningococcal serogroup C conjugate (MCC) vaccines were introduced in the United Kingdom for those under 19 years of age. The impact of this intervention on asymptomatic carriage of meningococci was investigated to establish whether serogroup replacement or protection by herd immunity occurred. METHODS: Multicenter surveys of carriage were conducted during vaccine introduction and on 2 successive years, resulting in a total of 48,309 samples, from which 8599 meningococci were isolated and characterized by genotyping and phenotyping. RESULTS: A reduction in serogroup C carriage (rate ratio, 0.19) was observed that lasted at least 2 years with no evidence of serogroup replacement. Vaccine efficacy against carriage was 75%, and vaccination had a disproportionate impact on the carriage of sequence type (ST)-11 complex serogroup C meningococci that (rate ratio, 0.06); these meningococci also exhibited high rates of capsule expression. CONCLUSIONS: The impact of vaccination with MCC vaccine on the prevalence of carriage of group C meningococci was consistent with herd immunity. The high impact on the carriage of ST-11 complex serogroup C could be attributed to high levels of capsule expression. High vaccine efficacy against disease in young children, who were not protected long-term by the schedule initially used, is attributed to the high vaccine efficacy against carriage in older age groups.

Abstract Rationale Initial reports of case fatality rates (CFRs) among adults with coronavirus disease (COVID-19) receiving invasive mechanical ventilation (IMV) are highly variable. Objectives To examine the CFR of patients with COVID-19 receiving IMV. Methods Two authors independently searched PubMed, Embase, medRxiv, bioRxiv, the COVID-19 living systematic review, and national registry databases. The primary outcome was the “reported CFR” for patients with confirmed COVID-19 requiring IMV. “Definitive hospital CFR” for patients with outcomes at hospital discharge was also investigated. Finally, CFR was analyzed by patient age, geographic region, and study quality on the basis of the Newcastle-Ottawa Scale. Measurements and Results: Sixty-nine studies were included, describing 57,420 adult patients with COVID-19 who received IMV. Overall reported CFR was estimated as 45% (95% confidence interval [CI], 39–52%). Fifty-four of 69 studies stated whether hospital outcomes were available but provided a definitive hospital outcome on only 13,120 (22.8%) of the total IMV patient population. Among studies in which age-stratified CFR was available, pooled CFR estimates ranged from 47.9% (95% CI, 46.4–49.4%) in younger patients (age ≤40 yr) to 84.4% (95% CI, 83.3–85.4%) in older patients (age &amp;gt;80 yr). CFR was also higher in early COVID-19 epicenters. Overall heterogeneity is high (I2 &amp;gt;90%), with nonsignificant Egger’s regression test suggesting no publication bias. Conclusions Almost half of patients with COVID-19 receiving IMV died based on the reported CFR, but variable CFR reporting methods resulted in a wide range of CFRs between studies. The reported CFR was higher in older patients and in early pandemic epicenters, which may be influenced by limited ICU resources. Reporting of definitive outcomes on all patients would facilitate comparisons between studies. Systematic review registered with PROSPERO (CRD42020186997).

Background: Inflammation plays a crucial role in clinical manifestations and complications of acute coronary syndromes (ACS). Colchicine, a commonly used treatment for gout, has recently emerged as a novel therapeutic option in cardiovascular medicine owing to its anti-inflammatory properties. We sought to determine the potential usefulness of colchicine treatment in patients with ACS. Methods: This was a multicenter, randomized, double-blind, placebo-controlled trial involving 17 hospitals in Australia that provide acute cardiac care service. Eligible participants were adults (18–85 years) who presented with ACS and had evidence of coronary artery disease on coronary angiography managed with either percutaneous coronary intervention or medical therapy. Patients were assigned to receive either colchicine (0.5 mg twice daily for the first month, then 0.5 mg daily for 11 months) or placebo, in addition to standard secondary prevention pharmacotherapy, and were followed up for a minimum of 12 months. The primary outcome was a composite of all-cause mortality, ACS, ischemia-driven (unplanned) urgent revascularization, and noncardioembolic ischemic stroke in a time to event analysis. Results: A total of 795 patients were recruited between December 2015 and September 2018 (mean age, 59.8±10.3 years; 21% female), with 396 assigned to the colchicine group and 399 to the placebo group. Over the 12-month follow-up, there were 24 events in the colchicine group compared with 38 events in the placebo group ( P =0.09, log-rank). There was a higher rate of total death (8 versus 1; P =0.017, log-rank) and, in particular, noncardiovascular death in the colchicine group (5 versus 0; P =0.024, log-rank). The rates of reported adverse effects were not different (colchicine 23.0% versus placebo 24.3%), and they were predominantly gastrointestinal symptoms (colchicine, 23.0% versus placebo, 20.8%). Conclusions: The addition of colchicine to standard medical therapy did not significantly affect cardiovascular outcomes at 12 months in patients with ACS and was associated with a higher rate of mortality. Registration: URL: https://www.anzctr.org.au ; Unique identifier: ACTRN12615000861550.

Modern imaging techniques are an essential component of preoperative planning in plastic and reconstructive surgery. However, conventional modalities, including three-dimensional (3D) reconstructions, are limited by their representation on 2D workstations. 3D printing, also known as rapid prototyping or additive manufacturing, was once the province of industry to fabricate models from a computer-aided design (CAD) in a layer-by-layer manner. The early adopters in clinical practice have embraced the medical imaging-guided 3D-printed biomodels for their ability to provide tactile feedback and a superior appreciation of visuospatial relationship between anatomical structures. With increasing accessibility, investigators are able to convert standard imaging data into a CAD file using various 3D reconstruction softwares and ultimately fabricate 3D models using 3D printing techniques, such as stereolithography, multijet modeling, selective laser sintering, binder jet technique, and fused deposition modeling. However, many clinicians have questioned whether the cost-to-benefit ratio justifies its ongoing use. The cost and size of 3D printers have rapidly decreased over the past decade in parallel with the expiration of key 3D printing patents. Significant improvements in clinical imaging and user-friendly 3D software have permitted computer-aided 3D modeling of anatomical structures and implants without outsourcing in many cases. These developments offer immense potential for the application of 3D printing at the bedside for a variety of clinical applications. In this review, existing uses of 3D printing in plastic surgery practice spanning the spectrum from templates for facial transplantation surgery through to the formation of bespoke craniofacial implants to optimize post-operative esthetics are described. Furthermore, we discuss the potential of 3D printing to become an essential office-based tool in plastic surgery to assist in preoperative planning, developing intraoperative guidance tools, teaching patients and surgical trainees, and producing patient-specific prosthetics in everyday surgical practice.

IMPORTANCE: Effective therapy has not been established for patients with agitated delirium receiving mechanical ventilation. OBJECTIVE: To determine the effectiveness of dexmedetomidine when added to standard care in patients with agitated delirium receiving mechanical ventilation. DESIGN, SETTING, AND PARTICIPANTS: The Dexmedetomidine to Lessen ICU Agitation (DahLIA) study was a double-blind, placebo-controlled, parallel-group randomized clinical trial involving 74 adult patients in whom extubation was considered inappropriate because of the severity of agitation and delirium. The study was conducted at 15 intensive care units in Australia and New Zealand from May 2011 until December 2013. Patients with advanced dementia or traumatic brain injury were excluded. INTERVENTIONS: Bedside nursing staff administered dexmedetomidine (or placebo) initially at a rate of 0.5 µg/kg/h and then titrated to rates between 0 and 1.5 µg/kg/h to achieve physician-prescribed sedation goals. The study drug or placebo was continued until no longer required or up to 7 days. All other care was at the discretion of the treating physician. MAIN OUTCOMES AND MEASURES: Ventilator-free hours in the 7 days following randomization. There were 21 reported secondary outcomes that were defined a priori. RESULTS: Of the 74 randomized patients (median age, 57 years; 18 [24%] women), 2 withdrew consent later and 1 was found to have been randomized incorrectly, leaving 39 patients in the dexmedetomidine group and 32 patients in the placebo group for analysis. Dexmedetomidine increased ventilator-free hours at 7 days compared with placebo (median, 144.8 hours vs 127.5 hours, respectively; median difference between groups, 17.0 hours [95% CI, 4.0 to 33.2 hours]; P = .01). Among the 21 a priori secondary outcomes, none were significantly worse with dexmedetomidine, and several showed statistically significant benefit, including reduced time to extubation (median, 21.9 hours vs 44.3 hours with placebo; median difference between groups, 19.5 hours [95% CI, 5.3 to 31.1 hours]; P < .001) and accelerated resolution of delirium (median, 23.3 hours vs 40.0 hours; median difference between groups, 16.0 hours [95% CI, 3.0 to 28.0 hours]; P = .01). Using hierarchical Cox modeling to adjust for imbalanced baseline characteristics, allocation to dexmedetomidine was significantly associated with earlier extubation (hazard ratio, 0.47 [95% CI, 0.27-0.82]; P = .007). CONCLUSIONS AND RELEVANCE: Among patients with agitated delirium receiving mechanical ventilation in the intensive care unit, the addition of dexmedetomidine to standard care compared with standard care alone (placebo) resulted in more ventilator-free hours at 7 days. The findings support the use of dexmedetomidine in patients such as these. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01151865.

AIMS AND OBJECTIVES: To investigate the prevalence and extent of burnout on nurses and its association with personal resilience. BACKGROUND: With the worldwide shortage of nurses, nurse burnout is considered one of the main contributing factors and has been the focus of studies in recent years. Given the well-documented high level of burnout among nurses, resilience is expected to be a significant predictor of nurse burnout. The association between burnout and resilience has not previously been investigated extensively. DESIGN: A cross-sectional survey design was selected. METHODS: A total of 1,061 nurses from six separate three-level hospitals in Hunan Province, China, returned self-reported questionnaires from March-June 2015. Data were collected using a socio-demographic sheet, Maslach Burnout Inventory-General Survey and the Connor-Davidson Resilience Scale. RESULTS: Nurses experienced severe burnout symptoms and showed a moderate level of resilience. Three metrics of burnout had significantly negative correlations with the total score and following variables of resilience. Linear regression analysis showed resilience, especially strength, demographic characteristics (exercise, alcohol use and marital status) and job characteristics (income per month, ratio of patients to nurses, shift work and professional rank) were the main predictors of the three metrics of burnout. CONCLUSION: The findings of this study may help nurse managers and hospital administrators to have a better understanding of nurse burnout and resilience. The significantly negative relationship between burnout symptoms and resilience has been demonstrated, and this informs the role of resilience in influencing burnout. RELEVANCE TO CLINICAL PRACTICE: Adaptable and effective interventions for improving resilience are needed to relieve nurses' burnout and reduce workplace stress. Moreover, nurse managers and hospital administrators should establish an effective management system to cultivate a healthy workplace and adopt positive attitudes and harmonious relationships.

Accurately identifying patients with high-grade serous ovarian carcinoma (HGSOC) who respond to poly(ADP-ribose) polymerase inhibitor (PARPi) therapy is of great clinical importance. Here we show that quantitative BRCA1 methylation analysis provides new insight into PARPi response in preclinical models and ovarian cancer patients. The response of 12 HGSOC patient-derived xenografts (PDX) to the PARPi rucaparib was assessed, with variable dose-dependent responses observed in chemo-naive BRCA1/2-mutated PDX, and no responses in PDX lacking DNA repair pathway defects. Among BRCA1-methylated PDX, silencing of all BRCA1 copies predicts rucaparib response, whilst heterozygous methylation is associated with resistance. Analysis of 21 BRCA1-methylated platinum-sensitive recurrent HGSOC (ARIEL2 Part 1 trial) confirmed that homozygous or hemizygous BRCA1 methylation predicts rucaparib clinical response, and that methylation loss can occur after exposure to chemotherapy. Accordingly, quantitative BRCA1 methylation analysis in a pre-treatment biopsy could allow identification of patients most likely to benefit, and facilitate tailoring of PARPi therapy.

OBJECTIVE: To evaluate long-term safety and efficacy of esketamine nasal spray plus a new oral antidepressant (OAD) in patients with treatment-resistant depression (TRD). METHODS: This phase 3, open-label, multicenter, long-term (up to 1 year) study was conducted between October 2015 and October 2017. Patients (≥ 18 years) with TRD (DSM-5 diagnosis of major depressive disorder and nonresponse to ≥ 2 OAD treatments) were enrolled directly or transferred from a short-term study (patients aged ≥ 65 years). Esketamine nasal spray (28-mg, 56-mg, or 84-mg) plus new OAD was administered twice a week in a 4-week induction (IND) phase and weekly or every-other-week for patients who were responders and entered a 48-week optimization/maintenance (OP/MAINT) phase. RESULTS: Of 802 enrolled patients, 86.2% were direct-entry and 13.8% were transferred-entry; 580 (74.5%) of 779 patients who entered the IND phase completed the phase, and 150 (24.9%) of 603 who entered the OP/MAINT phase completed the phase. Common treatment-emergent adverse events (TEAEs) were dizziness (32.9%), dissociation (27.6%), nausea (25.1%), and headache (24.9%). Seventy-six patients (9.5%) discontinued esketamine due to TEAEs. Fifty-five patients (6.9%) experienced serious TEAEs. Most TEAEs occurred on dosing days, were mild or moderate in severity, and resolved on the same day. Two deaths were reported; neither was considered related to esketamine. Cognitive performance generally either improved or remained stable postbaseline. There was no case of interstitial cystitis or respiratory depression. Treatment-emergent dissociative symptoms were transient and generally resolved within 1.5 hours postdose. Montgomery-Åsberg Depression Rating Scale total score decreased during the IND phase, and this reduction persisted during the OP/MAINT phase (mean [SD] change from baseline of respective phase to endpoint: IND, -16.4 [8.76]; OP/MAINT, 0.3 [8.12]). CONCLUSIONS: Long-term esketamine nasal spray plus new OAD therapy had a manageable safety profile, and improvements in depression appeared to be sustained in patients with TRD. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02497287.

BACKGROUND: A multidisciplinary collaboration investigated the world's largest, most catastrophic epidemic thunderstorm asthma event that took place in Melbourne, Australia, on Nov 21, 2016, to inform mechanisms and preventive strategies. METHODS: Meteorological and airborne pollen data, satellite-derived vegetation index, ambulance callouts, emergency department presentations, and data on hospital admissions for Nov 21, 2016, as well as leading up to and following the event were collected between Nov 21, 2016, and March 31, 2017, and analysed. We contacted patients who presented during the epidemic thunderstorm asthma event at eight metropolitan health services (each including up to three hospitals) via telephone questionnaire to determine patient characteristics, and investigated outcomes of intensive care unit (ICU) admissions. FINDINGS: ). At 1800 AEDT, a gust front crossed Melbourne, plunging temperatures 10°C, raising humidity above 70%, and concentrating particulate matter. Within 30 h, there were 3365 (672%) excess respiratory-related presentations to emergency departments, and 476 (992%) excess asthma-related admissions to hospital, especially individuals of Indian or Sri Lankan birth (10% vs 1%, p<0·0001) and south-east Asian birth (8% vs 1%, p<0·0001) compared with previous 3 years. Questionnaire data from 1435 (64%) of 2248 emergency department presentations showed a mean age of 32·0 years (SD 18·6), 56% of whom were male. Only 28% had current doctor-diagnosed asthma. 39% of the presentations were of Asian or Indian ethnicity (25% of the Melbourne population were of this ethnicity according to the 2016 census, relative risk [RR] 1·93, 95% CI 1·74-2·15, p <0·0001). Of ten individuals who died, six were Asian or Indian (RR 4·54, 95% CI 1·28-16·09; p=0·01). 35 individuals were admitted to an intensive care unit, all had asthma, 12 took inhaled preventers, and five died. INTERPRETATION: Convergent environmental factors triggered a thunderstorm asthma epidemic of unprecedented magnitude, tempo, and geographical range and severity on Nov 21, 2016, creating a new benchmark for emergency and health service escalation. Asian or Indian ethnicity and current doctor-diagnosed asthma portended life-threatening exacerbations such as those requiring admission to an ICU. Overall, the findings provide important public health lessons applicable to future event forecasting, health care response coordination, protection of at-risk populations, and medical management of epidemic thunderstorm asthma. FUNDING: None.

BACKGROUND: Enhanced influenza vaccines are needed to provide improved protection for elderly individuals. The intradermal vaccination route was hypothesized to provide immunogenicity superior to that provided by the intramuscular vaccination route. METHODS: In a multicenter, randomized study, 1107 volunteers >60 years of age received intradermal trivalent inactivated influenza vaccine containing 15 or 21 microg of hemagglutinin per strain or intramuscular control vaccine. Intradermal vaccines used a novel microinjection system designed to ensure easy, convenient, consistent vaccination. The primary end points of the study were the strain-specific hemagglutination inhibition geometric mean titers (GMTs) noted 21 days after vaccination. Groups were compared using noninferiority and superiority analyses. RESULTS: For each strain, the GMTs noted in association with each intradermal vaccine were superior to those noted with the intramuscular control (adjusted P< .0001). Seroprotection rates, seroconversion rates, and mean titer increases were also superior for intradermally administered vaccine in all but one of the analyses undertaken. Systemic reactogenicity was comparable between routes. Local injection site reactions, particularly erythema but not pain, were more commonly associated with intradermal vaccination. CONCLUSIONS: For the first time, the intradermal vaccination route has been used to elicit immune responses significantly superior to those noted in association with the conventional intramuscular vaccination route. This was done using an easy-to-use, reliable microinjection system. This superior response is expected to enhance annual protection against influenza in this vulnerable population. TRIAL REGISTRATION: Clinicaltrials.gov registry number: NCT00296829.

AIMS: Recent randomized trials demonstrated a benefit of low-dose colchicine added to guideline-based treatment in patients with recent myocardial infarction or chronic coronary disease. We performed a systematic review and meta-analysis to obtain best estimates of the effects of colchicine on major adverse cardiovascular events (MACE). METHODS AND RESULTS: We searched the literature for randomized clinical trials of long-term colchicine in patients with atherosclerosis published up to 1 September 2020. The primary efficacy endpoint was MACE, the composite of myocardial infarction, stroke, or cardiovascular death. We combined the results of five trials that included 11 816 patients. The primary endpoint occurred in 578 patients. Colchicine reduced the risk for the primary endpoint by 25% [relative risk (RR) 0.75, 95% confidence interval (CI) 0.61-0.92; P = 0.005], myocardial infarction by 22% (RR 0.78, 95% CI 0.64-0.94; P = 0.010), stroke by 46% (RR 0.54, 95% CI 0.34-0.86; P = 0.009), and coronary revascularization by 23% (RR 0.77, 95% CI 0.66-0.90; P < 0.001). We observed no difference in all-cause death (RR 1.08, 95% CI 0.71-1.62; P = 0.73), with a lower incidence of cardiovascular death (RR 0.82, 95% CI 0.55-1.23; P = 0.34) counterbalanced by a higher incidence of non-cardiovascular death (RR 1.38, 95% CI 0.99-1.92; P = 0.060). CONCLUSION: Our meta-analysis indicates that low-dose colchicine reduced the risk of MACE as well as that of myocardial infarction, stroke, and the need for coronary revascularization in a broad spectrum of patients with coronary disease. There was no difference in all-cause mortality and fewer cardiovascular deaths were counterbalanced by more non-cardiovascular deaths.

BACKGROUND: Inflammation is associated with adverse cardiovascular events. Data from recent trials suggest that colchicine reduces the risk of cardiovascular events. METHODS: In this multicenter trial with a 2-by-2 factorial design, we randomly assigned patients who had myocardial infarction to receive either colchicine or placebo and either spironolactone or placebo. The results of the colchicine trial are reported here. The primary efficacy outcome was a composite of death from cardiovascular causes, recurrent myocardial infarction, stroke, or unplanned ischemia-driven coronary revascularization, evaluated in a time-to-event analysis. C-reactive protein was measured at 3 months in a subgroup of patients, and safety was also assessed. RESULTS: A total of 7062 patients at 104 centers in 14 countries underwent randomization; at the time of analysis, the vital status was unknown for 45 patients (0.6%), and this information was most likely missing at random. A primary-outcome event occurred in 322 of 3528 patients (9.1%) in the colchicine group and 327 of 3534 patients (9.3%) in the placebo group over a median follow-up period of 3 years (hazard ratio, 0.99; 95% confidence interval [CI], 0.85 to 1.16; P = 0.93). The incidence of individual components of the primary outcome appeared to be similar in the two groups. The least-squares mean difference in C-reactive protein levels between the colchicine group and the placebo group at 3 months, adjusted according to the baseline values, was -1.28 mg per liter (95% CI, -1.81 to -0.75). Diarrhea occurred in a higher percentage of patients with colchicine than with placebo (10.2% vs. 6.6%; P<0.001), but the incidence of serious infections did not differ between groups. CONCLUSIONS: Among patients who had myocardial infarction, treatment with colchicine, when started soon after myocardial infarction and continued for a median of 3 years, did not reduce the incidence of the composite primary outcome (death from cardiovascular causes, recurrent myocardial infarction, stroke, or unplanned ischemia-driven coronary revascularization). (Funded by the Canadian Institutes of Health Research and others; CLEAR ClinicalTrials.gov number, NCT03048825.).

BACKGROUND AND AIMS: Hepatocyte nuclear factor-1 alpha (HNF1A) gene mutations are the commonest cause of monogenic diabetes, but patients are often misdiagnosed as having Type 1 diabetes and started on insulin treatment. Patients with HNF1A diabetes are particularly sensitive to the glucose-lowering effect of sulphonylureas, which are the pharmacological treatment of choice. We aimed to assess if patients do change from insulin to sulphonylurea treatment when HNF1A diabetes is confirmed and the impact of this treatment change on long-term glycaemic control. METHODS: We investigated the clinical course of 43 patients who were insulin treated from diagnosis for a median 4 years (range 1-14) before an HNF1A gene mutation was identified. RESULTS: Thirty-four patients (79%) stopped insulin following genetic testing and transferred to sulphonylureas. Twenty-four of them (71%) remained off insulin at a median 39 months (range 17-90) post-transfer. The 10 patients who recommenced insulin had a trend towards a longer duration of diabetes (18 vs. 7 years, P = 0.066) compared with those remaining on tablets. The median glycated haemoglobin (HbA(1c)) was good (6.9%; interquartile range 6.3-8.0%) in the patients who remained off insulin and 19/24 patients (79%) achieved HbA(1c) < 7.5% or improved their pre-genetic diagnosis HbA(1c) by > 1.0%. Transfer off insulin was not attempted in eight patients: one of these was planning pregnancy and two chose to remain on insulin. CONCLUSION: In this observational study we found that a molecular genetic diagnosis of HNF1A diabetes does alter treatment in clinical practice, with 79% attempting transfer to sulphonylureas. Transfer to sulphonylureas was successful in the majority of patients without deterioration in glycaemic control.

AIMS: The pelvis rotates in the sagittal plane during daily activities. These rotations have a direct effect on the functional orientation of the acetabulum. The aim of this study was to quantify changes in pelvic tilt between different functional positions. PATIENTS AND METHODS: Pre-operatively, pelvic tilt was measured in 1517 patients undergoing total hip arthroplasty (THA) in three functional positions - supine, standing and flexed seated (the moment when patients initiate rising from a seated position). Supine pelvic tilt was measured from CT scans, standing and flexed seated pelvic tilts were measured from standardised lateral radiographs. Anterior pelvic tilt was assigned a positive value. RESULTS: The mean pelvic tilt was 4.2° (-20.5° to 24.5°), -1.3° (-30.2° to 27.9°) and 0.6° (-42.0° to 41.3°) in the three positions, respectively. The mean sagittal pelvic rotation from supine to standing was -5.5° (-21.8° to 8.4°), from supine to flexed seated was -3.7° (-48.3° to 38.6°) and from standing to flexed seated was 1.8° (-51.8° to 39.5°). In 259 patients (17%), the extent of sagittal pelvic rotation could lead to functional malorientation of the acetabular component. Factoring in an intra-operative delivery error of ± 5° extends this risk to 51% of patients. CONCLUSION: Planning and measurement of the intended position of the acetabular component in the supine position may fail to predict clinically significant changes in its orientation during functional activities, as a consequence of individual pelvic kinematics. Optimal orientation is patient-specific and requires an evaluation of functional pelvic tilt pre-operatively. Cite this article: Bone Joint J 2017;99-B:184-91.

PURPOSE Palbociclib is a cyclin-dependent kinase 4 and 6 inhibitor approved for advanced breast cancer. In the adjuvant setting, the potential value of adding palbociclib to endocrine therapy for hormone receptor–positive breast cancer has not been confirmed. PATIENTS AND METHODS In the prospective, randomized, phase III PALLAS trial, patients with hormone receptor–positive, human epidermal growth factor receptor 2–negative early breast cancer were randomly assigned to receive 2 years of palbociclib (125 mg orally once daily, days 1-21 of a 28-day cycle) with adjuvant endocrine therapy or adjuvant endocrine therapy alone (for at least 5 years). The primary end point of the study was invasive disease-free survival (iDFS); secondary end points were invasive breast cancer–free survival, distant recurrence-free survival, locoregional cancer-free survival, and overall survival. RESULTS Among 5,796 patients enrolled at 406 centers in 21 countries worldwide over 3 years, 5,761 were included in the intention-to-treat population. At the final protocol-defined analysis, at a median follow-up of 31 months, iDFS events occurred in 253 of 2,884 (8.8%) patients who received palbociclib plus endocrine therapy and in 263 of 2,877 (9.1%) patients who received endocrine therapy alone, with similar results between the two treatment groups (iDFS at 4 years: 84.2% v 84.5%; hazard ratio, 0.96; CI, 0.81 to 1.14; P = .65). No significant differences were observed for secondary time-to-event end points, and subgroup analyses did not show any differences by subgroup. There were no new safety signals for palbociclib in this trial. CONCLUSION At this final analysis of the PALLAS trial, the addition of adjuvant palbociclib to standard endocrine therapy did not improve outcomes over endocrine therapy alone in patients with early hormone receptor–positive breast cancer.

Illicit drug use disorders are the most stigmatised health conditions worldwide, and stigma acts as a meaningful barrier to treatment entry and treatment provision. In the context of dramatically rising opioid-related harms, it is critical that we understand the drivers of stigma and how it affects opioid use disorder treatment and policy. The aim of this narrative review is to discuss how opioid-related stigma impacts treatment provision and harm reduction, and provide potential strategies to reduce stigma at a social and structural level. We used the Framework for Integrating Normative Influences on Stigma (FINIS) to identify sources of opioid-related stigma at the macro (structural stigma), meso (public stigma) and micro (internalised stigma) levels. Reducing stigma requires strategies that target multiple levels, however addressing inequity in the laws, regulations, and rules that segregate people with opioid and other substance use disorders from mainstream society is essential.

We have provided an overview on the profound impact of COVID-19 upon older people with Alzheimer's disease and other dementias and the challenges encountered in our management of dementia in different health-care settings, including hospital, out-patient, care homes, and the community during the COVID-19 pandemic. We have also proposed a conceptual framework and practical suggestions for health-care providers in tackling these challenges, which can also apply to the care of older people in general, with or without other neurological diseases, such as stroke or parkinsonism. We believe this review will provide strategic directions and set standards for health-care leaders in dementia, including governmental bodies around the world in coordinating emergency response plans for protecting and caring for older people with dementia amid the COIVD-19 outbreak, which is likely to continue at varying severity in different regions around the world in the medium term.