Rifaximin prophylaxis causes resistance to the last-resort antibiotic daptomycin.

Multidrug-resistant bacterial pathogens like vancomycin-resistant Enterococcus faecium (VREfm) are a critical threat to human health1. Daptomycin is a last-resort antibiotic for VREfm infections with a novel mode of action2, but for which resistance has been widely reported but is unexplained. Here we show that rifaximin, an unrelated antibiotic used prophylactically to prevent hepatic encephalopathy in patients with liver disease3, causes cross-resistance to daptomycin in VREfm. Amino acid changes arising within the bacterial RNA polymerase in response to rifaximin exposure cause upregulation of a previously uncharacterized operon (prdRAB) that leads to cell membrane remodelling and cross-resistance to daptomycin through reduced binding of the antibiotic. VREfm with these mutations are spread globally, making this a major mechanism of resistance. Rifaximin has been considered 'low risk' for the development of antibiotic resistance. Our study shows that this assumption is flawed and that widespread rifaximin use, particularly in patients with liver cirrhosis, may be compromising the clinical use of daptomycin, a major last-resort intervention for multidrug-resistant pathogens. These findings demonstrate how unanticipated antibiotic cross-resistance can undermine global strategies designed to preserve the clinical use of critical antibiotics.

Vedolizumab and Ustekinumab Levels in Pregnant Women With Inflammatory Bowel Disease and Infants Exposed In Utero.

BACKGROUND & AIMS: Vedolizumab and ustekinumab pharmacokinetics in pregnancy and the infant after in utero exposure remain incompletely defined. We aim to define the antenatal stability of ustekinumab and vedolizumab levels and the time at which infant drug levels become undetectable. METHODS: This multicenter prospective observational cohort study recruited pregnant or preconception women with inflammatory bowel disease receiving vedolizumab or ustekinumab. Trough drug levels, clinical data, and biochemical data were documented preconception, during each trimester of pregnancy, and postpartum. Maternal and cord blood drug levels were measured at delivery and in infants until undetectable. Infant outcomes were assessed until 2 years of age. RESULTS: A total of 102 participants (vedolizumab, n = 58) were included. The majority of mothers were, and remained, in clinical and biochemical remission. Maternal vedolizumab levels decreased over the course of pregnancy in association with increasing weight, rather than increasing gestation. Maternal ustekinumab levels remained stable. The median time to drug becoming undetectable in the infant was shorter for vedolizumab (11 wk; range, 5-19 wk; n = 32) than ustekinumab (14 wk; range, 9-36 wk; n = 17) and correlated positively with infant delivery level. Thirty-two of 41 (88%) and 17 of 30 (67%) vedolizumab- and ustekinumab-exposed infants had undetectable drug levels by 15 weeks of age, respectively. Pregnancy and infant outcomes were favorable. Twenty infants with undetectable drug levels received the rotavirus vaccine, with no adverse reactions reported. CONCLUSIONS: Maternal vedolizumab levels decreased, whereas ustekinumab levels remained stable over the course of pregnancy. Most vedolizumab- and approximately half of ustekinumab-exposed infants had undetectable drug levels by 15 weeks of age. No concerning maternal or infant safety signals were identified.

Effectiveness of direct delabelling of allergy labels in type A adverse drug reactions to penicillin: a multicentre hospitalwide prospective cohort study.

BACKGROUND: Patient-reported penicillin allergy labels (PALs) are associated with adverse patient outcomes and inappropriate antibiotic prescribing. Removal of PALs via direct oral challenge (DOC) is associated with increased penicillin utilization post removal. OBJECTIVES: To assess the impact of direct delabelling (allergy label removal via medical reconciliation alone) of type A adverse drug reaction (ADR) PALs on inpatient prescribing. METHODS: From January 2019 to December 2022 at two tertiary hospitals in Melbourne, patients aged ≥18 years with type A ADR PALs, as defined by the validated Antibiotic Allergy Assessment Tool, were offered direct delabelling or single-dose DOC. The primary endpoint was antibiotic use pre- and post-assessment (during index admission and 90 days post assessment). The secondary endpoint was the proportion of patients delabelled in the direct delabelling and DOC cohorts in the electronic medical record at 90 days post assessment. RESULTS: Allergy labels (n = 4108) were assessed for 488 participants, with 490 individual type A ADR PAL assessments included. Three hundred and thirty-seven patients were directly delabelled, 69 underwent DOC and 84 were not delabelled. There was increased use of any penicillin following direct delabelling (OR 19.19, 95% CI 2.48-148.36) and DOC (OR 56.98, 95% CI 6.82-476.19) during the index admission, higher in the DOC group compared with direct delabelling (OR 2.97, 95% CI 1.39-6.37). Relabelling at 90 days was low with no statistically significant difference between direct delabelling (5/337; 1.5%) and DOC (0/69; 0%). CONCLUSIONS: Both direct delabelling and DOC of type A ADR PALs increased penicillin usage; however, the impact was greatest with DOC. Most patients remain delabelled at 90 days.

Systemic and iatrogenic factors contribute to the development of severe hypernatraemia in vulnerable inpatients.

OBJECTIVES: To determine all-cause in-hospital mortality associated with severe hypernatraemia and the causes, comorbidities, time to treatment, discharge destination and postdischarge mortality. DESIGN: Retrospective observational cohort study. PATIENTS: Severe hypernatraemia, (sodium concentration ≥ 155 mmol/L), at any time during a tertiary hospital admission in Melbourne, Australia, 1 January 2019 to 31 December 2019 (pre-COVID19). MEASUREMENTS: Deaths, Charlson Comorbidity Index (CCI), hypernatraemia causes, time to treatment, discharge destination. RESULTS: One hundred and one inpatients: 64 community-acquired, 37 hospital-acquired. In-hospital mortality was 38%, but cumulative mortality was 65% by 1 month after discharge, with only a minor further increase at 6 and 12 months. After adjusting for peak sodium concentration, the community acquired group had significantly reduced odds of in-hospital mortality (odds ratio 0.15, 95% confidence interval [0.04-0.54], p = .003). Iatrogenic factors were present in 57% (21/37) of the hospital-acquired group. Only 55% of all cases received active sodium directed treatment. Time to start treatment did not affect outcomes. High levels of comorbidity were present, median CCI (IQR) was 6 (5-8) in the community and 5 (4-7) in the hospital group. Dementia prevalence was higher in the community group, 66% (42/64) versus 19% (7/37) (p = .001). Infection was the most common precipitant with 52% (33/64) in the community and 32% (12/37) in the hospital group. Of the survivors, 32% who had been living independently required residential care after discharge. CONCLUSIONS: Mortality was high and loss of independence in survivors common. To potentially improve outcomes, hypernatraemia-specific guidelines should be formulated and efforts made to reduce system and iatrogenic factors.

Repeated Endoscopic Dilation and Needle Knife Stricturotomy for Crohn's Disease Strictures.

BACKGROUND AND AIMS: Crohn's disease strictures are usually treated by a single endoscopic balloon dilation (EBD). We postulated repeat EBD and needle-knife stricturotomy (NKSt), together with inflammation controlled by intense drug therapy, may be more effective. METHODS: 21 patients with symptomatic strictures were randomised to single EBD or intensive treatment with 3 balloon dilations 3 weeks apart and/or NKSt RESULTS: Of 21 patients 2 of 5 (40%) five with a single EBD and 12/16 [72%] with intensive treatment had symptom improvement (OR 4.49 [95% CI 0.54 - 37.4]; P = 0.164). Eleven patients received >1 EBD without NKSt, 5 had ≥1 NKSt. NKSt treated patients and those with concurrent intensified drug treatment had the best outcomes. CONCLUSIONS: Crohn's disease stricture treatment with repeat dilations or stricturotomy is feasible, safe and may improve stricture outcomes. Concurrent intensified drug treatment to eliminate inflammation is also associated with improved outcome.

High end-of-treatment hepatitis B core-related antigen levels predict hepatitis flare after stopping nucleot(s)ide analogue therapy.

BACKGROUND AND AIMS: Accurate biomarkers to predict outcomes following discontinuation of nucleos(t)ide analogue (NA) therapy are needed. We evaluated serum hepatitis B core-related antigen (HBcrAg) level as a biomarker for predicting outcomes after NA discontinuation. METHODS: Patients with HBeAg-negative chronic hepatitis B (CHB) without cirrhosis were enrolled in a prospective trial evaluating clinical outcomes until 96 weeks after NA discontinuation. End of treatment (EOT) and off-treatment levels of serum HBcrAg, HBsAg, HBV RNA and HBV DNA were used to predict key clinical outcomes including hepatitis flare (ALT ≥5 × ULN and HBV DNA > 2000 IU/mL). The SCALE-B score was calculated for the purposes of model validation. RESULTS: HBcrAg was tested amongst 65 participants. The median age was 54 years, 54% were male and 83% were Asian. HBcrAg was detectable in 86% patients. HBcrAg level ≥4 log U/mL at EOT was predictive of hepatitis flare [8/10 (80%) vs. 17/55 (31%), p = .001]. The presence of either HBcrAg ≥4 log U/mL or detectable HBV RNA at EOT predicted for both biochemical relapse and hepatitis flare. The SCALE-B model at EOT predicted for virological relapse, biochemical relapse, hepatitis flare and HBsAg loss in this cohort. An increase in the serum HBcrAg level off-treatment was also associated with hepatitis flare. No participant with EOT HBcrAg level ≥4 log U/mL achieved HBsAg loss. CONCLUSIONS: High levels of serum HBcrAg predict for hepatitis flare after stopping NA therapy and low likelihood of HBsAg loss at week 96. People with high levels of serum HBcrAg are not suitable candidates for NA discontinuation.

Consumption of dairy foods to achieve recommended levels for older adults has no deleterious effects on serum lipids.

BACKGROUND AND AIMS: Correction of calcium and protein undernutrition using milk, yoghurt, and cheese in older adults in aged care homes is associated with reduced fractures and falls. However, these foods contain potentially atherogenic fats. We aimed to determine whether this intervention that increased dairy consumption to recommended levels adversely affects serum lipid profiles. METHOD AND RESULTS: This was a sub-group analysis of a 2-year cluster-randomised trial involving 60 aged care homes in Australia. Thirty intervention homes provided additional milk, yoghurt, and cheese on menus while 30 control homes continued with their usual menus. A sample of 159 intervention and 86 controls residents (69% female, median age 87.8 years) had dietary intakes recorded using plate waste analysis and fasting serum lipids measured at baseline and 12 months. Diagnosis of cardiovascular disease and use of relevant medications were determined from medical records. Outcome measures were serum total, HDL and LDL cholesterol and ApoA-1 & B. Intervention increased daily dairy servings from 1.9 ± 1.0 to 3.5 ± 1.4 (p < 0.001) while controls continued daily intakes of ≤2 servings daily (1.7 ± 1.0 to 2.0 ± 1.0 (p = 0.028). No group differences were observed for serum total cholesterol/high-density lipoprotein-C (TC/HDL-C) ratio, Apoprotein B/Apoprotein A-1 (ApoB/ApoA-1) ratio, low-density lipoprotein-C (LDL-C), non-HDL-C, or triglycerides (TGs) at 12 months. CONCLUSION: Among older adults in aged care homes, correcting insufficiency in intakes of calcium and protein using milk, yoghurt and cheese does not alter serum lipid levels, suggesting that this is a suitable intervention for reducing the risk of falls and fractures. CLINICAL TRIAL REGISTRY: Australian New Zealand Clinical Trials Registry (ACTRN12613000228785) 2012; https://www.anzctr.org.au.

Automated insulin delivery among adults with type 1 diabetes for up to 2 years: a real-world, multicentre study.

BACKGROUND AND AIMS: Automated insulin delivery (AID) improves glycaemia among people with type 1 diabetes in clinical trials and overseas real-world studies. Whether improvements are sustained beyond 12 months in the real world, and whether they occur in the Australian context, has not yet been established. We aimed to observe, up to 2 years, the effectiveness of initiating first-generation AID for type 1 diabetes management. METHODS: Retrospective, real-world, observational study using medical records, conducted across five sites in Australia. Adults with type 1 diabetes, who had AID initiated between February 2019 and December 2021, were observed for 6-24 months after initiation (until June 2022). Outcomes examined included glucose metrics assessed by glycated haemoglobin (HbA1c ) and continuous glucose monitoring (CGM), safety and therapy continuation. RESULTS: Ninety-four adults were studied (median age 39 years (interquartile range, IQR: 31-51); pre-initiation HbA1c 7.8% (7.2-8.6)). After AID initiation, HbA1c decreased by mean 0.5 percentage points (95% confidence interval (CI): -0.7 to -0.2) at 3 months (P < 0.001); CGM time in range 3.9-10.0 mmol/L increased by 11 percentage points (9-14) at 1 month (P < 0.001); these improvements were maintained up to 24 months (all P < 0.02). Median CGM time below 3.9 mmol/L was <1.5% pre- and post-AID initiation. The subgroup with pre-initiation HbA1c above 8.5% had the greatest HbA1c improvement (-1.4 percentage points (-1.8 to -1.1) at 3 months). Twelve individuals (13%) discontinued AID, predominantly citing difficulties with CGM. During the 150 person-years observed, four diabetes-related emergencies were documented: three severe hypoglycaemic events and one hyperglycaemic event without ketoacidosis. CONCLUSIONS: Early glucose improvements were observed after real-world AID initiation, sustained up to 2 years, without excess adverse events. The greatest benefits were observed among individuals with highest glycaemia before initiation. Future-generation systems with increased user-friendliness may enhance therapy continuation.

6-Thioguanine nucleotide levels are associated with infliximab but not adalimumab levels in inflammatory bowel disease patients on combination therapy.

BACKGROUND: Thiopurine co-therapy with anti-tumour necrosis factor-alpha (anti-TNFα) agents is associated with higher anti-TNFα drug levels and reduced immunogenicity in inflammatory bowel disease (IBD). AIMS: We aimed to evaluate the association between 6-thioguanine nucleotide (6-TGN) and anti-TNFα levels and the optimal 6-TGN threshold level associated with higher anti-TNFα levels in combination therapy. METHODS: We performed a retrospective cross-sectional multicentre study of patients with IBD on combination anti-TNFα and thiopurine maintenance therapy between January 2015 and August 2021. Primary outcomes were infliximab and adalimumab levels. Secondary outcomes were antibodies to infliximab (ATI) or adalimumab (ATA). Univariable and multivariable linear regression were performed to identify variables associated with anti-TNFα levels. Receiver operator characteristic curves were used to define the optimal 6-TGN cut-off levels associated with therapeutic anti-TNFα levels. RESULTS: The study included 743 paired 6-TGN and anti-TNFα levels (640 infliximab and 103 adalimumab). 6-TGN levels were associated with infliximab levels, but not adalimumab levels, on univariable and multivariable regression. The optimal 6-TGN cut-off associated with therapeutic infliximab levels (≥5 mcg/mL) was 261 pmol/8 × 108 red blood cell (RBC) (area under the curve (AUC) = 0.57) for standard infliximab dosing and 227.5 pmol/8 × 108 RBC (AUC = 0.58) for escalated dosing. For therapeutic adalimumab levels (≥7.5 mcg/mL), the 6-TGN cut-off was 218.5 pmol/8 × 108 RBC (AUC = 0.59) for standard adalimumab dosing and 237.5 pmol/8 × 108 RBC (AUC = 0.63) for escalated dosing. CONCLUSION: 6-TGN levels were weakly associated with infliximab but not adalimumab levels in combination therapy. 6-TGN levels in the lower end of the therapeutic range (230-260 pmol/8 × 108 RBC) may be adequate to maintain higher infliximab levels, particularly with escalated infliximab dosing.

Early Discharge to Clinic-Based Therapy of Patients Presenting With Decompensated Heart Failure (EDICT-HF): Study Protocol for a Multi-Centre Randomised Controlled Trial.

BACKGROUND: Acute decompensated heart failure involves a high rate of mortality and complications. Management typically involves a multi-day hospital admission. However, patients often lose part of their function with each successive admission, and are at a high risk for hospital-associated complications such as nosocomial infection. This study aims to determine the safety and efficacy of the management of patients presenting with acute decompensated heart failure to clinic-based therapy vs usual inpatient care using a reproducible management pathway. METHOD: An investigator-initiated, prospective, non-inferiority, 1:1 randomised-controlled trial, stratified by left ventricular ejection fraction including 460 patients with a minimum follow-up of 7 days. This is a multi-centre study to be performed in centres across Victoria, Australia. Participants will be patients with either heart failure with reduced ejection fraction (HFrEF) or heart failure with preserved ejection fraction (HFpEF), admitted for acute decompensation of heart failure. INTERVENTION: Early discharge to an outpatient-based Heart Failure Rapid Access Clinical Review (RACER) in addition to frequent medical/nursing at-home review for patients admitted with decompensated heart failure. RESULTS: The primary endpoint will be a non-inferiority assessment of re-hospitalisation at 30 days. Secondary outcomes include superiority assessment of hospitalisation at 30 days, a composite clinical endpoint of major adverse cardiac and cerebrovascular event (MACCE), hospital re-admission or mortality at 3 months, achievement of guideline-directed medical therapy, patient assessment of symptoms (visual-analogue scale quantified as area under curve and Kansas City Cardiomyopathy Questionnaire-12 [KCCQ-12]), attendance at 3-month outpatient follow-up, number of bed stays/clinics attended, proportion of patients free from congestion, change in serum creatinine level, treatment for electrolyte disturbances, time to transition from intravenous to oral diuretics, and health economics analysis (cost-benefit analysis, cost-utility analysis, incremental cost-effectiveness ratio). CONCLUSIONS: The Early Discharge to Clinic-Based Therapy of Patients Presenting with Decompensated Heart Failure (EDICT-HF) trial will help determine whether earlier discharge to out-of-hospital care is non-inferior to the usual practice of inpatient care, in patients with heart failure admitted to hospital for acute decompensation, as an alternative model of care.

Effect of COVID-19 Pandemic Lockdown on Emergency Medical Service Utilisation, and Percutaneous Coronary Intervention Volume-An Australian Perspective.

BACKGROUND: Acute coronary syndrome (ACS) admissions and percutaneous coronary intervention (PCI) volume declined during periods of COVID-19 lockdown internationally in 2020. The effect of lockdown on emergency medical service (EMS) utilisation, and PCI volume during the initial phase of the pandemic in Australia has not been well described. METHOD: We analysed data from the Victorian Cardiac Outcomes Registry (VCOR), a state-wide PCI registry, linked with the Ambulance Victoria EMS registry. PCI volume, 30-day major adverse cardiovascular and cerebrovascular events (MACCE; composite of mortality, myocardial infarction, stent thrombosis, unplanned revascularisation, and stroke), and EMS utilisation were compared over four time periods: lockdown (26 Mar 2020-12 May 2020); pre-lockdown (26 Feb 2020-25 Mar 2020); post-lockdown (13 May 2020-10 Jul 2020); and the year prior (26 Mar 2019-12 May 2019). Interrupted time series analysis was performed to assess PCI trends within and between consecutive periods. RESULTS: The EMS utilisation for ACS during lockdown was higher compared with other periods: lockdown 39.4% vs pre-lockdown 29.7%; vs post-lockdown 33.6%; vs year prior 27.1%; all p<0.01. Median daily PCI cases were similar: 31 (IQR 10, 38) during lockdown; 39 (15, 49) pre-lockdown; 39.5 (11, 44) post-lockdown; and, 42 (10, 49) the year prior; all p>0.05. Median door-to-procedure time for ACS indication during lockdown was shorter at 3 hours (1.2, 20.6) vs pre-lockdown 3.9 (1.7, 21); vs post-lockdown 3.5 (1.5, 21.26); and, the year prior 3.5 (1.5, 23.7); all p<0.05. Lockdown period was associated with lower odds for 30-day MACCE compared to pre-lockdown (odds ratio [OR] 0.55 [0.33-0.93]; p=0.026); post-lockdown (OR 0.66; [0.40-1.06]; p=0.087); and the year prior (OR 0.55 [0.33-0.93]; p=0.026). CONCLUSIONS: Contrary to international trends, EMS utilisation for ACS increased during lockdown but PCI volumes remained similar throughout the initial stages of the pandemic in Victoria, with no observed adverse effect on 30-day MACCE during lockdown. These data suggest that the public health response in Victoria was not associated with poorer quality cardiovascular care in patients receiving PCI.

The Who, What, When, and Where of Inpatient Direct Oral Penicillin Challenge-Implications for Health Services Implementation.

Inpatient direct oral challenge programs are increasingly deployed as part of antimicrobial stewardship initiatives to reduce the burden and impacts of penicillin allergy labels on antibiotic prescribing. Using data from a prospective, multicenter cohort inpatient penicillin allergy program, we identify the key targets for delabeling to aid health service implementation.

Cholinergic signaling influences the expression of immune checkpoint inhibitors, PD-L1 and PD-L2, and tumor hallmarks in human colorectal cancer tissues and cell lines.

BACKGROUND: Cancer cells express immunosuppressive molecules, such as programmed death ligands (PD-L)1 and PD-L2, enabling evasion from the host's immune system. Cancer cells synthesize and secrete acetylcholine (ACh), acting as an autocrine or paracrine hormone to promote their proliferation, differentiation, and migration. METHODS: We correlated the expression of PD-L1, PD-L2, cholinergic muscarinic receptor 3 (M3R), alpha 7 nicotinic receptor (α7nAChR), and choline acetyltransferase (ChAT) in colorectal cancer (CRC) tissues with the stage of disease, gender, age, risk, and patient survival. The effects of a muscarinic receptor blocker, atropine, and a selective M3R blocker, 4-DAMP, on the expression of immunosuppressive and cholinergic markers were evaluated in human CRC (LIM-2405, HT-29) cells. RESULTS: Increased expression of PD-L1, M3R, and ChAT at stages III-IV was associated with a high risk of CRC and poor survival outcomes independent of patients' gender and age. α7nAChR and PD-L2 were not changed at any CRC stages. Atropine and 4-DAMP suppressed the proliferation and migration of human CRC cells, induced apoptosis, and decreased PD-L1, PD-L2, and M3R expression in CRC cells via inhibition of EGFR and phosphorylation of ERK. CONCLUSIONS: The expression of immunosuppressive and cholinergic markers may increase the risk of recurrence of CRC. These markers might be used in determining prognosis and treatment regimens for CRC patients. Blocking cholinergic signaling may be a potential therapeutic for CRC through anti-proliferation and anti-migration via inhibition of EGFR and phosphorylation of ERK. These effects allow the immune system to recognize and eliminate cancer cells.

Comparing the Fracture Profile of Osteosarcopenic Older Adults with Osteopenia/Osteoporosis Alone.

PURPOSE: To determine whether osteosarcopenia is associated with a greater likelihood of recurrent fractures, as well as type of fracture, than osteopenia/osteoporosis or sarcopenia alone. METHODS: Anthropometry (height/weight; scales and stadiometer), body composition (bone mineral density [BMD] and appendicular lean mass; dual-energy x-ray absorptiometry), grip strength (hydraulic dynamometer), and gait speed (4 m) were measured in an outpatient clinic. WHO definition for osteopenia/osteoporosis (BMD T-score below -1 SDs) while sarcopenia was defined by SDOC or EWGSOP2. Number and location of fractures within the past 5 years were self-reported and verified by medical records (unverified fractures excluded). Univariable and multivariable regressions were used to examine the association between the exposure and outcome while adjusting for confounders. RESULTS: 481 community-dwelling older adults (median age: 78, IQR: 72, 83; 75.9% women) were included. Prevalence of osteosarcopenia depended on the definition (SDOC: 179 (37.2%); EWGSOP2: 123 (25.6%)). In multivariable analysis adjusting for age, sex, alcohol, smoking, BMI, lowest BMD T-score, physical activity, and comorbidities, the likelihood of recurrent fractures (≥ 2 vs 0-1) was significantly higher in those with osteosarcopenia versus osteopenia/osteoporosis irrespective of the definition (SDOC: odds ratio [OR]: 1.63, 95% CI: 1.03, 2.59, p = 0.037; EWGSOP2: OR: 1.83, 95% CI: 1.12, 3.01, p = 0.016]. Associations with sarcopenia alone (SDOC: 10; EWGSOP2: 7) were not possible due to the extremely low prevalence of this condition in those with normal BMD. CONCLUSION: Our data suggest osteosarcopenia is associated with a greater likelihood of recurrent fractures versus osteopenia/osteoporosis alone. Further studies are needed to evaluate the relationship with sarcopenia alone.

Relationship Between Plasma Homocysteine and Bone Density, Lean Mass, Muscle Strength and Physical Function in 1480 Middle-Aged and Older Adults: Data from NHANES.

Hyperhomocysteinemia induces oxidative stress and chronic inflammation (both of which are catabolic to bone and muscle); thus, we examined the association between homocysteine and body composition and physical function in middle-aged and older adults. Data from the National Health and Nutrition Examination Survey was used to build regression models. Plasma homocysteine (fluorescence immunoassay) was used as the exposure and bone mineral density (BMD; dual-energy X-ray absorptiometry; DXA), lean mass (DXA), knee extensor strength (isokinetic dynamometer; newtons) and gait speed (m/s) were used as outcomes. Regression models were adjusted for confounders (age, sex, race/Hispanic origin, height, fat mass %, physical activity, smoking status, alcohol intakes, cardiovascular disease, diabetes, cancer and vitamin B12). All models accounted for complex survey design by using sampling weights provided by NHANES. 1480 adults (median age: 64 years [IQR: 56, 73]; 50.3% men) were included. In multivariable models, homocysteine was inversely associated with knee extensor strength (ß = 0.98, 95% CI 0.96, 0.99, p = 0.012) and gait speed (ß = 0.85, 95% CI 0.78, 0.94, p = 0.003) and borderline inversely associated with femur BMD (ß = 0.84, 95% CI 0.69, 1.03, p = 0.086). In the sub-group analysis of older adults (≥ 65 years), homocysteine was inversely associated with gait speed and femur BMD (p < 0.05) and the slope for knee extensor strength and whole-body BMD were in the same direction. No significant associations were observed between homocysteine and total or appendicular lean mass in the full or sub-group analysis. We found inverse associations between plasma homocysteine and muscle strength/physical function, and borderline significant inverse associations for femur BMD.

Lived experience of older adults with type 1 diabetes using closed-loop automated insulin delivery in a randomised trial.

AIM: To explore the lived experience of older adults with type 1 diabetes using closed-loop automated insulin delivery, an area previously receiving minimal attention. METHODS: Semi-structured interviews were conducted with adults aged 60 years or older with long-duration type 1 diabetes who participated in a randomised, open-label, two-stage crossover trial comparing first-generation closed-loop therapy (MiniMed 670G) versus sensor-augmented pump therapy. Interview recordings were transcribed, thematically analysed and assessed. RESULTS: Twenty-one older adults participated in interviews after using closed-loop therapy. Twenty were functionally independent, without frailty or major cognitive impairment; one was dependent on caregiver assistance, including for diabetes management. Quality of life benefits were identified, including improved sleep and reduced diabetes-related psychological burden, in the context of experiencing improved glucose levels. Gaps between expectations and reality of closed-loop therapy were also experienced, encountering disappointment amongst some participants. The cost was perceived as a barrier to continued closed-loop access post-trial. Usability issues were identified, such as disruptive overnight alarms and sensor inaccuracy. CONCLUSIONS: The lived experience of older adults without frailty or major cognitive impairment using first-generation closed-loop therapy was mainly positive and concordant with glycaemic benefits found in the trial. Older adults' lived experience using automated insulin delivery beyond trial environments requires exploration; moreover, the usability needs of older adults should be considered during future device development.

Effectiveness and safety of cold snare polypectomy and cold endoscopic mucosal resection for nonpedunculated colorectal polyps of 10-19 mm: a multicenter observational cohort study.

BACKGROUND : Cold snare polypectomy (CSP) is the standard of care for the resection of small (< 10 mm) colonic polyps. Limited data exist for its efficacy for medium-sized (10-19 mm) nonpedunculated polyps, especially conventional adenomas. This study evaluated the effectiveness and safety of CSP/cold endoscopic mucosal resection (C-EMR) for medium-sized nonpedunculated colonic polyps. METHODS : A prospective multicenter observational study was conducted of all morphologically suitable nonpedunculated colonic polyps of 10-19 mm removed by CSP/C-EMR between May 2018 and June 2021. Once resection was complete, multiple biopsies were taken of the margins circumferentially and centrally. The primary outcome was the incomplete resection rate (IRR), based on residual polyp in these biopsy specimens. Secondary outcomes were recurrence rate at first surveillance colonoscopy and rates of adverse events (AEs). RESULTS : CSP/C-EMR was performed for 350 polyps (median size 15 mm; 266 [76.0 %] Paris 0-IIa classification) in 295 patients. Submucosal injection was used for 87.1 % (n = 305) of polyps. Histology showed 68.6 % adenomas, 26.0 % sessile serrated lesions (SSLs) without dysplasia, 4.0 % SSL with dysplasia, and 1.4 % hyperplastic polyps. The IRRs based on margin or central biopsies being positive were 1.7 % (n = 6) and 0.3 % (n = 1), respectively. The polyp recurrence rate was 1.7 % (n = 4) at first surveillance colonoscopy - completed for 65.4 % (n = 229) of polyps at a median interval of 9.7 months. AEs occurred in 3.4 % (n = 10) of patients: four with post-polypectomy pain; three self-limiting post-polypectomy bleeds; two post-polypectomy-syndrome-like presentations; and one intraprocedural bleed treated with clips. There were no perforations. CONCLUSION : CSP/C-EMR for morphologically suitable nonpedunculated colonic polyps of 10-19 mm is effective and safe, including for conventional adenomas. Rates of incomplete resection and recurrence were low, with few AEs. Studies directly comparing this method with hot snare resection are required.

What difference does sleep make? Continuous glucose monitoring metrics during fixed-overnight time versus sleep periods among older adults with type 1 diabetes.

Hypoglycaemia during sleep is a common and clinically important issue for people living with insulin-treated diabetes. Continuous glucose monitoring devices can help to identify nocturnal hypoglycaemia and inform treatment strategies. However, sleep is generally inferred, with diabetes researchers and physicians using a fixed-overnight period as a proxy for sleep-wake status when analysing and interpretating continuous glucose monitoring data. No study to date has validated such an approach with established sleep measures. Continuous glucose monitoring and research-grade actigraphy devices were worn and sleep diaries completed for 2 weeks by 28 older adults (mean age 67 years [SD 5]; 17 (59%) women) with type 1 diabetes. Using continuous glucose monitoring data from a total of 356 nights, fixed-overnight (using the recommended period of 00:00 hours-06:00 hours) and objectively-measured sleep periods were compared. The fixed-overnight period approach missed a median 57 min per night (interquartile range: 49-64) of sleep for each participant, including five continuous glucose monitoring-detected hypoglycaemia episodes during objectively-measured sleep. Twenty-seven participants (96%) had at least 1 night with continuous glucose monitoring time-in-range and time-above-range discrepancies both ≥ 10 percentage points, a clinically significant discrepancy. The utility of fixed-overnight time continuous glucose monitoring as a proxy for sleep-awake continuous glucose monitoring is inadequate as it consistently excludes actual sleep time, obscures glycaemic patterns, and misses sensor hypoglycaemia episodes during sleep. The use of validated measures of sleep to aid interpretation of continuous glucose monitoring data is encouraged.

The efficacy and tolerability of adjunctive brivaracetam for the treatment of adult epilepsy: An Australian multi-center retrospective real-world observational cohort study.

OBJECTIVE: Assess the efficacy and tolerability of add-on therapy brivaracetam (BRV) in adult patients with epilepsy in a real-world setting. METHODS: This multi-center retrospective observational cohort study examined all adult patients who commenced on BRV at 11 Australian epilepsy centers between 2017 and 2020. Primary outcomes were seizure response (≥50% reduction in frequency) and seizure freedom 12 months post BRV commencement, and tolerability. We report three approaches to missing data (complete case analysis, CCA; last observation carried forward, LOCF; and intention to treat, ITT). Secondary outcomes included the durability of early BRV response and continuous seizure freedom from BRV initiation. Subgroup analysis examined patients with focal and generalized epilepsy and patients with refractory (≥4 prior ASMs) and highly refractory (≥7 prior ASMs) epilepsy. Outcomes were also assessed at 'personalized' seizure outcome time points based on baseline seizure frequency. RESULTS: Baseline and follow-up data were available for 228 patients. The mean age was 41.5 years (IQR 30, 50). Most had focal epilepsy (188/228, 82.5%). Median number of previous ASMs was 4 (2, 7), and concomitant ASMs 2 (2, 3). Twelve-month responder rate was: 46.3% using CCA (95% CI 34.0, 58.9); 39.5% using LOCF (33.1, 46.1); and 15.4% using ITT (10.9, 20.7). Twelve-month seizure freedom was: 23.9% using CCA (14.3, 35.9); 24.6% using LOCF (19.1, 30.7); and 7.9% using ITT (4.7, 12.1). The most frequent adverse effects were sedation or cognitive slowing (33/228, 14.5%), irritability or aggression (16/228, 7.0%), and low mood (14/228, 6.1%). Outcomes were similar using continuous outcome definitions and 'personalized' outcome assessment time points. Early responses were highly durable, with 3-month response maintained at all subsequent time points at 83%, and seizure freedom maintained at 85%. Outcomes were similar in focal (n = 187) and generalizsed (n = 25) subgroups. Outcomes were similar in refractory patients (n = 129), but lower in the highly refractory group (n = 62), however improvement with BRV was still observed with 12-month seizure freedom of 8.3% using CCA (1.0, 27), 6.5% using LOCF (1.8, 15.7); and 3.2% using ITT (0.4, 11.2). CONCLUSIONS: Meaningful real-world responder and seizure freedom rates can be still observed in a refractory epilepsy population. Brivaracetam response can occur early and appears to be maintained with minimal later relapse. The results should be interpreted with caution given the retrospective nature of the study and the quantities of missing data at later time points.

Safety and Efficacy of Testosterone Therapy on Musculoskeletal Health and Clinical Outcomes in Men: A Systematic Review and Meta-Analysis of Randomized Placebo-Controlled Trials.

OBJECTIVE: Age-related declines in muscle and bone, alongside a shift toward greater adiposity, contribute to falls and fracture risk. Testosterone is osteogenic, myogenic, and catabolic to fat. As such, we examined the effects of testosterone therapy on musculoskeletal health and clinical outcomes in men. METHODS: Electronic databases (Medline, Embase, Web of Science, Central) were systematically searched for randomized controlled trials (RCTs) reporting on the effects of testosterone therapy versus placebo on any primary outcome (bone density, muscle mass, fat mass, muscle strength/physical performance) or secondary outcome (falls, fractures, disability, adverse events) in men (≥18 years). A random effects meta-regression examined the effects of testosterone on prespecified outcomes. RESULTS: One thousand seven hundred twenty-eight men across 16 RCTs were included (mean age: 77.1 ± 7.6 years). Baseline mean serum testosterone ranged from 7.5 ± 0.3 to 18.9 ± 1.2 nmol/L. Compared to placebo, 6 months of testosterone therapy increased hip bone density and total lean mass, but effects for handgrip and total fat mass did not reach statistical significance. No significant effects of testosterone therapy on musculoskeletal outcomes were evident at 12 months. The limited number of RCTs reporting on adverse events/clinical outcomes, and the low incidence of these events across RCTs, prohibited statistical comparisons. CONCLUSION: After 6 months, testosterone effectively increases hip bone density and total lean mass in men, but its effects are unclear for lumbar spine bone density and handgrip strength. Further, RCTs are needed to clarify the safety and efficacy of testosterone on musculoskeletal health and clinical outcomes.