Research priorities regarding the use of bisphosphonates for osteoporosis: a UK priority setting exercise.

PURPOSE: Worldwide, many people who would benefit from osteoporosis drugs are not offered or receiving them, resulting in an osteoporosis care gap. Adherence with bisphosphonates is particularly low. This study aimed to identify stakeholder research priorities relating to bisphosphonate treatment regimens for prevention of osteoporotic fractures. METHODS: A three-step approach based on the James Lind Alliance methodology for identification and prioritisation of research questions was used. Research uncertainties were gathered from a large programme of related research studies about bisphosphonate regimens and from recent published international clinical guidelines. Clinical and public stakeholders refined the list of uncertainties into research questions. The third step prioritised the questions using a modified nominal group technique. RESULTS: In total, 34 draft uncertainties were finalised into 33 research questions by stakeholders. The top 10 includes questions relating to which people should be offered intravenous bisphosphonates first line (1); optimal duration of treatment (2); the role of bone turnover markers in treatment breaks (3); support patient need for medicine optimisation (4); support primary care practitioner need regarding bisphosphonates (5); comparing zoledronate given in community vs hospital settings (6); ensuring quality standards are met (7); the long-term model of care (8); best bisphosphonate for people aged under 50 (9); and supporting patient decision-making about bisphosphonates (10). CONCLUSION: This study reports, for the first time, topics of importance to stakeholders in the research of bisphosphonate osteoporosis treatment regimens. These findings have implications for research into implementation to address the care gap and education of healthcare professionals. Using James Lind Alliance methodology, this study reports prioritised topics of importance to stakeholders in the research of bisphosphonate treatment in osteoporosis. The priorities address how to better implement guidelines to address the care gap, understanding patient factors influencing treatment selection and effectiveness, and how to optimise long-term care.

Clinicians' views of prescribing oral and intravenous bisphosphonates for osteoporosis: a qualitative study.

BACKGROUND: Bisphosphonate medications, including alendronate, ibandronate and risedronate administered orally and zoledronate, administered intravenously, are commonly prescribed for the treatment of osteoporosis based on evidence that, correctly taken, bisphosphonates can improve bone strength and lead to a reduction in the risk of fragility fractures. However, it is currently unclear how decisions to select between bisphosphonate regimens, including intravenous regimen, are made in practice and how clinicians support patients with different treatments. METHODS: This was an interpretivist qualitative study. 23 semi-structured telephone interviews were conducted with a sample of general practitioners (GPs), secondary care clinicians, specialist experts as well as those providing and leading novel treatments including participants from a community intravenous (IV) zoledronate service. Data analysis was undertaken through a process of iterative categorisation. RESULTS: The results report clinicians varying experiences of making treatment choices, as well as wider aspects of osteoporosis care. Secondary care and specialist clinicians conveyed some confidence in making treatment choices including on selecting IV treatment. This was aided by access to diagnostic testing and medication expertise. In contrast GPs reported a number of challenges in prescribing bisphosphonate medications for osteoporosis and uncertainty about treatment choice. Results also highlight how administering IV zoledronate was seen as an opportunity to engage in broader care practices. CONCLUSION: Approaches to making treatment decisions and supporting patients when prescribing bisphosphonates for osteoporosis vary in practice. This study points to the need to co-ordinate osteoporosis treatment and care across different care providers.

Multiple hospital organisational factors are associated with adverse patient outcomes post-hip fracture in England and Wales: the REDUCE record-linkage cohort study.

OBJECTIVES: Despite established standards and guidelines, substantial variation remains in the delivery of hip fracture care across the United Kingdom. We aimed to determine which hospital-level organisational factors predict adverse patient outcomes in the months following hip fracture. METHODS: We examined a national record-linkage cohort of 178,757 patients aged ≥60 years who sustained a hip fracture in England and Wales in 2016-19. Patient-level hospital admissions datasets, National Hip Fracture Database and mortality data were linked to metrics from 18 hospital-level organisational-level audits and reports. Multilevel models identified organisational factors, independent of patient case-mix, associated with three patient outcomes: length of hospital stay (LOS), 30-day all-cause mortality and emergency 30-day readmission. RESULTS: Across hospitals mean LOS ranged from 12 to 41.9 days, mean 30-day mortality from 3.7 to 10.4% and mean readmission rates from 3.7 to 30.3%, overall means were 21.4 days, 7.3% and 15.3%, respectively. In all, 22 organisational factors were independently associated with LOS; e.g. a hospital's ability to mobilise >90% of patients promptly after surgery predicted a 2-day shorter LOS (95% confidence interval [CI]: 1.2-2.6). Ten organisational factors were independently associated with 30-day mortality; e.g. discussion of patient experience feedback at clinical governance meetings and provision of prompt surgery to >80% of patients were each associated with 10% lower mortality (95%CI: 5-15%). Nine organisational factors were independently associated with readmissions; e.g. readmissions were 17% lower if hospitals reported how soon community therapy would start after discharge (95%CI: 9-24%). CONCLUSIONS: Receipt of hip fracture care should be reliable and equitable across the country. We have identified multiple, potentially modifiable, organisational factors associated with important patient outcomes following hip fracture.

Radiology reporting of osteoporotic vertebral fragility fractures on computed tomography studies: results of a UK national audit.

OBJECTIVES: To evaluate organisational reporting infrastructure and patient-related reporting data in the diagnosis of vertebral fragility fractures (VFFs) as demonstrated on computed tomography (CT). METHODS: Organisational and patient-specific questionnaires were developed by consensus between The Royal College of Radiologists, the Royal College of Physicians, and the Royal Osteoporosis Society. The patient-specific component of the audit involved analysis of CT reporting data acquired from 50 consecutive non-traumatic studies including the thoracolumbar spine. Ethical approval for this type of study is not required in the UK. All UK radiology departments with an audit lead (auditor) registered with The Royal College of Radiologists (RCR) were invited to participate in this retrospective audit. RESULTS: In total, 127 out of 202 departments (63%) supplied data to the study, with inclusion of 6357 patients. Overall, 1362/6357 patients (21.4%) had a fracture present on auditor review of the CT imaging. There was a lack of compliance with all audit standards: 79% of reports commented on the vertebrae (target 100%), fracture severity was mentioned in 26.2% (target 100%), the recommended terminology 'vertebral fracture' was used in 60.1% (target 100%), and appropriate onward referral was recommended in 2.6% (target 100%). CONCLUSIONS: The findings from this study should be used to provide impetus to improve the diagnosis and care for patients with osteoporotic VFFs. Solutions are multifactorial, but radiologist and local osteoporosis/fracture liaison service engagement is fundamental, combined with necessary development of electronic report notification systems and expansion of supporting fracture services. KEY POINTS: • Early detection and diagnosis of vertebral fragility fractures (VFFs) significantly reduce patient morbidity and mortality. This study describes the results of a retrospective UK-wide audit evaluating current radiology reporting practice in the opportunistic diagnosis of VFFs as demonstrated on computed tomography (CT) studies including the spine. • Key audit standards included comment made on bone integrity in primary report (target 100%), comment made on severity of fractures (90%), report used recommended terminology 'fracture' (100%), and report made appropriate recommendations for referral/further assessment (100%). The audit results demonstrated a lack of compliance with all audit standards; lack of compliance was most marked in the use of recommended terminology (achieved 60.3%), in relation to comment on fracture severity (achieved 26.2%) and for recommendation for referral/further assessment (achieved 2.6%). • Solutions are challenging and multifactorial but the opportunity exists for all radiologists to examine their practice and directly improve patient care.

Valganciclovir for symptomatic congenital cytomegalovirus disease.

BACKGROUND: The treatment of symptomatic congenital cytomegalovirus (CMV) disease with intravenous ganciclovir for 6 weeks has been shown to improve audiologic outcomes at 6 months, but the benefits wane over time. METHODS: We conducted a randomized, placebo-controlled trial of valganciclovir therapy in neonates with symptomatic congenital CMV disease, comparing 6 months of therapy with 6 weeks of therapy. The primary end point was the change in hearing in the better ear ("best-ear" hearing) from baseline to 6 months. Secondary end points included the change in hearing from baseline to follow-up at 12 and 24 months and neurodevelopmental outcomes, with each end point adjusted for central nervous system involvement at baseline. RESULTS: A total of 96 neonates underwent randomization, of whom 86 had follow-up data at 6 months that could be evaluated. Best-ear hearing at 6 months was similar in the 6-month group and the 6-week group (2 and 3 participants, respectively, had improvement; 36 and 37 had no change; and 5 and 3 had worsening; P=0.41). Total-ear hearing (hearing in one or both ears that could be evaluated) was more likely to be improved or to remain normal at 12 months in the 6-month group than in the 6-week group (73% vs. 57%, P=0.01). The benefit in total-ear hearing was maintained at 24 months (77% vs. 64%, P=0.04). At 24 months, the 6-month group, as compared with the 6-week group, had better neurodevelopmental scores on the Bayley Scales of Infant and Toddler Development, third edition, on the language-composite component (P=0.004) and on the receptive-communication scale (P=0.003). Grade 3 or 4 neutropenia occurred in 19% of the participants during the first 6 weeks. During the next 4.5 months of the study, grade 3 or 4 neutropenia occurred in 21% of the participants in the 6-month group and in 27% of those in the 6-week group (P=0.64). CONCLUSIONS: Treating symptomatic congenital CMV disease with valganciclovir for 6 months, as compared with 6 weeks, did not improve hearing in the short term but appeared to improve hearing and developmental outcomes modestly in the longer term. (Funded by the National Institute of Allergy and Infectious Diseases; ClinicalTrials.gov number, NCT00466817.).

Prevalence of reduced bone mineral density in adults with coeliac disease - are we missing opportunities for detection in patients below 50 years of age?

OBJECTIVE: There are little data on the prevalence of reduced bone mineral density (BMD) in young adult patients with coeliac disease; guidelines do not support routine investigation of these patients. We assessed the prevalence of reduced BMD in our patients by age. PATIENTS AND METHODS: Prospective observational study of 260 coeliac patients having DXA one year after commencing gluten-free diet. Nonparametric tests and regression were used. RESULTS: Median age was 51years, BMI 24 and 85 (32.7%) were male. Reduced BMD was associated with increasing age (p < .001), female sex (p = .005), low BMI (p < .001) and previous fracture (p < .01); 49% of all patients and all patients under 20 years old had reduced BMD. The median age of patients with BMI <20 kgm2 was 56 (27, 70) years with the majority of younger patients having normal BMI. CONCLUSIONS: Low BMD is a common finding in young patients with coeliac disease, yet routine assessment of BMD is not currently supported by national guidelines. Early identification may improve motivation to comply with GFD and allow adequate calcium and vitamin D supplementation to reduce risk of fracture later in life.

Oral acyclovir suppression and neurodevelopment after neonatal herpes.

BACKGROUND: Poor neurodevelopmental outcomes and recurrences of cutaneous lesions remain unacceptably frequent among survivors of neonatal herpes simplex virus (HSV) disease. METHODS: We enrolled neonates with HSV disease in two parallel, identical, double-blind, placebo-controlled studies. Neonates with central nervous system (CNS) involvement were enrolled in one study, and neonates with skin, eye, and mouth involvement only were enrolled in the other. After completing a regimen of 14 to 21 days of parenteral acyclovir, the infants were randomly assigned to immediate acyclovir suppression (300 mg per square meter of body-surface area per dose orally, three times daily for 6 months) or placebo. Cutaneous recurrences were treated with open-label episodic therapy. RESULTS: A total of 74 neonates were enrolled--45 with CNS involvement and 29 with skin, eye, and mouth disease. The Mental Development Index of the Bayley Scales of Infant Development (in which scores range from 50 to 150, with a mean of 100 and with higher scores indicating better neurodevelopmental outcomes) was assessed in 28 of the 45 infants with CNS involvement (62%) at 12 months of age. After adjustment for covariates, infants with CNS involvement who had been randomly assigned to acyclovir suppression had significantly higher mean Bayley mental-development scores at 12 months than did infants randomly assigned to placebo (88.24 vs. 68.12, P=0.046). Overall, there was a trend toward more neutropenia in the acyclovir group than in the placebo group (P=0.09). CONCLUSIONS: Infants surviving neonatal HSV disease with CNS involvement had improved neurodevelopmental outcomes when they received suppressive therapy with oral acyclovir for 6 months. (Funded by the National Institute of Allergy and Infectious Diseases; CASG 103 and CASG 104 ClinicalTrials.gov numbers, NCT00031460 and NCT00031447, respectively.).

Organisational factors associated with hospital costs and patient mortality in the 365 days following hip fracture in England and Wales (REDUCE): a record-linkage cohort study.

BACKGROUND: Hip fracture care delivery varies between hospitals, which might explain variations in patient outcomes and health costs. The aim of this study was to identify hospital-level organisational factors associated with long-term patient outcomes and costs after hip fracture. METHODS: REDUCE was a record-linkage cohort study in which national databases for all patients aged 60 years and older who sustained a hip fracture in England and Wales were linked with hospital metrics from 18 organisational data sources. Multilevel models identified organisational factors associated with the case-mix adjusted primary outcomes: cumulative all-cause mortality, days spent in hospital, and inpatient costs over 365 days after hip fracture. FINDINGS: Between April 1, 2016, and March 31, 2019, 178 757 patients with an index hip fracture were identified from 172 hospitals in England and Wales. 126 278 (70·6%) were female, 52 479 (29·4%) were male, and median age was 84 years (IQR 77-89) in England and 83 years (77-89) in Wales. 365 days after hip fracture, 50 354 (28·2%) patients had died. Patients spent a median 21 days (IQR 11-41) in hospital, incurring costs of £14 642 (95% CI 14 600-14 683) per patient, ranging from £10 867 (SD 5880) to £23 188 (17 223) between hospitals. 11 organisational factors were independently associated with mortality, 24 with number of days in hospital, and 25 with inpatient costs. Having all patients assessed by an orthogeriatrician within 72 h of admission was associated with a mean cost saving of £529 (95% CI 148-910) per patient and a lower 365-day mortality (odds ratio 0·85 [95% CI 0·76-0·94]). Consultant orthogeriatrician attendance at clinical governance meetings was associated with cost savings of £356 (95% CI 188-525) and 1·47 fewer days (95% CI 0·89-2·05) in the hospital in the 365 days after hip fracture per patient. The provision of physiotherapy to patients on weekends was associated with a cost saving of £676 (95% CI 67-1285) per patient and with 2·32 fewer days (0·35-4·29) in hospital in the 365 days after hip fracture. INTERPRETATION: Multiple, potentially modifiable hospital-level organisational factors associated with important clinical outcomes and inpatient costs were identified that should inform initiatives to improve the effectiveness and efficiency of hip fracture services. FUNDING: Versus Arthritis.

REducing unwarranted variation in the Delivery of high qUality hip fraCture services in England and Wales (REDUCE): protocol for a mixed-methods study.

INTRODUCTION: Substantial variation in the delivery of hip fracture care, and patient outcomes persists between hospitals, despite established UK national standards and guidelines. Patients' outcomes are partly explained by patient-level risk factors, but it is hypothesised that organisational-level factors account for the persistence of unwarranted variation in outcomes. The mixed-methods REducing unwarranted variation in the Delivery of high qUality hip fraCture services in England and Wales (REDUCE) study, aims to determine key organisational factors to target to improve patient care. METHODS AND ANALYSIS: Quantitative analysis will assess the outcomes of patients treated at 172 hospitals in England and Wales (2016-2019) using National Hip Fracture Database data combined with English Hospital Episodes Statistics; Patient Episode Database for Wales; Civil Registration (deaths) and multiple organisational-level audits to characterise each service provider. Statistical analyses will identify which organisational factors explain variation in patient outcomes, and typify care pathways with high-quality consistent patient outcomes. Documentary analysis of 20 anonymised British Orthopaedic Association hospital-initiated peer-review reports, and qualitative interviews with staff from four diverse UK hospitals providing hip fracture care, will identify barriers and facilitators to care delivery. The COVID-19 pandemic has posed a major challenge to the resilience of services and interviews will explore strategies used to adapt and innovate. This system-wide understanding will inform the development, in partnership with key national stakeholders, of an 'Implementation Toolkit' to inform and improve commissioning and delivery of hip fracture services. ETHICS AND DISSEMINATION: This study was approved: quantitative study by London, City and East Research Ethics Committee (20/LO/0101); and qualitative study by Faculty of Health Sciences University of Bristol Research Ethics Committee (Ref: 108284), National Health Service (NHS) Health Research Authority (20/HRA/71) and each NHS Trust provided Research and Development approval. Findings will be disseminated through scientific conferences, peer-reviewed journals and online workshops.

The benefits of non-surgical weight management on weight and glycaemic control in people with complex type 2 diabetes: A primary care service evaluation of clinical outcomes at 12 months.

Optimizing diabetes management in patients with complex type 2 diabetes (T2DM) and obesity presents challenges. This study evaluates weight and HbA1c at 12 months (primary outcomes) and blood pressure, lipids, medication and lifestyle changes (secondary outcomes) in patients referred by a diabetes specialist (DSN) to the weight management intervention (Slimming World). Patients attended up to 12 or 24 funded weekly group sessions. The DSN recorded baseline and 12-month primary and secondary outcome data. A post-intervention questionnaire explored the lifestyle changes made. 69 patients achieved a mean weight loss of 5.5 (5.16) %, reduction in BMI [37.7(6.11) to 35.9 (6.30) kg/m2, P < 0.001] and HbA1c levels [62.8 (12.85) to 55.0 (13.02) mmol/mol, P < 0.001] at 12 months. 81.2% reduced their HbA1c levels. Small reductions were observed in SBP, DBP and triglycerides, and six patients reduced their diabetes medications. Twenty patients completed the questionnaire: unhealthy snacking reduced (P < 0.001) and going for walks increased (P < 0.001) with fewer people avoiding moderate activity (P < 0.05). Despite being a chronic, progressive condition, referral to a community-based programme was successful in supporting patients with established T2DM improve their diet and activity levels, lose weight and improve their glycaemic control 12 months later with a small number able to reduce their medication.

A report of dangerously high carbon monoxide levels within the passenger compartment of a snow-obstructed vehicle.

BACKGROUND: We sought to determine how quickly carbon monoxide would accumulate in the passenger compartment of a snow-obstructed vehicle. METHODS: A 1992 sedan was buried in snow to the level of the undercarriage, the ignition was then engaged and carbon monoxide levels recorded at 2.5-minute intervals. The primary outcome was the time at which a lethal carbon monoxide level was detected. Six trials were conducted: windows closed; windows open one inch; windows open 6 inches; windows closed and tailpipe swept clear of snow; windows closed and one cubic foot of snow removed around tailpipe; windows closed and tailpipe completely cleared of snow to ground level in a path 12 inches wide. RESULTS: Lethal levels of carbon monoxide occurred within 2.5 minutes in the vehicle when the windows were closed, within 5 minutes when the widows were opened one inch, and within 7.5 minutes when the widows were opened six inches. Dangerously high levels of carbon monoxide were detected within the vehicle when the tailpipe had been swept clear of snow and when a one cubic foot area had been cleared around the tailpipe. When the tailpipe was completely unobstructed the carbon monoxide level was zero. CONCLUSIONS: Lethal levels of carbon monoxide occurred within minutes in this snow-obstructed vehicle.

Safety of oseltamivir compared with the adamantanes in children less than 12 months of age.

BACKGROUND: When oseltamivir is administered in extremely high doses (500-1000 mg/kg) to young juvenile rats, central nervous system toxicity and death occurred in some animals. Mortality was not observed in older juvenile rats, suggesting a possible relationship between neurotoxicity and an immature blood-brain barrier. To assess potential neurologic adverse effects of oseltamivir use in infants, a retrospective chart review was performed in infants less than 12 months of age who received oseltamivir, amantadine, or rimantadine. METHODS: The primary objective was to describe the frequency of neurologic adverse events among children less than 12 months of age who received oseltamivir compared with those receiving adamantanes. Medical record databases, emergency department databases, and/or pharmacy records at 15 medical centers were searched to identify patients. RESULTS: Of the 180 infants identified as having received antiviral therapy, 115 (64%) received oseltamivir, 37 (20%) received amantadine, and 28 (16%) received rimantadine. The median dose of oseltamivir was 2.0 mg/kg/dose in 3- to 5-month-old and 2.2 mg/kg/dose in 9- to 12-month-old infants. The maximum dose administered was 7.0 mg/kg/dose. There were no statistically significant differences in the occurrence of adverse neurologic events during therapy among subjects treated with oseltamivir versus those treated with the adamantanes (P = 0.13). CONCLUSIONS: This is the largest report to date of oseltamivir use in children less than 12 months of age. Neurologic events were not more common with use of oseltamivir compared with that of the adamantanes. Dosing of oseltamivir was variable, illustrating the need for pharmacokinetic data in this younger population.

Pharmacokinetic and pharmacodynamic assessment of oral valganciclovir in the treatment of symptomatic congenital cytomegalovirus disease.

BACKGROUND: Intravenous ganciclovir administered for 6 weeks improves hearing outcomes in infants with symptomatic congenital cytomegalovirus (CMV) disease involving the central nervous system. METHODS: Twenty-four subjects received antiviral therapy for 6 weeks. Serial pharmacokinetic assessments were performed after administration of valganciclovir oral solution and of intravenous ganciclovir. RESULTS: On the basis of a previous pharmacokinetic study of the use of intravenous ganciclovir in this population, a target AUC12 (area under the concentration-time curve over a 12-h period) of 27 mg x h/L was defined. The median dose of oral valganciclovir administered in the present trial was 16 mg/kg, which produced a geometric mean AUC12 of 27.4 mg x h/L. The bioavailability of valganciclovir was 41.1%. Of the 18 subjects who had detectable CMV in whole blood at baseline or during therapy, 11 had <4 log viral DNA copies/mL at baseline, and 7 had > or =4 log viral DNA copies/mL at baseline; subjects who started the study with the higher viral burden experienced greater decreases in viral load but did not clear virus during the 42-day course of therapy. Neutropenia of grade 3 or 4 developed in 38% of subjects. CONCLUSIONS: In neonates with symptomatic congenital CMV disease, valganciclovir oral solution provides plasma concentrations of ganciclovir comparable to those achieved with administration of intravenous ganciclovir. The results of the present study cannot be extrapolated to extemporaneously compounded liquid formulations of valganciclovir.