Long-term efficacy and safety of erenumab in patients with chronic migraine and acute medication overuse: A subgroup analysis.

OBJECTIVE: Assess the long-term efficacy and safety of erenumab in patients with chronic migraine with acute medication overuse. BACKGROUND: Overuse of acute medication in patients with chronic migraine has been linked to greater pain intensity and disability and may diminish the effectiveness of preventive therapies. METHODS: This 52-week open-label extension study followed a 12-week double-blind placebo-controlled study in which patients with chronic migraine were randomized 3:2:2 to placebo or once-monthly erenumab 70 mg or 140 mg. Patients were stratified by region and medication overuse status. Patients received erenumab 70 mg or 140 mg throughout or switched from erenumab 70 to 140 mg (based on protocol amendment to augment safety data at higher dose). Efficacy was assessed in patients with and without medication overuse at parent study baseline. RESULTS: Of 609 patients enrolled in the extension study, 252/609 (41.4%) met the criteria for medication overuse at parent study baseline. At Week 52, the mean change in monthly migraine days from parent study baseline was -9.3 (95% confidence interval: -10.4, -8.1 days) in the medication overuse subgroup versus -9.3 (-10.1, -8.5 days) in the non-medication overuse subgroup (combined erenumab doses); proportion of patients achieving ≥50% reduction in monthly migraine days at Week 52 was 55.9% (90/161; 48.2%, 63.3%) versus 61.3% (136/222; 54.7%, 67.4%), respectively. Among baseline users of acute migraine-specific medication, the mean change in monthly migraine-specific medication days at Week 52 was -7.4 (-8.3, -6.4 days) in the medication overuse subgroup versus -5.4 (-6.1, -4.7 days) in the non-medication overuse subgroup. Most patients (197/298; 66.1%) in the medication overuse subgroup transitioned to non-overuse status by Week 52. Erenumab 140 mg was associated with numerically greater efficacy than erenumab 70 mg across all endpoints. No new safety signals were identified. CONCLUSION: Long-term erenumab treatment demonstrated sustained efficacy and safety in patients with chronic migraine with and without acute medication overuse.

Zucker Diabetic-Sprague Dawley (ZDSD) rat: Type 2 diabetes translational research model.

NEW FINDINGS: What is the topic of this review? The Zucker Diabetic-Sprague Dawley (ZDSD) rat is in the early adoption phase of use by researchers in the fields of diabetes, including prediabetes, obesity and metabolic syndrome. It is essential that physiology researchers choose preclinical models that model human type 2 diabetes appropriately and are aware of the limitations on experimental design. What advances does it highlight? Our review of the scientific literature finds that although sex, age and diets contribute to variability, the ZDSD phenotype and disease progression model the characteristics of humans who have prediabetes and diabetes, including co-morbidities. ABSTRACT: Type 2 diabetes (T2D) is a prevalent disease and a significant concern for global population health. For persons with T2D, clinical treatments target not only the characteristics of hyperglycaemia and insulin resistance, but also co-morbidities, such as obesity, cardiovascular and renal disease, neuropathies and skeletal bone conditions. The Zucker Diabetic-Sprague Dawley (ZDSD) rat is a rodent model developed for experimental studies of T2D. We reviewed the scientific literature to highlight the characteristics of T2D development and the associated phenotypes, such as metabolic syndrome, cardiovascular complications and bone and skeletal pathologies in ZDSD rats. We found that ZDSD phenotype characteristics are independent of leptin receptor signalling. The ZDSD rat develops prediabetes, then progresses to overt diabetes that is accelerated by introduction of a timed high-fat diet. In male ZDSD rats, glycated haemoglobin (HbA1c) increases at a constant rate from 7 to >30 weeks of age. Diabetic ZDSD rats are moderately hypertensive compared with other rat strains. Diabetes in ZDSD rats leads to endothelial dysfunction in specific vasculatures, impaired wound healing, decreased systolic and diastolic cardiac function, neuropathy and nephropathy. Changes to bone composition and the skeleton increase the risk of bone fractures. Zucker Diabetic-Sprague Dawley rats have not yet achieved widespread use by researchers. We highlight sex-related differences in the ZDSD phenotype and gaps in knowledge for future studies. Overall, scientific data support the premise that the phenotype and disease progression in ZDSD rats models the characteristics in humans. We conclude that ZDSD rats are an advantageous model to advance understanding and discovery of treatments for T2D through preclinical research.

Long-term efficacy and safety of erenumab in patients with chronic migraine in whom prior preventive treatments had failed: A subgroup analysis.

OBJECTIVE: To assess the long-term efficacy and safety of erenumab in the subgroup of patients with chronic migraine (CM) in whom prior preventive treatments had failed (TF) (≥1, ≥2, and ≥3 TF medication categories) and never failed (preventive naïve or prior preventive treatments had not failed), using the data from a 52-week, open-label treatment period (OLTP) of the parent study. BACKGROUND: Erenumab is a fully human monoclonal antibody that selectively binds to and inhibits the canonical calcitonin gene-related peptide receptor. There are limited long-term data evaluating the efficacy and safety of erenumab in patients with CM in whom prior preventive treatments had failed. METHODS: Patients who had completed the 12-week double-blind treatment period (DBTP) in the parent study were eligible to participate in the 52-week OLTP, during which they received erenumab every 4 weeks. The TF subgroups (≥1, ≥2, and ≥3 TF medication categories) were not mutually exclusive; patients in whom prior preventive treatments from ≥3 medication categories had failed were also counted in the ≥2 and ≥1 medication categories. Endpoints included monthly migraine days (MMD), monthly acute migraine-specific medication days (MSMD), achievement of ≥50%, ≥75%, and 100% reduction from baseline in MMD, and exposure-adjusted patient incidence rates of adverse events (AEs; per 100 patient-years). RESULTS: Erenumab treatment provided sustained mean reductions in MMD and MSMD relative to the parent study baseline throughout the 52 weeks of the OLTP across all TF subgroups. At Week 52, the mean MMD change was -8.6 (SD 6.6) (baseline: 18.4 [SD 4.5] days) in the ≥1 TF subgroup. A post hoc completer analysis (52 weeks [OLTP] erenumab) showed that compared with erenumab 70 mg, the 140 mg dose was associated with numerically greater reductions in the mean MMD (Week 40: -8.6 and -7.2 days; Week 52: -9.7 and -7.9 days [≥1 TF subgroup]) and a higher proportion of patients achieved ≥50%, ≥75%, and 100% response thresholds across all subgroups at Weeks 40 and 52. Overall the exposure-adjusted patient incidence rates of AEs did not increase during the OLTP versus the DBTP (≥1 TF subgroup: 141.9/100 versus 317.9/100 patient-years), and no new safety signals occurred. CONCLUSION: The long-term treatment with erenumab was well tolerated and showed sustained efficacy in patients with CM in whom prior preventive treatments had failed, with numerically greater treatment effects for 140 mg versus 70 mg.

Replisome activity slowdown after exposure to ultraviolet light in Escherichia coli.

The replisome is a multiprotein machine that is responsible for replicating DNA. During active DNA synthesis, the replisome tightly associates with DNA. In contrast, after DNA damage, the replisome may disassemble, exposing DNA to breaks and threatening cell survival. Using live cell imaging, we studied the effect of UV light on the replisome of Escherichia coli Surprisingly, our results showed an increase in Pol III holoenzyme (Pol III HE) foci post-UV that do not colocalize with the DnaB helicase. Formation of these foci is independent of active replication forks and dependent on the presence of the χ subunit of the clamp loader, suggesting recruitment of Pol III HE at sites of DNA repair. Our results also showed a decrease of DnaB helicase foci per cell after UV, consistent with the disassembly of a fraction of the replisomes. By labeling newly synthesized DNA, we demonstrated that a drop in the rate of synthesis is not explained by replisome disassembly alone. Instead, we show that most replisomes continue synthesizing DNA at a slower rate after UV. We propose that the slowdown in replisome activity is a strategy to prevent clashes with engaged DNA repair proteins and preserve the integrity of the replication fork.

"We were building the plane as we were flying it, and we somehow made it to the other end": syringe service program staff experiences and well-being during the COVID-19 pandemic.

BACKGROUND: Syringe service programs (SSPs) provide essential harm reduction and prevention services for people who inject drugs in the USA, where SSP coverage is expanding. During the COVID-19 pandemic, US SSPs underwent unprecedented shifts in operational procedures (e.g., closures of physical sites, staff redeployment into pandemic response efforts). Given the critical role of US SSP workers in the pandemic, we sought to explore the occupational experiences and well-being of SSP staff to inform future emergency response efforts. METHODS: From July-October 2020, we conducted semi-structured interviews with staff members of four SSPs in diverse regions of Massachusetts. Trained interviewers administered qualitative interviews virtually. Interviews were coded in NVivo v12 and thematic analysis identified common occupational experiences and related impacts on staff well-being in the context of the COVID-19 pandemic. RESULTS: Among 18 participants, 12 (67%) had client-facing roles such as harm reduction specialists and six (33%) worked in program management or leadership. We found that staff were frequently anxious about SARS-CoV-2 transmission, which contributed to staff turnover. SSPs rapidly adapted and expanded their services to meet increasing client needs during the pandemic (e.g., food distribution, COVID-19 testing), leading to staff overexertion. Simultaneously, public health measures such as physical distancing led to staff concerns about reduced social connections with clients and coworkers. Through these challenges, SSPs worked to protect staff well-being by implementing flexible and tangible COVID-19-related policies (e.g., paid sick leave), mental health resources, and frequent communication regarding pandemic-related operational changes. CONCLUSION: SSPs in the USA adapted to the COVID-19 pandemic out of necessity, resulting in operational changes that threatened staff well-being. Despite the protective factors revealed in some narratives, our findings suggest that during prolonged, complex public health emergencies, SSPs may benefit from enhanced occupational supports to prevent burnout and promote wellness for this essential public health workforce.

Factors Associated with Readmission Among General Internal Medicine Patients Experiencing Homelessness.

BACKGROUND: People who are homeless have a higher burden of illness and higher rates of hospital admission and readmission compared to the general population. Identifying the factors associated with hospital readmission could help healthcare providers and policymakers improve post-discharge care for homeless patients. OBJECTIVE: To identify factors associated with hospital readmission within 90 days of discharge from a general internal medicine unit among patients experiencing homelessness. DESIGN: This prospective observational study was conducted at an urban academic teaching hospital in Toronto, Canada. Interviewer-administered questionnaires and chart reviews were completed to assess medical, social, processes of care, and hospitalization data. Multivariable logistic regression with backward selection was used to identify factors associated with a subsequent readmission and estimate odds ratios and 95% confidence intervals. PARTICIPANTS: Adults (N = 129) who were admitted to the general internal medicine service between November 2017 and November 2018 and who were homeless at the time of admission. MAIN MEASURES: Unplanned all-cause readmission to the study hospital within 90 days of discharge. KEY RESULTS: Thirty-five of 129 participants (27.1%) were readmitted within 90 days of discharge. Factors associated with lower odds of readmission included having an active case manager (adjusted odds ratios [aOR]: 0.31, 95% CI, 0.13-0.76), having informal support such as friends and family (aOR: 0.25, 95% CI, 0.08-0.78), and sending a copy of the patient's discharge plan to a primary care physician who had cared for the patient within the last year (aOR: 0.44, 95% CI, 0.17-1.16). A higher number of medications prescribed at discharge was associated with higher odds of readmission (aOR: 1.12, 95% CI, 1.02-1.23). CONCLUSION: Interventions to reduce hospital readmission for people who are homeless should evaluate tailored discharge planning and dedicated resources to support implementation of these plans in the community.

Timing and durability of response to erenumab in patients with episodic migraine.

OBJECTIVE: We sought to evaluate temporal response patterns to erenumab treatment in patients with episodic migraine. BACKGROUND: Although many patients treated with erenumab experience onset of efficacy as early as 1 week, clinical benefits of migraine preventive therapies may accrue with continued treatment. Furthermore, details about the maintenance of clinical responses have not been reported. METHODS: This was a post hoc analysis of a 6-month, randomized, double-blind, placebo-controlled, phase 3 study of erenumab for the prevention of episodic migraine. We analyzed temporal responses to erenumab using a threshold of ≥50% reduction from baseline in monthly migraine days (MMDs). RESULTS: During the 6-month treatment period, 73.7% (230/312) and 79.6% (253/318) of patients in the erenumab 70 mg (n = 312) and 140 mg (n = 318) groups, respectively, achieved a response in at least 1 month. In this group of responders, at least half reached first monthly response (first month with ≥50% reduction from baseline in MMDs) by month 2 and at least 75% of them by month 3. The remainder responded in months 4-6. Of patients in the erenumab 70 and 140 mg groups, 35.3% (110/312) and 41.8% (133/318), respectively, responded over months 1-3 (mean response over first 3 months). Of these patients, 81.8% (90/110) and 81.9% (109/133) maintained this response over months 4-6 (mean response over last 3 months) in the 70 and 140 mg groups, respectively. Many patients who did not achieve an initial response (≥50% reduction from baseline in MMDs during month 1) responded later with continued treatment, with approximately one-half or more of initial nonresponders responding by months 4-6. CONCLUSIONS: These results support guidelines recommending at least 3 months following the initiation of erenumab for migraine prevention before the assessment of response.

Timing and durability of response to erenumab in patients with chronic migraine.

BACKGROUND: Erenumab is a human anti-calcitonin gene-related peptide receptor monoclonal antibody approved for migraine prevention. We sought to further assess the temporal patterns of response to erenumab in patients with chronic migraine (CM), specifically the onset and sustainability of monthly migraine day (MMD) response. METHODS: This is a post hoc analysis of a 12-week, randomized, double-blind, placebo-controlled study of erenumab for migraine prevention in patients with CM (≥15 headache days/month, including ≥8 migraine days/month). Onset and sustainability were assessed according to MMD reduction from baseline, with the following response categories: responders (≥50% reduction), partial responders (≥30% and <50%), or nonresponders (<30%). RESULTS: Among the erenumab 140 mg group (n = 187), 54.0% (101/187) achieved a response at any month during the study with a median time to onset of monthly response of 1 month. This improvement was maintained in most patients with continued treatment. An initial response was achieved at Month 1 by 28.3% (53/187) of patients; 69.8% (37/53) of whom maintained a response at Months 2 and 3. Although many patients responded early, some patients required longer treatment to achieve a response; 79.4% (27/34) of initial partial responders and 21.0% (21/100) of initial nonresponders subsequently achieved a response. Similar findings were observed for the erenumab 70mg group (n = 188). CONCLUSION: A majority of erenumab-treated patients with CM who achieved an initial response at Month 1 sustained this benefit. Many patients responded later with continued treatment. Our data support recommendations to assess outcomes after ≥3 months of preventive treatment with erenumab in CM.

Dental problems and chronic diseases in mentally ill homeless adults: a cross-sectional study.

BACKGROUND: Dental problems (DPs) and physical chronic diseases (CDs) are highly prevalent and incident in people with low socioeconomic status such as homeless individuals. Yet, evidence on the association between DPs and physical CDs in this population is limited. In the present study, we assessed the association between DPs and type and number of CDs in individuals experienced chronic homelessness and serious mental health problems. METHODS: We analyzed cross-sectional baseline data from 575 homeless adults with serious mental health problems participating in the Toronto site of the At Home/Chez Soi randomized controlled trial. Chronic DPs (lasting at least 6 months) were the primary exposure variable. Presence of self-reported CDs, including heart disease, effect of stroke, hypertension, diabetes, asthma, chronic bronchitis/emphysema, stomach or intestinal ulcer, inflammatory bowel disease, migraine, thyroid problems, arthritis, kidney/bladder problems, liver disease (other than hepatitis), and iron-deficiency anemia, were the primary outcomes. The total number of CDs was also analyzed as a secondary outcome. Logistic regression models were used to assess the association between DPs with each of the studied CDs, and negative binomial regression was used to test the association between DPs with the number of CDs. RESULTS: In our 575 homeless participants (68.5% males) with mean age 40.3 (11.8) years, a high proportion had DPs (42.5%). The presence of DPs was positively associated with heart disease (adjusted odds ratio (AOR):4.19,1.67-10.52), diabetes (AOR:2.17,1.13-4.17), chronic bronchitis (AOR:2.34,1.28-4.29), stomach or intestinal ulcer (AOR:3.48,1.80-6.73), inflammatory bowel disease (AOR:2.52,1.38-4.60), migraine (AOR:1.80,1.20-2.72), arthritis (AOR:2.71,1.71-4.29), kidney/bladder problems (AOR:2.43,1.30-4.54), and iron-deficiency anemia (AOR:3.28,1.90-5.65). DPs were also associated with a higher number of CDs (IRR: 1.62,1.38-1.90). CONCLUSION: Dental health problems in homeless individuals with serious mental disorders are associated with several CDs. Dental care should be better integrated into existing social and health programs serving this population to improve their overall health status. The AH/CS study is registered with the International Standard Randomized Control Trial Number Register (ISRCTN42520374).

Long-term tolerability and nonvascular safety of erenumab, a novel calcitonin gene-related peptide receptor antagonist for prevention of migraine: A pooled analysis of four placebo-controlled trials with long-term extensions.

BACKGROUND: Efficacy and safety of erenumab have been evaluated in a comprehensive clinical development program resulting in approval for migraine prevention in over 40 countries to date. METHODS: This integrated safety analysis included four double-blind randomized trials and their extensions (up to three-plus years). Safety endpoints included exposure-adjusted patient incidences of adverse events, serious adverse events, and anti-erenumab antibodies. RESULTS: In all, 2375 of the patients randomized across the four studies received at least one dose of erenumab (70 mg or 140 mg), with cumulative exposure of 2641.2 patient-years. Exposure-adjusted adverse event rates during the double-blind treatment phase were similar to placebo, with the exception of injection-site reactions (17.1 vs. 10.8 per 100 patient-years), constipation (7.0 vs. 3.8 per 100 patient-years), and muscle spasm (2.3 vs. 1.2 per 100 patient-years). During the long-term extensions, adverse events reported were similar to those observed during the double-blind treatment phase, and rates of injection site reactions, constipation, and muscle spasm were reported at lower rates than in the double-blind treatment phase. There were two deaths reported, both confounded by pre-existing conditions. CONCLUSIONS: This pooled safety analysis revealed a favorable and stable adverse event profile over time for erenumab with more than three years of exposure. TRIAL REGISTRATION: ClinicalTrials.gov NCT01952574, NCT02483585, NCT02456740, NCT02066415, and NCT02174861.

Effect of denosumab on fasting glucose in women with diabetes or prediabetes from the FREEDOM trial.

BACKGROUND: RANKL is a key regulator of bone resorption that may also modulate glucose metabolism. Denosumab (DMAb) is a fully human monoclonal antibody that binds RANKL and was associated with fracture risk reduction in the FREEDOM trial. We hypothesized that DMAb treatment decreased fasting serum glucose (FSG) relative to placebo in women with diabetes or prediabetes enrolled in FREEDOM trial. METHODS: Post hoc analysis of FREEDOM, in which 7808 postmenopausal osteoporotic women were randomized to receive DMAb or placebo every 6 months for 36 months. All diabetes group included subjects with a self-report of diabetes, use of antidiabetic medication (ADM), or an FSG ≥ 126 mg/dL at baseline. The diabetes group without prior ADM use included subjects with a self-reported history of diabetes or FSG level ≥ 126 mg/dL at baseline. Prediabetes was defined as an FSG of 100 to 125 mg/dL on no ADM. Average postbaseline FSG across visits was estimated and compared between DMAb and placebo. Main outcome measures are the difference in average postbaseline FSG across follow-up visits between DMAb and placebo. RESULTS: Estimated average postbaseline FSG across visits was not different between DMAb and placebo in either all diabetes group (P = .20) or those with prediabetes (P = .42); in diabetic women not on ADM, estimated average postbaseline FSG across visits was lower with DMAb than placebo (-6.8 mg/dL; 95% CI, -12.6 to -1.0; P = .02). CONCLUSIONS: DMAb did not affect FSG in postmenopausal osteoporotic women with prediabetes or diabetes. There was evidence of modest FSG lowering with DMAb in those with diabetes who were not on ADM. It remains to be determined whether blockade of RANKL has a clinically important effect on glucose metabolism.

Influence of subject discontinuation on long-term nonvertebral fracture rate in the denosumab FREEDOM Extension study.

BACKGROUND: Denosumab treatment for up to 8 years in the FREEDOM study and Extension was associated with low fracture incidence. It was not clear whether subjects who discontinued during the study conduct had a higher risk of fracture than those who remained enrolled, thereby underestimating the true fracture risk for the entire trial cohort. Thus, we explored the influence of early withdrawals on nonvertebral fracture incidence during the Extension study. METHODS: To understand the potential effect of depletion of susceptible subjects on fracture incidence, we first evaluated subject characteristics in patients who were enrolled in the Extension vs those who were not. We subsequently employed a Kaplan-Meier multiple imputation (KMMI) approach to consider subjects who discontinued as if they remained enrolled with a 0%, 20%, 50%, and 100% increase in fracture risk compared with participants remaining on study. RESULTS: Extension enrollees were generally similar to nonparticipants in median age (71.9 and 73.1 years, respectively), mean total hip bone mineral density T-score (-1.9 and -2.0, respectively), and probability of fracture risk by Fracture Risk Assessment Tool (FRAX®) at FREEDOM baseline (16.9% and 17.7% for major osteoporotic fracture and 6.7% and 7.4% for hip fracture, respectively). When we assumed a doubled fracture risk (100% increase) after discontinuation in KMMI analyses, nonvertebral fracture rate estimates were only marginally higher than the observed rates for both the crossover group (10.32% vs 9.16%, respectively) and the long-term group (7.63% vs 6.63%, respectively). CONCLUSION: The observation of continued denosumab efficacy over 8 years of treatment was robust and does not seem to be explained by depletion of susceptible subjects. TRIAL REGISTRATION: ClincalTrials.gov registration number NCT00523341 ; registered August 30, 2007.

How accurate is the human olfactory system in detecting peanuts?

KEY POINTS: This is the first study to quantify the accuracy, sensitivity, and specificity of the human olfactory system in detecting peanuts in common food items. With more competing sensory input, the human olfactory sensitivity to peanuts decreases; this is especially evident when peanuts are mixed in sauces. Metrics established in this study can be used to develop standards for determining the clinical utility of allergen detecting devices that are currently under development.

Denosumab significantly increases DXA BMD at both trabecular and cortical sites: results from the FREEDOM study.

Denosumab is an approved therapy for postmenopausal women with osteoporosis at high or increased risk for fracture. In the FREEDOM study, denosumab reduced fracture risk and increased bone mineral density (BMD). We report the spine and hip dual-energy X-ray absorptiometry (DXA) BMD responses from the overall study of 7808 women and from a substudy of 441 participants in which more extensive spine and hip assessments as well as additional skeletal sites were evaluated. Significant BMD improvements were observed as early as 1 mo at the lumbar spine, total hip, and trochanter (all p<0.005 vs placebo and baseline). BMD increased progressively at the lumbar spine, total hip, femoral neck, trochanter, 1/3 radius, and total body from baseline to months 12, 24, and 36 (all p<0.005 vs placebo and baseline). BMD gains above the least significant change of more than 3% at 36 months were observed in 90% of denosumab-treated subjects at the lumbar spine and 74% at the total hip, and gains more than 6% occurred in 77% and 38%, respectively. In conclusion, denosumab treatment resulted in significant, early, and continued BMD increases at both trabecular and cortical sites throughout the skeleton over 36 mo with important gains observed in most subjects.

Denosumab densitometric changes assessed by quantitative computed tomography at the spine and hip in postmenopausal women with osteoporosis.

FREEDOM was a phase 3 trial in 7808 women aged 60-90yr with postmenopausal osteoporosis. Subjects received placebo or 60 mg denosumab subcutaneously every 6mo for 3yr in addition to daily calcium and vitamin D. Denosumab significantly decreased bone turnover; increased dual-energy X-ray absorptiometry (DXA) areal bone mineral density (aBMD); and significantly reduced new vertebral, nonvertebral, and hip fractures. In a subset of women (N=209), lumbar spine, total hip, and femoral neck volumetric BMD (vBMD) were assessed by quantitative computed tomography at baseline and months 12, 24, and 36. Significant improvement from placebo and baseline was observed in aBMD and vBMD in the denosumab-treated subjects at all sites and time points measured. The vBMD difference from placebo reached 21.8%, 7.8%, and 5.9%, respectively, for the lumbar spine, total hip, and femoral neck at 36mo (all p≤0.0001). Compared with placebo and baseline, significant increases were also observed in bone mineral content (BMC) at the total hip (p<0.0001) largely related to significant BMC improvement in the cortical compartment (p<0.0001). These results supplement the data from DXA on the positive effect of denosumab on BMD in both the cortical and trabecular compartments.

Effect of cone-beam computed tomography metal artefact reduction on incomplete subtle vertical root fractures.

Purpose: This study compared the accuracy of detection of incomplete vertical root fractures (VRFs) in filled and unfilled teeth on cone-beam computed tomography images with and without a metal artefact reduction (MAR) algorithm. Materials and Methods: Forty single-rooted maxillary premolars were selected and, after endodontic instrumentation, were categorized as unfilled teeth without fractures, filled teeth without fractures, unfilled teeth with fractures, or filled teeth with fractures. Each VRF was artificially created and confirmed by operative microscopy. The teeth were randomly arranged, and images were acquired with and without the MAR algorithm. The images were evaluated with OnDemand software (Cybermed Inc., Seoul, Korea). After training, 2 blinded observers each assessed the images for the presence and absence of VRFs 2 times separated by a 1-week interval. P-values<0.05 were considered to indicate significance. Results: Of the 4 protocols, unfilled teeth analysed with the MAR algorithm had the highest accuracy of incomplete VRF diagnosis (0.65), while unfilled teeth reviewed without MAR were associated with the least accurate diagnosis (0.55). With MAR, an unfilled tooth with an incomplete VRF was 4 times more likely to be identified as having an incomplete VRF than an unfilled tooth without this condition, while without MAR, an unfilled tooth with an incomplete VRF was 2.28 times more likely to be identified as having an incomplete VRF than an unfilled tooth without this condition. Conclusion: The use of the MAR algorithm increased the diagnostic accuracy in the detection of incomplete VRF on images of unfilled teeth.

Impact of iron supplementation on patient outcomes for women with abnormal uterine bleeding: a protocol for a systematic review and meta-analysis.

BACKGROUND: Abnormal uterine bleeding (AUB), which includes heavy menstrual bleeding (HMB), is a common condition placing women at increased risk for developing iron deficiency and iron deficiency anemia (IDA). Depletion of iron stores has negative implications on physical, social, and emotional health, as well as quality of life. Iron supplements are safe, effective, and readily available, while red blood cell (RBC) transfusions have inherent risks including infectious and immune reactions. Despite high prevalence of IDA among women with AUB, there are limited studies on the impact of iron therapies on patient outcomes. This systematic review and meta-analysis will evaluate the impact of iron supplementation on patient outcomes for women with AUB, when compared to combination therapy, no intervention, placebo, or standard of care. METHODS: We will conduct a systematic review and meta-analysis of randomized controlled trials and observational studies evaluating the impact of iron interventions on patient outcomes for women with AUB. Systematic literature searches will be conducted in major databases including MEDLINE, EMBASE, CENTRAL, CINAHL, and Web of Science. Studies assessing the impact of iron interventions on patient outcomes in women experiencing AUB, in comparison to combination therapy, no intervention, placebo, or standard of care, will be included in the review. Independent reviewers will screen for eligibility, assess risk of bias, and abstract data. Overall certainty of evidence for each outcome will be assessed using the GRADE approach. We will meta-analyze outcomes which are sufficiently homogeneous to summarize intervention effects and narratively synthesize nonhomogeneous outcomes. The main outcomes of interest are hemoglobin levels immediately prior to surgery and post-operatively, number of RBC transfusions, and adverse effects. Secondary outcomes will include length of hospital stay, intraoperative blood loss, adverse and side effects, quality of life, and iron indices. DISCUSSION: This review will evaluate the impact of iron interventions on patient outcomes in women with IDA secondary to AUB with focus on changes in hematological and iron indices, red blood cell utilization, quality of life, cost of treatment, and adverse events. The results will inform evidence-based clinical practice for the management of iron deficiency and IDA secondary to AUB. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42019137282.

"When I think about my future, I just see darkness": How youth exiting homelessness navigate the hazy, liminal space between socioeconomic exclusion and inclusion.

OBJECTIVES: The overarching objective of this mixed methods longitudinal study was to understand whether and how rent subsidies and mentorship influenced socioeconomic inclusion outcomes for youth exiting homelessness. The focus of this paper is on the qualitative objectives, which evolved from a primary focus on exploring how study mentorship was working as a facilitator of socioeconomic inclusion to focusing on how participants navigated the hazy, liminal space between socioeconomic exclusion and inclusion. METHODS: This was a convergent mixed methods study scaffolded by community-based participatory action axiology. The quantitative component is reported elsewhere and involved a 2-year pilot randomized controlled trial where 24 participants received rent subsidies and 13 were randomly assigned a study mentor; proxy indicators of socioeconomic inclusion were measured every 6 months for 2.5 years. Qualitative objectives were explored using a qualitative descriptive design and theoretically framed using critical social theory. The lead author interviewed 12 participants every 6 months for 2.5 years. Qualitative interviews were analyzed using reflexive thematic analysis with an emphasis on critical interpretation. RESULTS: Navigating the liminal space between socioeconomic exclusion and inclusion was complex and non-linear, and the way youth navigated that journey was more strongly associated with factors like informal mentorship (naturally occurring "coach-like" mentorship) and identity capital (sense of purpose, control, self-efficacy, and self-esteem), rather than whether or not they were assigned a formal study mentor. CONCLUSION: A holistic approach integrating coaching and attention to identity capital alongside economic supports may be key to helping youth exiting homelessness achieve socioeconomic inclusion.

RéSUMé: OBJECTIFS: L'objectif primordial de cette étude longitudinale à méthodes mixtes était de comprendre si et comment les suppléments au loyer et le mentorat influencent les résultats sur le plan de l'inclusion socioéconomique pour les jeunes qui sortent du sans-abrisme. Notre article porte sur des objectifs qualitatifs; à l'origine, il visait principalement à explorer l'efficacité du mentorat des études comme moyen de faciliter l'inclusion socioéconomique, puis il a évolué en s'attachant à la manière dont les participantes et les participants trouvaient leurs repères dans l'espace liminaire flou entre l'exclusion et l'inclusion socioéconomique. MéTHODE: Cette étude à méthodes mixtes convergentes est échafaudée sur l'axiologie de l'action participative communautaire. L'élément quantitatif, qui fait l'objet d'un autre article, a impliqué un essai pilote comparatif randomisé de deux ans où 24 participantes et participants ont reçu des suppléments au loyer, et 13 ont été jumelés de façon aléatoire à un tuteur ou une tutrice scolaire; des indicateurs approximatifs de l'inclusion socioéconomique ont été mesurés tous les six mois pendant deux ans et demi. Les objectifs qualitatifs ont été explorés à l'aide d'un protocole descriptif qualitatif et encadrés théoriquement par la théorie sociale critique. L'autrice principale a interviewé 12 participantes et participants tous les six mois pendant deux ans et demi. Les entretiens qualitatifs ont été analysés en employant l'analyse thématique réflexive et en mettant l'accent sur l'interprétation critique. RéSULTATS: L'exploration de l'espace liminaire entre l'exclusion et l'inclusion socioéconomique était complexe et non linéaire, et le parcours des jeunes était davantage associé à des facteurs comme le mentorat informel (le mentorat naturel semblable à celui d'un entraîneur ou d'une entraîneuse) et le capital identitaire (le sentiment d'avoir un but, le contrôle, l'auto-efficacité et l'estime de soi) qu'au fait d'avoir ou non été jumelés à un tuteur ou une tutrice dans leurs études. CONCLUSION: Une démarche holistique intégrant l'encadrement et l'attention au capital identitaire, en plus des mesures de soutien économique, pourrait être essentielle pour aider les jeunes qui sortent du sans-abrisme à s'intégrer sur le plan socioéconomique.

Denosumab for prevention of fractures in postmenopausal women with osteoporosis.

BACKGROUND: Denosumab is a fully human monoclonal antibody to the receptor activator of nuclear factor-kappaB ligand (RANKL) that blocks its binding to RANK, inhibiting the development and activity of osteoclasts, decreasing bone resorption, and increasing bone density. Given its unique actions, denosumab may be useful in the treatment of osteoporosis. METHODS: We enrolled 7868 women between the ages of 60 and 90 years who had a bone mineral density T score of less than -2.5 but not less than -4.0 at the lumbar spine or total hip. Subjects were randomly assigned to receive either 60 mg of denosumab or placebo subcutaneously every 6 months for 36 months. The primary end point was new vertebral fracture. Secondary end points included nonvertebral and hip fractures. RESULTS: As compared with placebo, denosumab reduced the risk of new radiographic vertebral fracture, with a cumulative incidence of 2.3% in the denosumab group, versus 7.2% in the placebo group (risk ratio, 0.32; 95% confidence interval [CI], 0.26 to 0.41; P<0.001)--a relative decrease of 68%. Denosumab reduced the risk of hip fracture, with a cumulative incidence of 0.7% in the denosumab group, versus 1.2% in the placebo group (hazard ratio, 0.60; 95% CI, 0.37 to 0.97; P=0.04)--a relative decrease of 40%. Denosumab also reduced the risk of nonvertebral fracture, with a cumulative incidence of 6.5% in the denosumab group, versus 8.0% in the placebo group (hazard ratio, 0.80; 95% CI, 0.67 to 0.95; P=0.01)--a relative decrease of 20%. There was no increase in the risk of cancer, infection, cardiovascular disease, delayed fracture healing, or hypocalcemia, and there were no cases of osteonecrosis of the jaw and no adverse reactions to the injection of denosumab. CONCLUSIONS: Denosumab given subcutaneously twice yearly for 36 months was associated with a reduction in the risk of vertebral, nonvertebral, and hip fractures in women with osteoporosis. (ClinicalTrials.gov number, NCT00089791.)

The bar sinister: does handlebar level damage the pelvic floor in female cyclists?

INTRODUCTION: Cycling is associated with genital neuropathies and erectile dysfunction in males. Women riders also have decreased genital sensation; however, sparse information exists addressing the effects of modifiable risks on neurological injuries in females. AIM: This study assesses the effects of bicycle setup and cyclists' attributes on GS and saddle pressures among female cyclists. METHODS: Previously, we compared genital sensation in competitive female cyclists (N = 48) to that of female runners (N = 22). The current study is a subanalysis of the 48 cyclists from the original study group. Nonpregnant, premenopausal women who rode at least 10 miles per week, 4 weeks per month were eligible for participation. MAIN OUTCOME MEASURES: Genital sensation was measured in microns using biosthesiometry measures of vibratory thresholds (VTs). Perineal and total saddle pressures were determined using a specialized pressure map and recorded in kilopascals (kPA). RESULTS: Handlebars positioned lower than the saddle correlated with increased perineum saddle pressures and decreased anterior vaginal and left labial genital sensation (P < 0.05, P < 0.02, P < 0.03, respectively). Low handlebars were not associated with total saddle pressures or altered genital sensation in other areas. After adjusting for age and saddle type, low handlebars were associated with a 3.47-kPA increase in mean perineum saddle pressures (P < 0.04) and a 0.86-micron increase in anterior vagina VT (P < 0.01). CONCLUSION: Handlebars positioned lower than the saddle were significantly associated with increased perineum saddle pressures and decreased genital sensation in female cyclists. Modifying bicycle setup may help alleviate neuropathies in females. Additional research is warranted to further assess the extent of the associations.