Severe Hypocalcemia With Denosumab Among Older Female Dialysis-Dependent Patients.

Importance: Dialysis-dependent patients experience high rates of morbidity from fractures, yet little evidence is available on optimal treatment strategies. Chronic kidney disease-mineral and bone disorder is nearly universal in dialysis-dependent patients, complicating diagnosis and treatment of skeletal fragility. Objective: To examine the incidence and comparative risk of severe hypocalcemia with denosumab compared with oral bisphosphonates among dialysis-dependent patients treated for osteoporosis. Design, Setting, and Participants: Retrospective cohort study of female dialysis-dependent Medicare patients aged 65 years or older who initiated treatment with denosumab or oral bisphosphonates from 2013 to 2020. Clinical performance measures including monthly serum calcium were obtained through linkage to the Consolidated Renal Operations in a Web-Enabled Network database. Exposures: Denosumab, 60 mg, or oral bisphosphonates. Main Outcomes and Measures: Severe hypocalcemia was defined as total albumin-corrected serum calcium below 7.5 mg/dL (1.88 mmol/L) or a primary hospital or emergency department hypocalcemia diagnosis (emergent care). Very severe hypocalcemia (serum calcium below 6.5 mg/dL [1.63 mmol/L] or emergent care) was also assessed. Inverse probability of treatment-weighted cumulative incidence, weighted risk differences, and weighted risk ratios were calculated during the first 12 treatment weeks. Results: In the unweighted cohorts, 607 of 1523 denosumab-treated patients and 23 of 1281 oral bisphosphonate-treated patients developed severe hypocalcemia. The 12-week weighted cumulative incidence of severe hypocalcemia was 41.1% with denosumab vs 2.0% with oral bisphosphonates (weighted risk difference, 39.1% [95% CI, 36.3%-41.9%]; weighted risk ratio, 20.7 [95% CI, 13.2-41.2]). The 12-week weighted cumulative incidence of very severe hypocalcemia was also increased with denosumab (10.9%) vs oral bisphosphonates (0.4%) (weighted risk difference, 10.5% [95% CI, 8.8%-12.0%]; weighted risk ratio, 26.4 [95% CI, 9.7-449.5]). Conclusions and Relevance: Denosumab was associated with a markedly higher incidence of severe and very severe hypocalcemia in female dialysis-dependent patients aged 65 years or older compared with oral bisphosphonates. Given the complexity of diagnosing the underlying bone pathophysiology in dialysis-dependent patients, the high risk posed by denosumab in this population, and the complex strategies required to monitor and treat severe hypocalcemia, denosumab should be administered after careful patient selection and with plans for frequent monitoring.

The effects of acculturation and environment on lifestyle behaviors in Korean immigrants: the mediating role of acculturative stress and body image discrepancy.

OBJECTIVES: Despite high rates of cardiometabolic diseases in Korean immigrants (KIs), little is known about cultural and environmental factors contributing to lifestyle behaviors. The purpose of this cross-sectional study was to examine the relationships among acculturation, environment, and lifestyle behaviors (dietary behavior, physical activity, and sedentary behavior) through culturally sensitive psychological mediators, body image discrepancy and acculturative stress in middle-aged KIs. DESIGN: A cross-sectional study was conducted. KIs aged 30-65 years were recruited online and at Korean community centers and churches in the Northeastern US Participants completed validated measures of dietary behavior (the Nutrition Subscale of the Health Promoting Lifestyle Profile (HPLP) II), physical activity (the International Physical Activity Questionnaire (IPAQ) - short form), and sedentary behavior (the Sedentary Behavior Questionnaire). Acculturative stress was measured by the Acculturative Stress Index and body image discrepancy was measured by the Stunkard Figure Rating Scale. Acculturation was defined as a latent variable measured by Korean and American orientation (Vancouver Index of Acculturation), age of immigration to the US, length of residency in the US, and English proficiency. Data were analyzed with structural equation modeling (SEM). RESULTS: The sample included 361 KIs (mean age = 41.77 ± 10.28 years, 48.1% female, and 46.4% overweight or obese). In the SEM model, acculturation had significant indirect effects on dietary behavior, physical activity, and sedentary behavior through body image discrepancy. Acculturative stress mediated the relationship between acculturation and sedentary behavior. Greater environmental support for physical activity and better healthy food accessibility were related to higher levels of physical activity and healthier dietary behavior, respectively. CONCLUSION: In our study, acculturation and environmental support for physical activity and healthy food simultaneously influenced KIs' lifestyle behaviors. Addressing an unhealthy body image and acculturative stress may be additional strategies for lifestyle intervention programs to prevent cardiometabolic diseases in KIs.

Idelalisib for Treatment of Relapsed Follicular Lymphoma and Chronic Lymphocytic Leukemia: A Comparison of Treatment Outcomes in Clinical Trial Participants vs Medicare Beneficiaries.

Importance: Idelalisib (IDEL) is approved as monotherapy in relapsed follicular lymphoma (FL) and with rituximab (IDEL+R) for relapsed chronic lymphocytic leukemia (CLL). Toxic effects can be severe and treatment-limiting. Outcomes in a real-world population are not yet characterized. Objective: We compared IDEL treatment outcomes in the clinical setting with outcomes in clinical trial data. Design, Setting, and Participants: This cohort study compared clinical trial participants treated with IDEL, aged 65 years or older, in studies 101-09 and 312-0116 with Medicare beneficiaries treated with IDEL of the same disease state and treatment regimen. Study 101-09 was a phase 2, single-group, open-label trial supporting accelerated approval of IDEL for relapsed or refractory FL. Study 312-0116 was a phase 3, multicenter, randomized, double-blind trial supporting approval of IDEL+R for relapsed CLL. Analyses were conducted between February and December 2018. Main Outcomes and Measures: Treatment duration, on-treatment and overall mortality, and serious and fatal infections were compared between trial participants and Medicare beneficiaries. Cox proportional hazards models quantified differences by cohort. Results: We identified 26 trial participants (mean [SD] age, 73 [4.9] years; 12 [46.2%] women) and 305 Medicare beneficiaries (mean [SD] age, 76 [6.9] years; 103 [54.8%] women) receiving IDEL for FL and 89 trial participants (mean [SD] age, 74 [6.0] years; 30 [33.7%] women) and 294 Medicare beneficiaries (mean age, 76 [6.3] years; 111 [37.8%] women) receiving IDEL+R for CLL. Medicare beneficiaries were older with higher comorbidity; had a shorter median treatment duration for CLL (173 days vs 473 days, P < .001) but not FL (114, days vs 160 days, P = .38); a numerically higher mortality rate (CLL: HR, 1.40; 95% CI, 0.93-2.11; FL: HR, 1.39; 95% CI, 0.69-2.78); and a significantly higher fatal infection rate per 100 person-years for CLL (18.4 vs 9.8, P = .04) and a numerically higher rate for FL (27.6 vs 18.6, P = .54), compared with trial participants. Trial participants had approximately twice as many dose reductions (CLL: 32.6% vs 18.0%; P = .003; FL: 38.5% vs 16.1%; P = .02). Among Medicare beneficiaries, a hospitalized infection within 6 months prior to IDEL initiation was associated with a 2.11-fold increased risk for on-treatment fatal infections (95% CI, 1.44-3.10). Despite a March 2016 recommendation for Pneumocystis jirovecii pneumonia prophylaxis in patients treated with IDEL, prophylaxis rates were low after March 2016 (FL: 25%, CLL: 37%). Conclusions and Relevance: We observed substantial imbalances in baseline comorbidities and treatment outcomes between Medicare beneficiaries and trial participants aged 65 years or older. Immunosuppression-related toxic effects, including infections, may have been somewhat reduced in trials by more frequent dose reductions and exclusion of patients with ongoing infections. Selective eligibility criteria and closer monitoring of trial patients may be responsible for limited generalizability of trial data to clinical practice.

Analysis of the Impact of Antiretroviral Drug Changes on Survival of Patients with Advanced-Stage AIDS with Multidrug-Resistant HIV Infection.

OBJECTIVES: This article aims to elucidate the relationship between antiretroviral (ARV) medication changes and all-cause mortality using a total of 368 patients recruited from the United States (78%), United Kingdom (11%), and Canada (11%). METHODS: Data sources included demographic characteristics, ARV treatment history and modifications, and clinical biomarker data from the completed OPTions In Management with Antiretrovirals clinical trial. Descriptive analysis and graphical trajectory representation of ARV drug modifications and biomarker changes were undertaken. Three hypotheses aimed at assessing the impact of ARV modification parameters on clinical outcomes were tested. Kaplan-Meier survival techniques as well as Cox proportional hazard regression models were employed. RESULTS: Results from the analyses suggest that (1) switching therapy strategy from an intensified ARV regimen to a less intense one or vice versa, (2) having a moderate number (up to 2) of ARV drug changes per 6 months, and (3) changes based on clinical/HIV-related reasons or nonclinical reasons compared to ARV drug regimen changes due to clinical non-HIV reasons improved survival. CONCLUSION: Modifications in the ARV regimens of HIV-infected patients with multidrug resistance are associated with improved survival.

A joint model for recurrent events and a semi-competing risk in the presence of multi-level clustering.

Clinical trial designs often include multiple levels of clustering in which patients are nested within clinical sites and recurrent outcomes are nested within patients who may also experience a semi-competing risk. Traditional survival methods that analyze these processes separately may lead to erroneous inferences as they ignore possible dependencies. To account for the association between recurrent events and a semi-competing risk in the presence of two levels of clustering, we developed a semi-parametric joint model. The Gaussian quadrature with a piecewise constant baseline hazard was used to estimate the unspecified baseline hazards and the likelihood. Simulations showed that the proposed joint model has good statistical properties (i.e. <5% bias and 95% coverage) compared to the shared frailty and joint frailty models when informative censoring and multiple levels of clustering were present. The proposed method was applied to data from an AIDS clinical trial to investigate the impact of antiretroviral treatment on recurrent AIDS-defining events in the presence of a semi-competing risk of death and multi-level clustering and showed a significant dependency between AIDS-defining events and death at the patient level but not at the clinic level.

Temporal and spatial associations between influenza and asthma hospitalisations in New York City from 2002 to 2012: a longitudinal ecological study.

OBJECTIVES: To determine whether asthma hospitalisations of children and adults in the five boroughs of New York City are correlated with influenza hospitalisations temporally and spatially. DESIGN: A longitudinal ecological study. INCLUSION CRITERIA: We reviewed the Statewide Planning and Research Cooperative System's records of hospitalisations in Manhattan, Bronx, Queens, Brooklyn and Staten Island from 2002 to 2012. All hospitalisations with a primary diagnosis of either asthma or influenza were identified using the International Classification of Diseases, Ninth Revision, Clinical Modification diagnosis codes. METHODS: A time-series regression analysis was performed using aggregate monthly counts of influenza hospitalisations as predictors of asthma hospitalisations. Time-series regression models were also applied to different age groups and boroughs to examine the magnitude of influenza and asthma correlations across strata. The per cent excess risk was also calculated across age groups and boroughs. RESULTS: Time-series analysis of the overall population revealed a significant positive correlation between influenza and asthma hospitalisations (p=0.011). When stratifying by age, there was a significant positive correlation between asthma and influenza hospitalisations for individuals 18 and older (p<0.01), and no significant correlation found for age groups younger than 18. Percentages of excess risk of influenza-related asthma hospitalisations also increased with increasing age with adults 18-44, 45-64 and 65+ having excess risk percentages of 2.9%, 3.4% and 4%, respectively. Time-series analysis by location revealed positive significant correlations between asthma and influenza hospitalisations in Brooklyn (p=0.03) and Manhattan (p<0.01). Manhattan and Brooklyn had a 2.5% and 1.6%, respectively, percentage of excess risk of influenza-related asthma hospitalisations. CONCLUSION: Influenza and asthma hospitalisations are significantly associated at the population level among adults. These associations vary by age and geographical location. Influenza prevention strategies targeting adult populations, particularly individuals living in Manhattan and Brooklyn, have the potential for meaningful reduction of influenza-related asthma hospitalisations.

A joint frailty model provides for risk stratification of human immunodeficiency virus-infected patients based on unobserved heterogeneity.

OBJECTIVES: To investigate the association between recurrent AIDS-defining events and a semicompeting risk of death in patients with advanced, multidrug-resistant human immunodeficiency virus infection and to identify individuals at increased risk for these events using a joint frailty model. STUDY DESIGN AND SETTING: Three hundred sixty-eight patients with antiretroviral treatment failure in the Options in Management of Antiretrovirals Trial randomized to two antiretroviral treatment strategies using a 2 × 2 factorial design, intensive vs. standard and interruption vs. continuation, and followed for development of AIDS-defining events and death. RESULTS: Participants were heterogeneous for risk of AIDS-defining events and death (P < 0.001), and AIDS-defining events were strongly associated with death (P < 0.001), irrespective of treatment. The frailty model was used to classify individuals into high- and low-risk groups based on unobserved heterogeneity. Low-risk individuals were unlikely to die (0%) or have an AIDS-defining event (<4%), whereas high-risk individuals had event rates approaching 70%. About one-third of high-risk individuals had accelerated mortality, all who died before experiencing an AIDS-defining event. High-risk was associated with being immunocompromised and higher predicted 5-year mortality. CONCLUSION: The joint frailty model permits classification of individuals into risk groups based on unobserved heterogeneity that may be identifiable based on observed covariates, providing advantages over the traditional Cox model.

Spectral Decomposition of Missing Transverse Energy at Hadron Colliders.

We propose a spectral decomposition to systematically extract information of dark matter at hadron colliders. The differential cross section of events with missing transverse energy (E_{T}) can be expressed by a linear combination of basis functions. In the case of s-channel mediator models for dark matter particle production, basis functions are identified with the differential cross sections of subprocesses of virtual mediator and visible particle production while the coefficients of basis functions correspond to dark matter invariant mass distribution in the manner of the Källén-Lehmann spectral decomposition. For a given E_{T} data set and mediator model, we show that one can differentiate a certain dark matter-mediator interaction from another through spectral decomposition.

Gluons to Diphotons via New Particles with Half the Signal's Invariant Mass.

Any new particle charged under SU(3)_{C} and carrying an electric charge will leave an imprint in the diphoton invariant mass spectrum, as it can mediate the gg→γγ process through loops. The combination of properties of loop functions, threshold resummation, and gluon parton distribution functions can result in a peaklike feature in the diphoton invariant mass around twice the mass of a given particle even if the particle is short lived, and thus it does not form a narrow bound state. Using a recent ATLAS analysis, we set upper limits on the combined SU(3)_{C} and electric charge of new particles and indicate future prospects. We also discuss the possibility that the excess of events in the diphoton invariant mass spectrum around 750 GeV originates from loops of a particle with a mass of around 375 GeV.

Radiative electroweak symmetry breaking model perturbative all the way to the Planck scale.

We discuss an extension of the standard model by fields not charged under standard model gauge symmetry in which the electroweak symmetry breaking is driven by the Higgs quartic coupling itself without the need for a negative mass term in the potential. This is achieved by a scalar field S with a large coupling to the Higgs field at the electroweak scale which is driven to very small values at high energies by the gauge coupling of a hidden symmetry under which S is charged. This model can remain perturbative all the way to the Planck scale. The Higgs boson is fully standard-model-like in its couplings to fermions and gauge bosons. However, the effective cubic and quartic self-couplings of the Higgs boson are significantly enhanced.