Subhazard Ratio Research Articles

Antithrombotic treatment switching in elderly patients with atrial fibrillation and the risk of thromboembolism, bleeding, and cardiac death

BackgroundRisks of antithrombotic switching is not investigated in elderly atrial fibrillation patients. ObjectivesTo investigate the effectiveness and safety of antithrombotic treatment and switching of antithrombotic treatment in elderly patients (aged 75 years or older) with atrial fibrillation (AF). MethodsWe conducted a cohort study of 2943 patients with AF (Carrebean‐elderly), hospitalized during 2010–2017. Cox models were used to estimate the association of antithrombotic treatment (warfarin, direct oral anticoagulants [DOAC] and non–guideline‐recommended therapy [NG], i.e., aspirin and low‐molecular‐weight heparin) at discharge and antithrombotic treatment switching during follow‐up with the risk of a composite and single end points of thromboembolism, bleeding, and cardiac death. Crude and adjusted risk estimates were expressed as hazard ratios (HRs) with 95% confidence intervals (CIs). All‐cause death was evaluated, with competing risk regression and estimates expressed as subhazard ratios and 95% CIs. ResultsWe observed an increased risk for the composite end point associated with NG as compared to warfarin at discharge (HR, 1.18; 95% CI, 1.01–1.38) with congruent competing risk regression results, while no significant risk difference was seen for DOACs compared to warfarin (HR, 1.12; 95% CI, 0.92–1.36). Switching from NG to warfarin/DOAC and from warfarin to DOAC occurred in 30.4% and 33.1% of respective antithrombotic treatment groups at discharge and was associated with a decreased risk for the composite end point with an adjusted HR of 0.45 (95% CI, 0.32–0.63) and a HR of 0.50 (95% CI, 0.38–0.65), respectively. ConclusionsAntithrombotic treatment switching is common in the elderly AF population. Importantly, switching to guideline‐recommended treatment has a favorable impact on both effectiveness and safety.

Paid Care Services and Transitioning out of the Community Among Black and White Older Adults With Dementia.

Paid care provided in the home includes important support services for older adults with dementia such as cleaning and personal care assistance. By reducing unmet needs, these services could delay the transition to residential long-term care, but access may differ across racial groups. This study examined the relationship between paid care and transitioning out of the community among Black and White older adults with dementia. Using data from 303 participants (29.4% Black) with probable dementia in the 2011 National Health and Aging Trends Study, competing risk hazards models estimated the association between receiving paid care at baseline and the probability of transitioning out of the community over 8 years (through 2019). Covariate selection was guided by the Andersen model of health care utilization. Paid care was associated with lower risk of transitioning out of the community (subhazard ratios [SHR] = 0.70, 95% CI [0.50, 0.98]). This effect was similar after controlling for predisposing factors and most prominent after controlling for enabling and need for services factors (SHR = 0.65, 95% CI [0.44, 0.95]). There was no racial difference in the use of paid care despite evidence of greater care needs in Blacks. Furthermore, Black participants were less likely to transition out of the community than Whites. Paid care services may help delay transitions out of the community. Future research should seek to explain racial differences in access to and/or preferences for home-based, community-based, and residential care.

Incidence & outcomes of clinically significant bleeding events in critically ill COVID-19 patients receiving Therapeutic dose AntiCoagulanTs: A retrospective cohort study (INTerACT study).

The high mortality associated with the thrombotic events in hospitalized COVID-19 patients resulted in the usage of anticoagulants in varying doses. Whether high-dose anticoagulants have led to better outcomes or higher incidence of clinically significant bleeding events is debatable. Thus, this study was conducted to find the incidence of clinically significant bleeding events in moderate-to-severe COVID-19 ARDS (acute respiratory distress syndrome) patients on therapeutic anticoagulation and their outcomes. In this retrospective, single-centre study of 155 critically ill COVID-19 patients, the incidence of clinically significant bleeding was observed. Multivariate regression models were used to evaluate the association between anticoagulant regimen, coagulation and inflammatory markers with the incidence of bleeding and thrombotic events. The incidence of clinically relevant non-major bleeding was 33.54 per cent (26.17-41.46%) and major bleeding was 9.03 per cent (5.02-14.69%). The anticoagulation intensity at baseline had a high odds of major bleeding when enoxaparin and dual antiplatelet therapy were used together [adjusted odds ratio OR of 434.09 (3.81-49502.95), P<0.05]. At admission, bleeders had a poorer PaO2/FiO2 ratio with more patients on invasive ventilation. At the time of bleeding, the bleeders had a higher D-dimer, ferritin, C-reactive protein and procalcitonin compared to non-bleeders. The subhazard ratio for death in bleeders was 3.35 (95% confidence interval, 1.97-5.65; P<0.001). The incidence of bleeding in critically ill COVID-19 patients on therapeutic anticoagulation may increase with the severity of the disease as well as with concurrent use of dual antiplatelets. Major bleeding may also contribute to higher mortality.

Incomplete chimerism following myeloablative and anti-thymocyte globulin-conditioned hematopoietic cell transplantation is a risk factor for relapse and chronic graft-versus-host disease

Background aimsThe value of routine chimerism determination after myeloablative hematopoietic cell transplantation (HCT) is unclear, particularly in the setting of anti-thymocyte globulin (ATG)-based graft-versus-host disease (GVHD) prophylaxis. MethodsBlood samples were collected at 3 months post-HCT from 558 patients who received myeloablative conditioning and ATG-based GVHD prophylaxis. Chimerism was assessed using multiplex polymerase chain reaction of short tandem repeats in sorted T cells (CD3+) and leukemia lineage cells (CD13+CD33+ for myeloid malignancies and CD19+ for B-lymphoid malignancies). ATG exposure was determined using a flow cytometry-based assay. The primary outcomes of interest were relapse and chronic GVHD (cGVHD). ResultsIncomplete (<95%) T-cell chimerism and leukemia lineage chimerism were present in 17% and 4% of patients, respectively. Patients with incomplete T-cell chimerism had a significantly greater incidence of relapse (36% versus 22%, subhazard ratio [SHR] = 2.03, P = 0.001) and lower incidence of cGVHD (8% versus 25%, SHR = 0.29, P < 0.001) compared with patients with complete chimerism. In multivariate modeling, patients with high post-transplant ATG area under the curve and any cytomegalovirus (CMV) serostatus other than donor/recipient seropositivity (non-D+R+) had an increased likelihood of incomplete T-cell chimerism. Patients with incomplete leukemia lineage chimerism had a significantly greater incidence of relapse (50% versus 23%, SHR = 2.70, P = 0.011) and, surprisingly, a greater incidence of cGVHD (45% versus 20%, SHR = 2.64, P = 0.003). ConclusionsHigh post-transplant ATG exposure and non-D+R+ CMV serostatus predispose patients to incomplete T-cell chimerism, which is associated with an increased risk of relapse. The increased risk of cGVHD with incomplete B-cell/myeloid chimerism is a novel finding that suggests an important role for recipient antigen-presenting cells in cGVHD pathogenesis.

The Association of Baseline Plasma SARS-CoV-2 Nucleocapsid Antigen Level and Outcomes in Patients Hospitalized With COVID-19.

Levels of plasma SARS-CoV-2 nucleocapsid (N) antigen may be an important biomarker in patients with COVID-19 and enhance our understanding of the pathogenesis of COVID-19. To evaluate whether levels of plasma antigen can predict short-term clinical outcomes and identify clinical and viral factors associated with plasma antigen levels in hospitalized patients with SARS-CoV-2. Cross-sectional study of baseline plasma antigen level from 2540 participants enrolled in the TICO (Therapeutics for Inpatients With COVID-19) platform trial from August 2020 to November 2021, with additional data on day 5 outcome and time to discharge. 114 centers in 10 countries. Adults hospitalized for acute SARS-CoV-2 infection with 12 days or less of symptoms. Baseline plasma viral N antigen level was measured at a central laboratory. Delta variant status was determined from baseline nasal swabs using reverse transcriptase polymerase chain reaction. Associations between baseline patient characteristics and viral factors and baseline plasma antigen levels were assessed using both unadjusted and multivariable modeling. Association between elevated baseline antigen level of 1000 ng/L or greater and outcomes, including worsening of ordinal pulmonary scale at day 5 and time to hospital discharge, were evaluated using logistic regression and Fine-Gray regression models, respectively. Plasma antigen was below the level of quantification in 5% of participants at enrollment, and 1000 ng/L or greater in 57%. Baseline pulmonary severity of illness was strongly associated with plasma antigen level, with mean plasma antigen level 3.10-fold higher among those requiring noninvasive ventilation or high-flow nasal cannula compared with room air (95% CI, 2.22 to 4.34). Plasma antigen level was higher in those who lacked antispike antibodies (6.42 fold; CI, 5.37 to 7.66) and in those with the Delta variant (1.73 fold; CI, 1.41 to 2.13). Additional factors associated with higher baseline antigen level included male sex, shorter time since hospital admission, decreased days of remdesivir, and renal impairment. In contrast, race, ethnicity, body mass index, and immunocompromising conditions were not associated with plasma antigen levels. Plasma antigen level of 1000 ng/L or greater was associated with a markedly higher odds of worsened pulmonary status at day 5 (odds ratio, 5.06 [CI, 3.41 to 7.50]) and longer time to hospital discharge (median, 7 vs. 4 days; subhazard ratio, 0.51 [CI, 0.45 to 0.57]), with subhazard ratios similar across all levels of baseline pulmonary severity. Plasma samples were drawn at enrollment, not hospital presentation. No point-of-care test to measure plasma antigen is currently available. Elevated plasma antigen is highly associated with both severity of pulmonary illness and clinically important patient outcomes. Multiple clinical and viral factors are associated with plasma antigen level at presentation. These data support a potential role of ongoing viral replication in the pathogenesis of SARS-CoV-2 in hospitalized patients. U.S. government Operation Warp Speed and National Institute of Allergy and Infectious Diseases.

Factors Associated With Mechanical Ventilation Duration in Pediatric Burn Patients in a Regional Burn Center in the United States.

Among burned children who arrive at a burn center and require invasive mechanical ventilation (IMV), some may have prolonged IMV needs. This has implications for patient-centered outcomes as well as triage and resource allocation decisions. Our objective was to identify factors associated with the duration of mechanical ventilation in pediatric patients with acute burn injury in this setting. Single-center, retrospective cohort study. Registry data from a regional, pediatric burn center in the United States. Children less than or equal to 18 years old admitted with acute burn injury who received IMV between January 2005 and December 2020. None. Ventilator days were defined as any full or partial day having received IMV via an endotracheal tube or tracheostomy, not inclusive of time spent ventilated for procedures. Of 5,766 admissions for acute burn care, 4.3% ( n = 249) required IMV with a median duration of 10 days. A multivariable model for freedom from mechanical ventilation showed that the presence of inhalational injury (subhazard ratio [sHR], 0.62; 95% CI, 0.46-0.85) and burns to the head and neck region (sHR, 0.94; 95% CI, 0.90-0.98) were associated with increased risk of remaining mechanically ventilated at any time point. Older (sHR, 1.03; 95% CI, 1.01-1.04) and male children (sHR, 1.39; 95% CI, 1.05-1.84) were more likely to discontinue mechanical ventilation. A majority of children (94.8%) survived to hospital discharge. The presence of inhalational injury and burns to the head and neck region were associated with a longer duration of mechanical ventilation. Older age and male gender were associated with a shorter duration of mechanical ventilation. These factors should help clinicians better estimate a burned child's expected trajectory and resource-intensive needs upon arrival to a burn center.

A 50-step walking test for analysis of recovery after decompressive surgery for thoracolumbar disc herniation in dogs.

BackgroundDespite its importance, there is no agreed definition of recovery of ambulation in dogs with spinal cord injury.ObjectivesTo validate a new walking test in dogs recovering from thoracolumbar spinal cord injury.AnimalsTwo hundred twenty‐four dogs weighing <20 kg: 120 normally ambulatory dogs, plus 104 dogs undergoing decompressive surgery for acute thoracolumbar intervertebral disc herniation.MethodsProspective cohort studies. The distance each freely‐ambulatory dog walked during 50 step cycles was regressed on ulna length. For each postsurgical dog, we recorded when the calculated 50‐step distance was completed without falling, or their inability to complete this distance by 4 months or more after surgery. Bayesian analysis compared outcomes for presurgical neurologic categories; association of recovery with several preoperative variables was explored using logistic and time‐to‐event regression.ResultsFor control dogs, 50‐step distance (m) = 1.384 × ulnar length (cm) + 2.773. In postsurgical dogs, the 50‐step test provided decisive evidence that deep pain‐negative dogs were less likely to recover ambulation than dogs with intact pain perception (12/29 recovered vs 71/75; Bayes factor [BF] = 5.9 × 106) and, if they did recover, it took much longer (median 91 days vs median 14 days; BF = 1.5 × 103). Exploratory analysis suggested that presurgical neurologic status (subhazard ratio [SHR] = 0.022; P < .001) and duration of presurgical anesthesia (SHR = 0.740; P = .04) were associated with rapidity of recovery.Conclusions and Clinical ImportanceThis straightforward 50‐step walking test provides robust data on ambulatory recovery well‐suited to large scale pragmatic trials on treatment of thoracolumbar spinal cord injury in dogs.

Randomized clinical trial comparing outcomes after fentanyl or ketamine-dexmedetomidine analgesia in thoracolumbar spinal surgery in dogs.

BackgroundOpioids are widely used for perioperative pain control in dogs undergoing spinal surgery, but alternatives may be required because data suggest that opioids exacerbate inflammation in the injured spinal cord and veterinary access to opioids may become more restricted in the future.ObjectivesTo compare recovery of ambulation and other functions between spinal cord‐injured dogs receiving peri‐operative fentanyl and those receiving a ketamine‐dexmedetomidine combination.AnimalsA total of 102 client‐owned dogs undergoing decompressive surgery for thoracolumbar intervertebral disc herniation.MethodsRandomized clinical trial. Dogs were randomized 1:1 to fentanyl or a ketamine‐dexmedetomidine combination for intra and postoperative analgesia. Primary outcome was time to recovery of ambulation; secondary outcomes were the postoperative Colorado Acute Pain Scale, the short‐form Glasgow Composite Measure Pain Scale, time to recovery of voluntary urination and time to unassisted eating.ResultsNo difference was found in time to recovery of ambulation between groups (adjusted sub‐hazard ratio, 0.83; 95% confidence interval [CI], 0.55‐1.24; P = .36) or in pain scores (Colorado: χ 2 = 14.74; P = .32; Glasgow: χ 2 = 6.61; P = .76). Differences in time to recovery of eating and urination were small but favored ketamine‐dexmedetomidine (adjusted odds ratios, 3.31; 95% CI, 1.53‐7.16; P = .002 and 2.43; 95% CI, 1.00‐5.96; P = .05, respectively).Conclusions and Clinical ImportanceThere was no evidence that, at the doses used, fentanyl impaired ambulatory outcome after surgery for thoracolumbar intervertebral disc herniation in dogs. Pain control appeared similar between groups. Secondary outcomes suggested minor benefits associated with ketamine‐dexmedetomidine. The ketamine‐dexmedetomidine combination appears to be a reasonable alternative to peri‐operative opioids.

Efficacy and Safety of Ensovibep for Adults Hospitalized With COVID-19 : A Randomized Controlled Trial.

Ensovibep (MP0420) is a designed ankyrin repeat protein, a novel class of engineered proteins, under investigation as a treatment of SARS-CoV-2 infection. To investigate if ensovibep, in addition to remdesivir and other standard care, improves clinical outcomes among patients hospitalized with COVID-19 compared with standard care alone. Double-blind, randomized, placebo-controlled, clinical trial. (ClinicalTrials.gov: NCT04501978). Multinational, multicenter trial. Adults hospitalized with COVID-19. Intravenous ensovibep, 600 mg, or placebo. Ensovibep was assessed for early futility on the basis of pulmonary ordinal scores at day 5. The primary outcome was time to sustained recovery through day 90, defined as 14 consecutive days at home or place of usual residence after hospital discharge. A composite safety outcome that included death, serious adverse events, end-organ disease, and serious infections was assessed through day 90. An independent data and safety monitoring board recommended that enrollment be halted for early futility after 485 patients were randomly assigned and received an infusion of ensovibep (n=247) or placebo (n=238). The odds ratio (OR) for a more favorable pulmonary outcome in the ensovibep (vs. placebo) group at day 5 was 0.93 (95% CI, 0.67 to 1.30; P=0.68; OR>1 would favor ensovibep). The 90-day cumulative incidence of sustained recovery was 82% for ensovibep and 80% for placebo (subhazard ratio [sHR], 1.06 [CI, 0.88 to 1.28]; sHR>1 would favor ensovibep). The primary composite safety outcome at day 90 occurred in 78 ensovibep participants (32%) and 70 placebo participants (29%) (HR, 1.07 [CI, 0.77 to 1.47]; HR<1 would favor ensovibep). The trial was prematurely stopped because of futility, limiting power for the primary outcome. Compared with placebo, ensovibep did not improve clinical outcomes for hospitalized participants with COVID-19 receiving standard care, including remdesivir; no safety concerns were identified. National Institutes of Health.

Blood type O heart transplant candidates have longer waitlist time and higher delisting under the new allocation system

ObjectivePrior studies have examined the effect of blood type on heart transplantation (HTx) waitlist outcomes in cohorts through 2015. We aim to analyze the effect of blood type on contemporary waitlist outcomes with a new allocation system focus. MethodsAdults listed for HTx between April 2015 and December 2020 were included. Survival to HTx and waitlist death/deterioration was compared between type O and non-type O candidates using competing risks regression. Donor/recipient ABO compatibility trends were further investigated. ResultsCandidates with blood type O (n = 7509) underwent HTx less frequently than candidates with blood type other than type O (n = 9699) (subhazard ratio [sHR], 0.56; 95% CI, 0.53-0.58) with higher rates of waitlist death/deterioration (sHR, 1.18; 95% CI, 1.04-1.34). Subgroup analyses demonstrated persistence of this trend under the new donor heart allocation system (HTx: sHR, 0.58; 95% CI, 0.54-0.62; death/clinical deterioration: sHR, 1.27; 95% CI, 1.02-1.60), especially among those listed at high status (1, 2, or 3) (HTx: sHR, 0.69; 95% CI, 0.63-0.75; death/deterioration: sHR, 1.61; 95% CI, 1.16-2.22). Among those listed at status 3, waitlist death/deterioration was modified by presence of a durable left ventricular assist device (left ventricular assist device: sHR, 1.57; 95% CI, 0.58-4.29; no left ventricular assist device: sHR, 3.79; 95% CI, 1.28-11.2). Type O donor heart allocation to secondary ABO candidates increased in the new system (14.5% vs 12.0%; P < .01); post-HTx survival remained comparable between recipients with blood type O and non-type O (log-rank P = .07). ConclusionsFurther logistical considerations are warranted to minimize allocation inequity regarding blood type under the new allocation system.

Long-term clinical outcomes in older patients with acute venous thromboembolism who have renal impairment

IntroductionRenal impairment (RI) may induce an inflammatory/procoagulant state as well as platelet dysfunction. Little is known on the prevalence of RI and long-term prognosis of older patients with venous thromboembolism (VTE) who have concomitant RI. MethodsIn a prospective multicenter cohort, we analyzed 912 patients aged ≥65 years with acute VTE. Using the CKD-EPI formula, we defined three categories of baseline renal function: estimated glomerular filtration rate ≥60 ml/min/1.73m2 (no RI), 30–59 ml/min/1.73m2 (moderate RI), and <30 ml/min/1.73m2 (severe RI). The outcomes were VTE recurrence, major bleeding, and overall mortality. We examined the association between renal function and clinical outcomes using competing risk regression models, adjusting for relevant confounders and periods of anticoagulation. ResultsWe followed 912 patients over a median duration of 29.6 months. Overall, 313 (34%) patients had moderate and 51 (6%) severe RI. One hundred and seven patients (12%) had VTE recurrence, 125 (14%) had major bleeding, and 186 (20%) died during follow-up. After adjustment, severe RI was associated with a 2-fold increased risk of major bleeding (sub-hazard ratio [SHR] 2.1, 95% CI 1.1–4.0) compared to no RI, but not with VTE recurrence (SHR 0.6, 95% CI 0.2–1.8) or overall mortality (hazard ratio 1.0, 95% CI 0.6–1.9). Moderate RI was not significantly associated with adverse clinical outcomes. ConclusionsRI was common among older patients with acute VTE. Severe RI was associated with a 2-fold increased long-term risk of major bleeding, without a risk increase in terms of VTE recurrence and overall mortality. Older patients with moderate RI did not carry worse prognosis.

Association between duration of gonadotrophin-releasing hormone agonist use and cardiovascular risks: A population-based competing-risk analysis.

Although androgen deprivation therapy has known cardiovascular risks, it is unclear if its duration is related to cardiovascular risks. This study thus aimed to investigate the associations between gonadotrophin-releasing hormone (GnRH) agonist use duration and cardiovascular risks. This retrospective cohort study included adult patients with prostate cancer receiving GnRH agonists in Hong Kong during 1999-2021. Patients who switched to GnRH antagonists, underwent bilateral orchidectomy, had <6 months of GnRH agonist, prior myocardial infarction (MI), or prior stroke was excluded. All patients were followed up until September 2021 for a composite endpoint of MI and stroke. Multivariable competing-risk regression using the Fine-Gray subdistribution model was used, with mortality from any cause as the competing event. In total, 4038 patients were analyzed (median age 74.9 years old, interquartile range (IQR) 68.7-80.8 years old). Over a median follow-up of 4.1 years (IQR 2.1-7.5 years), longer GnRH agonists use was associated with higher risk of the endpoint (sub-hazard ratio per year 1.04 [1.01-1.06], p = 0.001), with those using GnRH agonists for ≥2 years having an estimated 23% increase in the sub-hazard of the endpoint (sub-hazard ratio 1.23 [1.04-1.46], p = 0.017). Longer GnRH agonist use may be associated with greater cardiovascular risks.

Characteristics and outcomes of left ventricular assist device recipients transplanted before and after the new donor heart allocation system.

Concerns about the impact of the new donor heart allocation system on posttransplant outcomes have emerged after its implementation. We sought to evaluate the characteristics and outcomes of left ventricular assist device (LVAD) recipients transplanted before and after the implantation of the new policy on October 18, 2018. Data on bridge to transplantation of adult patients with LVAD between January 2015 and October 2021, with durable LVAD as a (BTT), was queried from the United Network of Organ Sharing (UNOS) registry. The main outcomes were 30-day all-cause mortality, 30-day fatal graft failure, 1-year all-cause mortality, treated acute rejection at 1 year and renal replacement therapy (RRT) for acute renal failure. In our study, 7096 patients met the inclusion criteria including 2435 in the new allocation system. The transplanted patients in the new allocation system era had older donor age, longer ischemic time, and higher proportion of newer generation LVADs. Adjusted 30-day all-cause mortality was significantly lower for LVAD recipients in the new allocation system era (2.5% vs. 3.6%; sub-hazard ratio [SHR] 0.36, 95% Confidence intervals [CI] 0.27-0.48, p < 0.001) without differences in the risk of fatal graft failure and 1-year mortality (7.8% vs. 9.6%). Significantly lower adjusted 30-day mortality with HVAD and HM3 devices than HM2 in the new allocation system era was found, without differences in 1-year mortality. Acute allograft rejection requiring treatment was significantly lower (Odds Ratio 0.78, 95% CI 0.65-0.94, p=0.01), whereas a trend toward higher risk of renal failure requiring RRT was identified. Despite changing donor characteristics and longer ischemic times, posttransplant outcomes in LVAD recipients have not worsened with the implementation of the new allocation system and this finding is related to the use of newer generation continuous flow LVADs.

Stereotactic Body Radiation Therapy for Metastases in Long Bones

To evaluate the cumulative incidence of fracture and local failure and associated risk factors after stereotactic body radiation therapy (SBRT) for long bone metastases. Data from 111 patients with 114 metastases in the femur, humerus, and tibia treated with SBRT in 7 international centers between October 2011 and February 2021 were retrospectively reviewed and analyzed using a competing risk regression model. The median follow-up was 21 months (range, 6-91 months). All but 1 patient had a Karnofsky performance status ≥70. There were 84 femur (73.7%), 26 humerus (22.8%), and 4 tibia (3.5%) metastases from prostate (45 [39.5%]), breast (22 [19.3%]), lung (15 [13.2%]), kidney (13 [11.4%]), and other (19 [16.6%]) malignancies. Oligometastases accounted for 74.8% of metastases and 28.1% were osteolytic. The most common total doses were 30 to 50 Gy in 5 daily fractions (50.9%). Eight fractures (5 in the femur, 2 in the tibia, and 1 in the humerus) were observed with a median time to fracture of 12 months (range, 0.8-33 months). In 6 out of 8 patients, fracture was not associated with local failure. The cumulative incidence of fracture was 3.5%, 6.1%, and 9.8% at 1, 2, and 3 years, respectively. The cumulative incidence of local failure (9/110 metastases with imaging follow-up) was 5.7%, 7.2%, and 13.5% at 1, 2, and 3 years, respectively. On multivariate analysis, extraosseous disease extension was significantly associated with fracture (P=.001; subhazard ratio, 10.8; 95% confidence interval, 2.8-41.9) and local failure (P=.02; subhazard ratio, 7.9; 95% confidence interval, 1.4-44.7). SBRT for metastases in long bones achieved high rates of durable local metastasis control without an increased risk of fracture. Similar to spine SBRT, patients with extraosseous disease extension are at higher risk of local failure and fracture.

The influence of multiple frailty profiles on institutionalization and all-cause mortality in community-living older adults.

BackgroundFrailty in older adults is associated with adverse geriatric outcomes. Physical frailty is often accompanied by problems in the cognitive, psychological, and social domains. This study investigated the ability of physical frailty combined with other health domains to predict institutionalization and mortality.MethodsA national sample of 9171 Koreans aged 65 years or older were surveyed at baseline in 2008 and 3 year follow‐up. Those who were prefrail or frail according to the Fried criteria were conceived to have physical frailty. Psychological frailty, cognitive frailty, and social frailty were defined as having depressive symptoms, cognitive impairment, and social vulnerabilities, respectively, in addition to physical frailty. Using Cox proportional hazards and competing‐risks regression, the risk of mortality and institutionalization by the number and profiles of different frailty domains was analysed.ResultsAt baseline, the 9171 participants were aged 73.1 (±6.8) years on average (median: 72, range: 65 to 103), and 59.2% were women. Multidomain frailty was highly prevalent (49.3%), with 6.1% concurrently displaying frailty in all four domains (mixed frailty). The risk of negative health outcomes increased with frailty in a higher number of domains with a subhazard ratio (SHR) of 3.48 (95% confidence interval [CI]: 1.83, 6.62; P < 0.001) for institutionalization and a hazard ratio (HR) of 3.95 (95% CI: 2.62, 5.93; P < 0.001) for mortality among those presenting mixed frailty. Psychological frailty (depressive symptoms combined with physical frailty) was strongly predictive of institutionalization (SHR = 2.85; 95% CI: 1.45, 5.59; P = 0.002) and mortality (HR = 2.47; 95% CI: 1.61, 3.78; P < 0.001). When combined with physical frailty and either depressive symptoms or social vulnerabilities, cognitive impairment also exhibited a significantly elevated risk of negative events. Physical frailty alone was not a strong predictor of adverse events, especially for mortality (HR = 1.13; 95% CI: 0.77, 1.67; P = 0.53).ConclusionsCo‐occurrence of physical frailty with other domains is common in late life. The presence of frailty in multiple domains raises the risk of adverse outcomes, with the effects varying by multidimensional profiles.

Early Autonomic Symptoms Predict Functional Decline in Parkinson’s Disease Independent of Dopaminergic Therapy

Introduction: Parkinson’s disease (PD) has variable progression; identifying determinants of functional decline in PD is needed for accurate prognostication. Autonomic symptoms can result from dopaminergic therapy but may also independently predict functional decline. Methods: The sample included individuals with newly diagnosed PD in Parkinson’s Progression Markers Initiative. Autonomic symptoms were measured with the Scales-for-Outcomes-in-Parkinson’s-Disease-Autonomic (SCOPA-AUT). Presence/absence of autonomic symptoms for SCOPA-AUT total scale and seven subscales was defined, and baseline demographic/clinical data were compared between groups with and without autonomic symptoms. Time-to-functional-dependence, or Schwab-and-England Activities-of-Daily-Living (SE-ADL) ≤70, was compared between groups using hazard models, adjusting for covariates including time-varying levodopa-equivalent daily dosage. If a subscale was associated with a significant subhazard ratio (SHR), hazard models for items in that subscale were generated and gender was evaluated as an effect modifier. Results: 399 participants were included. Over a median of 72 months (range 6–84), 91 (22.81%) reached SE-ADL ≤70. SCOPA-AUT total/gastrointestinal/urinary/pupillomotor scales were associated with SE-ADL ≤70; respective multivariable SHRs (95% CI, p value) were 1.98 (1.06–3.70, 0.03), 1.71 (1.04–2.81, 0.03), 1.94 (1.25–3.01, <0.01), 2.56 (1.24–5.31, 0.01). Individual items in the gastrointestinal and urinary scales drove associations. Urinary scale associations were seen in males only. Conclusions: Symptoms of gastrointestinal, urinary, pupillomotor dysfunction are associated with functional decline risk in PD, independent of dopaminergic therapy. Detailed assessments of autonomic symptomatology should be utilized in studies attempting to refine predictive models of PD progression.

Durable Left Ventricular Assist Device as a Bridge to Heart Transplantation Under the New Donor Heart Allocation System.

The new donor heart allocation system prioritizes candidates supported by temporary devices. However, waitlist and posttransplant outcomes in candidates with durable left ventricular assist device (LVAD) remain to be elucidated. The United Network for Organ Sharing database was queried for adults listed from October 2015 to March 2020 for a single-organ, first-time heart transplant (HTx) with a durable LVAD. Waitlist removal within 1 year because of death or clinical deterioration and HTx was analyzed using competing risks regression. Candidates who underwent HTx within 1 year of listing were identified for examination of post-HTx survival using the Kaplan-Meier method and Cox proportional hazards models. Compared with candidates listed under the old system (n = 2,122), candidates listed under the new system (n = 1,562) were slightly younger ( p = 0.04) but had higher body mass index ( p < 0.01). Those listed under the new system were significantly less likely to experience waitlist removal because of death or clinical deterioration (subhazard ratio [HR] 0.68, 95% CI 0.52-0.90) but were also less likely to undergo HTx (sub-HR 0.91, 95% CI 0.83-0.998). Those who survived to HTx were more likely to experience death or need for re-HTx within 1 year of HTx under the new system (adjusted HR 1.50, 95% CI 1.11-2.03). Candidates with durable LVAD experience favorable waitlist outcomes under the new allocation system, although those who undergo HTx may be at increased mortality risk. Thus, candidates with a durable LVAD should be carefully selected for HTx listing under the new allocation system.

Associations between HIV viremia during antiretroviral therapy and cardiovascular disease.

To investigate the association between HIV viremia exposure during antiretroviral therapy (ART) and cardiovascular disease (CVD) risk. Nationwide observational cohort. Participants (age >15 years) from the Swedish nationwide InfCareHIV register initiating ART 1996-2017 were categorized in a time-updated manner into four viremia categories, starting from 12 months after ART initiation: suppression (<50 copies/ml), low-level viremia (50-199 copies/ml and 200-999 copies/ml, respectively), and high-level viremia (≥1000 copies/ml). In addition, cumulative viremia was estimated as the area under the log viral load (VL) curve. Proportional subhazard models adjusted for sex, age, pre-ART CD4 and VL, injection drug use, and country of birth were used to analyze the association between viremia exposure and CVD risk (ischemic heart disease, stroke, and heart failure; data obtained by linkage to national registers), accounting for the competing risk of non-CVD death. In all, 337 cases of CVD were observed during 44 937 person-years of follow-up ( n = 6562). Higher viremia exposure was associated with CVD, both when parameterized as cumulative viremia (adjusted subhazard ratio [aSHR] per 1 log 10 copy × year/ml, 1.03; 95% confidence interval [CI], 1.01-1.05) and as viremia category (aSHR for high-level viremia versus suppression, 1.45; 95% CI, 1.03-2.05). We observed no association between CVD and low-level viremia compared with those with suppression. Higher exposure to HIV viremia was linked to CVD in ART recipients, whereas no increased risk was detected for people with low-level viremia compared with viral suppression. Causal inference is limited by the observational nature of this study.

Severe Acute Respiratory Syndrome Coronavirus 2 Infection and Pregnancy in Sub-Saharan Africa: A 6-Country Retrospective Cohort Analysis.

BackgroundFew data are available on COVID-19 outcomes among pregnant women in sub-Saharan Africa (SSA), where high-risk comorbidities are prevalent. We investigated the impact of pregnancy on SARS-CoV-2 infection and of SARS-CoV-2 infection on pregnancy to generate evidence for health policy and clinical practice.MethodsWe conducted a 6-country retrospective cohort study among hospitalized women of childbearing age between 1 March 2020 and 31 March 2021. Exposures were (1) pregnancy and (2) a positive SARS-CoV-2 RT-PCR test. The primary outcome for both analyses was intensive care unit (ICU) admission. Secondary outcomes included supplemental oxygen requirement, mechanical ventilation, adverse birth outcomes, and in-hospital mortality. We used log-binomial regression to estimate the effect between pregnancy and SARS-CoV-2 infection. Factors associated with mortality were evaluated using competing-risk proportional subdistribution hazards models.ResultsOur analyses included 1315 hospitalized women: 510 pregnant women with SARS-CoV-2, 403 nonpregnant women with SARS-CoV-2, and 402 pregnant women without SARS-CoV-2 infection. Among women with SARS-CoV-2 infection, pregnancy was associated with increased risk for ICU admission (adjusted risk ratio [aRR]: 2.38; 95% CI: 1.42–4.01), oxygen supplementation (aRR: 1.86; 95% CI: 1.44–2.42), and hazard of in-hospital death (adjusted sub-hazard ratio [aSHR]: 2.00; 95% CI: 1.08–3.70). Among pregnant women, SARS-CoV-2 infection increased the risk of ICU admission (aRR: 2.0; 95% CI: 1.20–3.35), oxygen supplementation (aRR: 1.57; 95% CI: 1.17–2.11), and hazard of in-hospital death (aSHR: 5.03; 95% CI: 1.79–14.13).ConclusionsAmong hospitalized women in SSA, both SARS-CoV-2 infection and pregnancy independently increased risks of ICU admission, oxygen supplementation, and death. These data support international recommendations to prioritize COVID-19 vaccination among pregnant women.

Progression-Free Survival and Local Control After SABR for up to 5 Oligometastases: An Analysis From the Population-Based Phase 2 SABR-5 Trial

Despite increasing utilization of SABR for oligometastatic cancer, prospective outcomes are lacking. The purpose of this study was to determine progression-free survival (PFS), local control (LC), and prognostic factors from the population-based phase 2 SABR-5 trial. The SABR-5 trial was a single-arm phase 2 study with the primary endpoint of toxicity, conducted at the 6 regional cancer centers across British Columbia (BC), Canada, during which time SABR for oligometastases was only offered on trial. Patients with up to 5 oligometastases (total or not controlled by prior treatment and including induced oligometastatic disease) underwent SABR to all lesions. Patients were 18 years of age or older, had an Eastern Cooperative Oncology Group score of 0 to 2, and had life expectancy ≥ 6 months. The secondary outcomes of PFS and LC are presented here. Between November 2016 and July 2020, 381 patients underwent SABR on trial. Median follow-up was 27 months (interquartile range, 18-36). Median PFS was 15 months (95% confidence interval [CI], 12-18). LC at 1 and 3 years were 93% (95% CI, 91-95) and 87% (95% CI, 84-90), respectively. On multivariable analysis, increasing tumor diameter (hazard ratio [HR], 1.09; P < .001), declining performance status (HR, 2.13; P < .001), disease-free interval <18 months (HR, 1.52; P=.003), 4 or more metastases at SABR (HR, 1.48; P=.048), initiation or change in systemic treatment (HR, 0.50; P < .001), and oligoprogression (HR, 1.56; P=.008) were significant independent predictors of PFS. Tumor diameter (sub-hazard ratio [SHR], 1.28; P < .001), colorectal histology (SHR, 4.33; P=.002), and "other" histology (SHR, 3.90; P < .001) were associated with worse LC. In this population-based cohort including patients with genuine oligometastatic, oligoprogressive, and induced oligometastatic disease, the median PFS was 15 months and LC at 3 years was 87%. This supports ongoing efforts to randomize patients in phase 3 trials, even outside the original 1 to 5 metachronous oligometastatic paradigm.