University of Illinois Hospital & Health Sciences System

Importance: SARS-CoV-2 infection is associated with persistent, relapsing, or new symptoms or other health effects occurring after acute infection, termed postacute sequelae of SARS-CoV-2 infection (PASC), also known as long COVID. Characterizing PASC requires analysis of prospectively and uniformly collected data from diverse uninfected and infected individuals. Objective: To develop a definition of PASC using self-reported symptoms and describe PASC frequencies across cohorts, vaccination status, and number of infections. Design, Setting, and Participants: Prospective observational cohort study of adults with and without SARS-CoV-2 infection at 85 enrolling sites (hospitals, health centers, community organizations) located in 33 states plus Washington, DC, and Puerto Rico. Participants who were enrolled in the RECOVER adult cohort before April 10, 2023, completed a symptom survey 6 months or more after acute symptom onset or test date. Selection included population-based, volunteer, and convenience sampling. Exposure: SARS-CoV-2 infection. Main Outcomes and Measures: PASC and 44 participant-reported symptoms (with severity thresholds). Results: A total of 9764 participants (89% SARS-CoV-2 infected; 71% female; 16% Hispanic/Latino; 15% non-Hispanic Black; median age, 47 years [IQR, 35-60]) met selection criteria. Adjusted odds ratios were 1.5 or greater (infected vs uninfected participants) for 37 symptoms. Symptoms contributing to PASC score included postexertional malaise, fatigue, brain fog, dizziness, gastrointestinal symptoms, palpitations, changes in sexual desire or capacity, loss of or change in smell or taste, thirst, chronic cough, chest pain, and abnormal movements. Among 2231 participants first infected on or after December 1, 2021, and enrolled within 30 days of infection, 224 (10% [95% CI, 8.8%-11%]) were PASC positive at 6 months. Conclusions and Relevance: A definition of PASC was developed based on symptoms in a prospective cohort study. As a first step to providing a framework for other investigations, iterative refinement that further incorporates other clinical features is needed to support actionable definitions of PASC.

This document provides clinical recommendations for treatment of chronic obstructive pulmonary disease (COPD) exacerbations.Comprehensive evidence syntheses, including meta-analyses, were performed to summarise all available evidence relevant to the Task Force's questions. The evidence was appraised using the Grading of Recommendations, Assessment, Development and Evaluation approach and the results were summarised in evidence profiles. The evidence syntheses were discussed and recommendations formulated by a multidisciplinary Task Force of COPD experts.After considering the balance of desirable and undesirable consequences, quality of evidence, feasibility, and acceptability of various interventions, the Task Force made: 1) a strong recommendation for noninvasive mechanical ventilation of patients with acute or acute-on-chronic respiratory failure; 2) conditional recommendations for oral corticosteroids in outpatients, oral rather than intravenous corticosteroids in hospitalised patients, antibiotic therapy, home-based management, and the initiation of pulmonary rehabilitation within 3 weeks after hospital discharge; and 3) a conditional recommendation against the initiation of pulmonary rehabilitation during hospitalisation.The Task Force provided recommendations related to corticosteroid therapy, antibiotic therapy, noninvasive mechanical ventilation, home-based management, and early pulmonary rehabilitation in patients having a COPD exacerbation. These recommendations should be reconsidered as new evidence becomes available.

OBJECTIVE: Impaired awareness of hypoglycemia (IAH) and severe hypoglycemic events (SHEs) cause substantial morbidity and mortality in patients with type 1 diabetes (T1D). Current therapies are effective in preventing SHEs in 50-80% of patients with IAH and SHEs, leaving a substantial number of patients at risk. We evaluated the effectiveness and safety of a standardized human pancreatic islet product in subjects in whom IAH and SHEs persisted despite medical treatment. RESEARCH DESIGN AND METHODS: This multicenter, single-arm, phase 3 study of the investigational product purified human pancreatic islets (PHPI) was conducted at eight centers in North America. Forty-eight adults with T1D for >5 years, absent stimulated C-peptide, and documented IAH and SHEs despite expert care were enrolled. Each received immunosuppression and one or more transplants of PHPI, manufactured on-site under good manufacturing practice conditions using a common batch record and standardized lot release criteria and test methods. The primary end point was the achievement of HbA1c <7.0% (53 mmol/mol) at day 365 and freedom from SHEs from day 28 to day 365 after the first transplant. RESULTS: The primary end point was successfully met by 87.5% of subjects at 1 year and by 71% at 2 years. The median HbA1c level was 5.6% (38 mmol/mol) at both 1 and 2 years. Hypoglycemia awareness was restored, with highly significant improvements in Clarke and HYPO scores (P > 0.0001). No study-related deaths or disabilities occurred. Five of the enrollees (10.4%) experienced bleeds requiring transfusions (corresponding to 5 of 75 procedures), and two enrollees (4.1%) had infections attributed to immunosuppression. Glomerular filtration rate decreased significantly on immunosuppression, and donor-specific antibodies developed in two patients. CONCLUSIONS: Transplanted PHPI provided glycemic control, restoration of hypoglycemia awareness, and protection from SHEs in subjects with intractable IAH and SHEs. Safety events occurred related to the infusion procedure and immunosuppression, including bleeding and decreased renal function. Islet transplantation should be considered for patients with T1D and IAH in whom other, less invasive current treatments have been ineffective in preventing SHEs.

PURPOSE: To develop an evidence-based clinical practice guideline to assist in clinical decision making for patients with advanced hepatocellular carcinoma (HCC). METHODS: ASCO convened an Expert Panel to conduct a systematic review of published phase III randomized controlled trials (2007-2020) on systemic therapy for advanced HCC and provide recommended care options for this patient population. RESULTS: Nine phase III randomized controlled trials met the inclusion criteria. RECOMMENDATIONS: Atezolizumab + bevacizumab (atezo + bev) may be offered as first-line treatment of most patients with advanced HCC, Child-Pugh class A liver disease, Eastern Cooperative Oncology Group Performance Status (ECOG PS) 0-1, and following management of esophageal varices, when present, according to institutional guidelines. Where there are contraindications to atezolizumab and/or bevacizumab, tyrosine kinase inhibitors sorafenib or lenvatinib may be offered as first-line treatment of patients with advanced HCC, Child-Pugh class A liver disease, and ECOG PS 0-1. Following first-line treatment with atezo + bev, and until better data are available, second-line therapy with a tyrosine kinase inhibitor may be recommended for appropriate candidates. Following first-line therapy with sorafenib or lenvatinib, second-line therapy options for appropriate candidates include cabozantinib, regorafenib for patients who previously tolerated sorafenib, or ramucirumab (for patients with α-fetoprotein ≥ 400 ng/mL), or atezo + bev where patients did not have access to this option as first-line therapy. Pembrolizumab or nivolumab are also reasonable options for appropriate patients following sorafenib or lenvatinib. Consideration of nivolumab + ipilimumab as an option for second-line therapy and third-line therapy is discussed. Further guidance on choosing between therapy options is included within the guideline. Additional information is available at www.asco.org/gastrointestinal-cancer-guidelines.

Hepatocellular carcinoma (HCC) cells are metabolically distinct from normal hepatocytes by expressing the high-affinity hexokinase (HK2) and suppressing glucokinase (GCK). This is exploited to selectively target HCC. Hepatic HK2 deletion inhibits tumor incidence in a mouse model of hepatocarcinogenesis. Silencing HK2 in human HCC cells inhibits tumorigenesis and increases cell death, which cannot be restored by GCK or mitochondrial binding deficient HK2. Upon HK2 silencing, glucose flux to pyruvate and lactate is inhibited, but TCA fluxes are maintained. Serine uptake and glycine secretion are elevated suggesting increased requirement for one-carbon contribution. Consistently, vulnerability to serine depletion increases. The decrease in glycolysis is coupled to elevated oxidative phosphorylation, which is diminished by metformin, further increasing cell death and inhibiting tumor growth. Neither HK2 silencing nor metformin alone inhibits mTORC1, but their combination inhibits mTORC1 in an AMPK-independent and REDD1-dependent mechanism. Finally, HK2 silencing synergizes with sorafenib to inhibit tumor growth.

Minimal clinically important difference (MCID) scores are commonly used by clinicians when determining patient response to treatment and to guide clinical decision-making during the course of treatment. For research purposes, the MCID score is often used in sample size calculations for adequate powering of a study to minimize the false-positives (type 1 errors) and the false-negatives (type 2 errors). For clinicians and researchers alike, it is critical that the MCID score is a valid and stable measure. A low MCID value may result in overestimating the positive effects of treatment, whereas a high MCID value may incorrectly classify patients as failing to respond to treatment when in fact the treatment was beneficial. The wide range of methodologies for calculating the MCID score results in varied outcomes, which leads to difficulties with interpretation and application. This clinimetrics corner outlines key factors influencing MCID estimates and discusses limitations with the use of the MCID in both clinical and research practice settings.

Importance: Parkinson disease is a progressive neurologic disorder. Limited evidence suggests endurance exercise modifies disease severity, particularly high-intensity exercise. Objectives: To examine the feasibility and safety of high-intensity treadmill exercise in patients with de novo Parkinson disease who are not taking medication and whether the effect on motor symptoms warrants a phase 3 trial. Design, Setting, and Participants: The Study in Parkinson Disease of Exercise (SPARX) was a phase 2, multicenter randomized clinical trial with 3 groups and masked assessors. Individuals from outpatient and community-based clinics were enrolled from May 1, 2012, through November 30, 2015, with the primary end point at 6 months. Individuals with idiopathic Parkinson disease (Hoehn and Yahr stages 1 or 2) aged 40 to 80 years within 5 years of diagnosis who were not exercising at moderate intensity greater than 3 times per week and not expected to need dopaminergic medication within 6 months participated in this study. A total of 384 volunteers were screened by telephone; 128 were randomly assigned to 1 of 3 groups (high-intensity exercise, moderate-intensity exercise, or control). Interventions: High-intensity treadmill exercise (4 days per week, 80%-85% maximum heart rate [n = 43]), moderate-intensity treadmill exercise (4 days per week, 60%-65% maximum heart rate [n = 45]), or wait-list control (n = 40) for 6 months. Main Outcomes and Measures: Feasibility measures were adherence to prescribed heart rate and exercise frequency of 3 days per week and safety. The clinical outcome was 6-month change in Unified Parkinson's Disease Rating Scale motor score. Results: A total of 128 patients were included in the study (mean [SD] age, 64 [9] years; age range, 40-80 years; 73 [57.0%] male; and 108 [84.4%] non-Hispanic white). Exercise rates were 2.8 (95% CI, 2.4-3.2) days per week at 80.2% (95% CI, 78.8%-81.7%) maximum heart rate in the high-intensity group and 3.2 (95% CI, 2.8-3.6; P = .13) days per week at 65.9% (95% CI, 64.2%-67.7%) maximum heart rate in the moderate-intensity group (P < .001). The mean change in Unified Parkinson's Disease Rating Scale motor score in the high-intensity group was 0.3 (95% CI, -1.7 to 2.3) compared with 3.2 (95% CI, 1.4 to 5.1) in the usual care group (P = .03). The high-intensity group, but not the moderate-intensity group, reached the predefined nonfutility threshold compared with the control group. Anticipated adverse musculoskeletal events were not severe. Conclusions and Relevance: High-intensity treadmill exercise may be feasible and prescribed safely for patients with Parkinson disease. An efficacy trial is warranted to determine whether high-intensity treadmill exercise produces meaningful clinical benefits in de novo Parkinson disease. Trial Registration: clinicaltrials.gov Identifier: NCT01506479.

Importance: Coronary artery calcification (CAC) is highly prevalent in dialysis-naive patients with chronic kidney disease (CKD). However, there are sparse data on the association of CAC with subsequent risk of cardiovascular disease and all-cause mortality in this population. Objective: To study the prospective association of CAC with risk of cardiovascular disease and all-cause mortality among dialysis-naive patients with CKD. Design, Setting, and Participants: The prospective Chronic Renal Insufficiency Cohort study recruited adults with an estimated glomerular filtration rate of 20 to 70 mL/min/1.73 m2 from 7 clinical centers in the United States. There were 1541 participants without cardiovascular disease at baseline who had CAC scores. Exposures: Coronary artery calcification was assessed using electron-beam or multidetector computed tomography. Main Outcomes and Measures: Incidence of cardiovascular disease (including myocardial infarction, heart failure, and stroke) and all-cause mortality were reported every 6 months and confirmed by medical record adjudication. Results: During an average follow-up of 5.9 years in 1541 participants aged 21 to 74 years, there were 188 cardiovascular disease events (60 cases of myocardial infarction, 120 heart failures, and 27 strokes; patients may have had >1 event) and 137 all-cause deaths. In Cox proportional hazards models adjusted for age, sex, race, clinical site, education level, physical activity, total cholesterol level, high-density lipoprotein cholesterol level, systolic blood pressure, use of antihypertensive treatment, current cigarette smoking, diabetes status, body mass index, C-reactive protein level, hemoglobin A1c level, phosphorus level, troponin T level, log N-terminal pro-B-type natriuretic peptide level, fibroblast growth factor 23 level, estimated glomerular filtration rate, and proteinuria, the hazard ratios associated with per 1 SD log of CAC were 1.40 (95% CI, 1.16-1.69; P < .001) for cardiovascular disease, 1.44 (95% CI, 1.02-2.02; P = .04) for myocardial infarction, 1.39 (95% CI, 1.10-1.76; P = .006) for heart failure, and 1.19 (95% CI, 0.94-1.51; P = .15) for all-cause mortality. In addition, inclusion of CAC score led to an increase in the C statistic of 0.02 (95% CI, 0-0.09; P < .001) for predicting cardiovascular disease over use of all the above-mentioned established and novel cardiovascular disease risk factors. Conclusions and Relevance: Coronary artery calcification is independently and significantly related to the risks of cardiovascular disease, myocardial infarction, and heart failure in patients with CKD. In addition, CAC improves risk prediction for cardiovascular disease, myocardial infarction, and heart failure over use of established and novel cardiovascular disease risk factors among patients with CKD; however, the changes in the C statistic are small.

The American Joint Committee on Cancer (AJCC) has increasingly recognized the need for more personalized probabilistic predictions than those delivered by ordinal staging systems, particularly through the use of accurate risk models or calculators. However, judging the quality and acceptability of a risk model is complex. The AJCC Precision Medicine Core conducted a 2-day meeting to discuss characteristics necessary for a quality risk model in cancer patients. More specifically, the committee established inclusion and exclusion criteria necessary for a risk model to potentially be endorsed by the AJCC. This committee reviewed and discussed relevant literature before creating a checklist unique to this need of AJCC risk model endorsement. The committee identified 13 inclusion and 3 exclusion criteria for AJCC risk model endorsement in cancer. The emphasis centered on performance metrics, implementation clarity, and clinical relevance. The facilitation of personalized probabilistic predictions for cancer patients holds tremendous promise, and these criteria will hopefully greatly accelerate this process. Moreover, these criteria might be useful for a general audience when trying to judge the potential applicability of a published risk model in any clinical domain. CA Cancer J Clin 2016;66:370-374. © 2016 American Cancer Society.

Spine surgery has experienced much technological innovation over the past several decades. The field has seen advancements in operative techniques, implants and biologics, and equipment such as computer-assisted navigation and surgical robotics. With the arrival of real-time image guidance and navigation capabilities along with the computing ability to process and reconstruct these data into an interactive three-dimensional spinal "map", so too have the applications of surgical robotic technology. While spinal robotics and navigation represent promising potential for improving modern spinal surgery, it remains paramount to demonstrate its superiority as compared to traditional techniques prior to assimilation of its use amongst surgeons.The applications for intraoperative navigation and image-guided robotics have expanded to surgical resection of spinal column and intradural tumors, revision procedures on arthrodesed spines, and deformity cases with distorted anatomy. Additionally, these platforms may mitigate much of the harmful radiation exposure in minimally invasive surgery to which the patient, surgeon, and ancillary operating room staff are subjected.Spine surgery relies upon meticulous fine motor skills to manipulate neural elements and a steady hand while doing so, often exploiting small working corridors utilizing exposures that minimize collateral damage. Additionally, the procedures may be long and arduous, predisposing the surgeon to both mental and physical fatigue. In light of these characteristics, spine surgery may actually be an ideal candidate for the integration of navigation and robotic-assisted procedures.With this paper, we aim to critically evaluate the current literature and explore the options available for intraoperative navigation and robotic-assisted spine surgery.

BACKGROUND: Treatment of chronic diseases such as chronic obstructive pulmonary disease (COPD) is complicated by the presence of comorbidities. The objective of this analysis was to estimate the prevalence of comorbidity in COPD using nationally-representative data. METHODS: This study draws from a multi-year analytic sample of 14,828 subjects aged 45+, including 995 with COPD, from the National Health and Nutrition Examination Survey (NHANES), 1999-2008. COPD was defined by self-reported physician diagnosis of chronic bronchitis or emphysema; patients who reported a diagnosis of asthma were excluded. Using population weights, we estimated the age-and-gender-stratified prevalence of 22 comorbid conditions that may influence COPD and its treatment. RESULTS: Subjects 45+ with physician-diagnosed COPD were more likely than subjects without physician-diagnosed COPD to have coexisting arthritis (54.6% vs. 36.9%), depression (20.6% vs. 12.5%), osteoporosis (16.9% vs. 8.5%), cancer (16.5% vs. 9.9%), coronary heart disease (12.7% vs. 6.1%), congestive heart failure (12.1% vs. 3.9%), and stroke (8.9% vs. 4.6%). Subjects with COPD were also more likely to report mobility difficulty (55.6% vs. 32.5%), use of >4 prescription medications (51.8% vs. 32.1), dizziness/balance problems (41.1% vs. 23.8%), urinary incontinence (34.9% vs. 27.3%), memory problems (18.5% vs. 8.8%), low glomerular filtration rate (16.2% vs. 10.5%), and visual impairment (14.0% vs. 9.6%). All reported comparisons have p < 0.05. CONCLUSIONS: Our study indicates that COPD management may need to take into account a complex spectrum of comorbidities. This work identifies which conditions are most common in a nationally-representative set of COPD patients (physician-diagnosed), a necessary step for setting research priorities and developing clinical practice guidelines that address COPD within the context of comorbidity.

Diagnostic computed tomography (CT) scans provide numerous opportunities for body composition analysis, including quantification of abdominal circumference, abdominal adipose tissues (subcutaneous, visceral, and intermuscular), and skeletal muscle (SM). CT scans are commonly performed for diagnostic purposes in clinical settings, and methods for estimating abdominal circumference and whole-body SM mass from them have been reported. A supine abdominal circumference is a valid measure of waist circumference (WC). The valid correlation between a single cross-sectional CT image (slice) at third lumbar (L3) for abdominal SM and whole-body SM is also well established. Sarcopenia refers to the age-associated decreased in muscle mass and function. A single dimensional definition of sarcopenia using CT images that includes only assessment of low whole-body SM has been validated in clinical populations and significantly associated with negative outcomes. However, despite the availability and precision of SM data from CT scans and the relationship between these measurements and clinical outcomes, they have not become a routine component of clinical nutrition assessment. Lack of time, training, and expense are potential barriers that prevent clinicians from fully embracing this technique. This tutorial presents a systematic, step-by-step guide to quickly quantify abdominal circumference as a proxy for WC and SM using a cross-sectional CT image from a regional diagnostic CT scan for clinical identification of sarcopenia. Multiple software options are available, but this tutorial uses ImageJ, a free public-domain software developed by the National Institutes of Health.

Angiogenesis, or new blood vessel growth, is a key process in the development of synovial inflammation in rheumatoid arthritis (RA). Integral to this pathologic proliferation are proinflammatory cytokines. We hypothesized a role for IL-18 as an angiogenic mediator in RA. We examined the effect of human IL-18 on human microvascular endothelial cell (HMVEC) migration. IL-18 induced HMVEC migration at 1 nM (p < 0.05). RA synovial fluids potently induced endothelial cell migration, but IL-18 immunodepletion resulted in a 68 +/- 5% decrease in HMVEC migration (p < 0.05). IL-18 appears to act on HMVECs via alpha(v)beta(3) integrin. To test whether IL-18 induced endothelial cell tube formation in vitro, we quantitated the degree of tube formation on Matrigel matrix. IL-18, 1 or 10 nM, resulted in a 77% or 87% increase in tube formation compared with control (p < 0.05). To determine whether IL-18 may be angiogenic in vivo, we implanted IL-18 in Matrigel plugs in mice, and IL-18 at 1 and 10 nM induced angiogenesis (p < 0.05). The angiogenesis observed appears to be independent of the contribution of local TNF-alpha, as evidenced by adding neutralizing anti-TNF-alpha Ab to the Matrigel plugs. In an alternative in vivo model, sponges embedded with IL-18 or control were implanted into mice. IL-18 (10 nM) induced a 4-fold increase in angiogenesis vs the control (p < 0.05). These findings support a novel function for IL-18 as an angiogenic factor in RA and may elucidate a potential therapeutic target for angiogenesis-directed diseases.

IMPORTANCE: To effectively guide interventions aimed at reducing mortality in low-volume hospitals, the underlying mechanisms of the volume-outcome relationship must be further explored. Reducing mortality after major postoperative complications may represent one point along the continuum of patient care that could significantly affect overall hospital mortality. OBJECTIVE: To determine whether increased mortality at low-volume hospitals performing cardiovascular surgery is a function of higher postoperative complication rates or of less successful rescue from complications. DESIGN, SETTING, AND PARTICIPANTS: We used patient-level data from 119434 Medicare fee-for-service beneficiaries aged 65 to 99 years undergoing coronary artery bypass grafting, aortic valve repair, or abdominal aortic aneurysm repair between January 1, 2005, and December 31, 2006. For each operation, we first divided hospitals into quintiles of procedural volume. We then assessed hospital risk-adjusted rates of mortality, major complications, and failure to rescue (ie, case fatality among patients with complications) within each volume quintile. EXPOSURE: Hospital procedural volume. MAIN OUTCOMES AND MEASURES: Hospital rates of risk-adjusted mortality, major complications, and failure to rescue. RESULTS: For each operation, hospital volume was more strongly related to failure-to-rescue rates than to complication rates. For example, patients undergoing aortic valve replacement at very low-volume hospitals (lowest quintile) were 12% more likely to have a major complication than those at very high-volume hospitals (highest quintile) but were 57% more likely to die if a complication occurred. CONCLUSIONS AND RELEVANCE: High-volume and low-volume hospitals performing cardiovascular surgery have similar complication rates but disparate failure-to-rescue rates. While preventing complications is important, hospitals should also consider interventions aimed at quickly recognizing and managing complications once they occur.

RATIONALE: Microvascular inflammation and endothelial dysfunction secondary to unchecked activation of endothelium play a critical role in the pathophysiology of sepsis and organ failure. The intrinsic signaling mechanisms responsible for dampening excessive activation of endothelial cells are not completely understood. OBJECTIVE: To determine the central role of YAP (Yes-associated protein), the major transcriptional coactivator of the Hippo pathway, in modulating the strength and magnitude of endothelial activation and vascular inflammation. METHODS AND RESULTS: Endothelial-specific YAP knockout mice showed increased basal expression of E-selectin and ICAM (intercellular adhesion molecule)-1 in endothelial cells, a greater number of adherent neutrophils in postcapillary venules and increased neutrophil counts in bronchoalveolar lavage fluid. Lipopolysaccharide challenge of these mice augmented NF-κB (nuclear factor-κB) activation, expression of endothelial adhesion proteins, neutrophil and monocyte adhesion to cremaster muscle venules, transendothelial neutrophil migration, and lung inflammatory injury. Deletion of YAP in endothelial cells also markedly augmented the inflammatory response and cardiovascular dysfunction in a polymicrobial sepsis model induced by cecal ligation and puncture. YAP functioned by interacting with the E3 ubiquitin-protein ligase TLR (Toll-like receptor) signaling adaptor TRAF6 (tumor necrosis factor receptor-associated factor 6) to ubiquitinate TRAF6, and thus promoted TRAF6 degradation and modification resulting in inhibition of NF-κB activation. TRAF6 depletion in endothelial cells rescued the augmented inflammatory phenotype in mice with endothelial cell-specific deletion of YAP. CONCLUSIONS: YAP modulates the activation of endothelial cells and suppresses vascular inflammation through preventing TRAF6-mediated NF-κB activation and is hence essential for limiting the severity of sepsis-induced inflammation and organ failure.

The Prechtl General Movement Assessment (GMA) has become a cornerstone assessment in early identification of cerebral palsy (CP), particularly during the fidgety movement period at 3–5 months of age. Additionally, assessment of motor repertoire, such as antigravity movements and postural patterns, which form the Motor Optimality Score (MOS), may provide insight into an infant’s later motor function. This study aimed to identify early specific markers for ambulation, gross motor function (using the Gross Motor Function Classification System, GMFCS), topography (unilateral, bilateral), and type (spastic, dyskinetic, ataxic, and hypotonic) of CP in a large worldwide cohort of 468 infants. We found that 95% of children with CP did not have fidgety movements, with 100% having non-optimal MOS. GMFCS level was strongly correlated to MOS. An MOS &gt; 14 was most likely associated with GMFCS outcomes I or II, whereas GMFCS outcomes IV or V were hardly ever associated with an MOS &gt; 8. A number of different movement patterns were associated with more severe functional impairment (GMFCS III–V), including atypical arching and persistent cramped-synchronized movements. Asymmetrical segmental movements were strongly associated with unilateral CP. Circular arm movements were associated with dyskinetic CP. This study demonstrated that use of the MOS contributes to understanding later CP prognosis, including early markers for type and severity.

RATIONALE: Relationships between chronic health conditions and acute infections remain poorly understood. Preclinical studies suggest crosstalk between nervous and immune systems. OBJECTIVES: To determine bidirectional relationships between cognition and pneumonia. METHODS: We conducted longitudinal analyses of a population-based cohort over 10 years. We determined whether changes in cognition increase risk of pneumonia hospitalization by trajectory analyses and joint modeling. We then determined whether pneumonia hospitalization increased risk of subsequent dementia using a Cox model with pneumonia as a time-varying covariate. MEASUREMENTS AND MAIN RESULTS: Of the 5,888 participants, 639 (10.9%) were hospitalized with pneumonia at least once. Most participants had normal cognition before pneumonia. Three cognition trajectories were identified: no, minimal, and severe rapid decline. A greater proportion of participants hospitalized with pneumonia were on trajectories of minimal or severe decline before occurrence of pneumonia compared with those never hospitalized with pneumonia (proportion with no, minimal, and severe decline were 67.1%, 22.8%, and 10.0% vs. 76.0%, 19.3%, and 4.6% for participants with and without pneumonia, respectively; P < 0.001). Small subclinical changes in cognition increased risk of pneumonia, even in those with normal cognition and physical function before pneumonia (β = -0.02; P < 0.001). Participants with pneumonia were subsequently at an increased risk of dementia (hazard ratio, 2.24 [95% confidence interval, 1.62-3.11]; P = 0.01). Associations were independent of demographics, health behaviors, other chronic conditions, and physical function. Bidirectional relationship did not vary based on severity of disease, and similar associations were noted for those with severe sepsis and other infections. CONCLUSIONS: A bidirectional relationship exists between pneumonia and cognition and may explain how a single episode of infection in well-appearing older individuals accelerates decline in chronic health conditions and loss of functional independence.

Quality of life (QOL) considerations are important in the treatment decision making process for prostate cancer patients. Although patient involvement in the treatment decision process has been encouraged, low health literacy can limit patient understanding of the complex information about treatments and their probable QOL outcomes and is a barrier to patient participation in the decision-making process. The objectives of the study were to evaluate (i) knowledge, level of satisfaction, and treatment preferences and intentions of men newly diagnosed with prostate cancer after participation in a CD-ROM shared decision making program; and (ii) the relationship between prostate cancer knowledge and health literacy. Thirty newly diagnosed prostate cancer patients from two Veteran's Administration (VA) hospitals in Chicago completed a demographic questionnaire and participated in an interactive CD-ROM shared decision making program. Subsequently, knowledge of prostate cancer, satisfaction with the information in the computer CD-ROM program, treatment preferences, and likelihood of following treatment preferences were assessed using interviewer-administered questionnaires. Health literacy was assessed using the Rapid Estimate of Adult Literacy in Medicine (REALM). The Pearson correlation test was used to assess the relationship between health literacy and prostate cancer knowledge. The chi2 test and the Fischer exact test were used to evaluate relationships between patient demographics and other variables. More than three-quarters of the patients rated the information in the CD-ROM as "very satisfactory" (highest possible rating). Two-thirds of the patients (21 of 30) selected a treatment after participation in the CD-ROM program and 90.5% of these patients stated that they were very or somewhat likely to adhere to their selection. However, prostate cancer knowledge was variable, with one-third of the patients scoring 69.9% or lower. Participants' health literacy was equivalent to a 7th-8th grade reading level (mean = 57.1+/-10.9), and more than one-third of participants (36.7%) had lower than 9th grade literacy levels. Participants' prostate cancer knowledge was correlated with health literacy (Pearson correlation rhor = 0.65, rhop = 0.0001). Patients were satisfied with the interactive shared decision making CD-ROM program, and two-thirds of patients were able to select a preferred treatment based on the information presented in the program that they intended to follow. However, prostate cancer knowledge scores varied among participants after participation in the CD-ROM program, raising doubts that patients were adequately informed to make appropriate choices regarding their treatment. Lower prostate cancer knowledge scores corresponded to lower literacy scores, indicating that low literacy may have hindered patient understanding of the shared decision making program. The development of shared decision making tools should include collaborative efforts with the target population to improve the success of shared decision making programs among patients with low health literacy.

BACKGROUND: Twice-yearly subcutaneous lenacapavir has been shown to be efficacious for prevention of human immunodeficiency virus (HIV) infection in cisgender women. The efficacy of lenacapavir for preexposure prophylaxis (PrEP) in cisgender men, transgender women, transgender men, and gender-nonbinary persons is unclear. METHODS: In this phase 3, double-blind, randomized, active-controlled trial, we randomly assigned participants in a 2:1 ratio to receive subcutaneous lenacapavir every 26 weeks or daily oral emtricitabine-tenofovir disoproxil fumarate (F/TDF). The primary efficacy analysis compared the incidence of HIV infection in the lenacapavir group with the background HIV incidence in the screened population. The secondary efficacy analysis compared the incidence of HIV infection in the lenacapavir group with that in the F/TDF group. RESULTS: Among 3265 participants who were included in the modified intention-to-treat analysis, HIV infections occurred in 2 participants in the lenacapavir group (0.10 per 100 person-years; 95% confidence interval [CI], 0.01 to 0.37) and in 9 participants in the F/TDF group (0.93 per 100 person-years; 95% CI, 0.43 to 1.77). The background HIV incidence in the screened population (4634 participants) was 2.37 per 100 person-years (95% CI, 1.65 to 3.42). The incidence of HIV infection in the lenacapavir group was significantly lower than both the background incidence (incidence rate ratio, 0.04; 95% CI, 0.01 to 0.18; P<0.001) and the incidence in the F/TDF group (incidence rate ratio, 0.11; 95% CI, 0.02 to 0.51; P = 0.002). No safety concerns were identified. A total of 26 of 2183 participants (1.2%) in the lenacapavir group and 3 of 1088 (0.3%) in the F/TDF group discontinued the trial regimen because of injection-site reactions. CONCLUSIONS: The HIV incidence with twice-yearly lenacapavir was significantly lower than the background incidence and the incidence with F/TDF. (Funded by Gilead Sciences; PURPOSE 2 ClinicalTrials.gov number, NCT04925752.).

Eight manufacturing facilities participating in the National Institutes of Health-sponsored Clinical Islet Transplantation (CIT) Consortium jointly developed and implemented a harmonized process for the manufacture of allogeneic purified human pancreatic islet (PHPI) product evaluated in a phase 3 trial in subjects with type 1 diabetes. Manufacturing was controlled by a common master production batch record, standard operating procedures that included acceptance criteria for deceased donor organ pancreata and critical raw materials, PHPI product specifications, certificate of analysis, and test methods. The process was compliant with Current Good Manufacturing Practices and Current Good Tissue Practices. This report describes the manufacturing process for 75 PHPI clinical lots and summarizes the results, including lot release. The results demonstrate the feasibility of implementing a harmonized process at multiple facilities for the manufacture of a complex cellular product. The quality systems and regulatory and operational strategies developed by the CIT Consortium yielded product lots that met the prespecified characteristics of safety, purity, potency, and identity and were successfully transplanted into 48 subjects. No adverse events attributable to the product and no cases of primary nonfunction were observed.