Low copy numbers of complement C4 and C4A deficiency are risk factors for myositis, its subgroups and autoantibodies.

BACKGROUND: Idiopathic inflammatory myopathies (IIM) are a group of autoimmune diseases characterised by myositis-related autoantibodies plus infiltration of leucocytes into muscles and/or the skin, leading to the destruction of blood vessels and muscle fibres, chronic weakness and fatigue. While complement-mediated destruction of capillary endothelia is implicated in paediatric and adult dermatomyositis, the complex diversity of complement C4 in IIM pathology was unknown. METHODS: We elucidated the gene copy number (GCN) variations of total C4, C4A and C4B, long and short genes in 1644 Caucasian patients with IIM, plus 3526 matched healthy controls using real-time PCR or Southern blot analyses. Plasma complement levels were determined by single radial immunodiffusion. RESULTS: The large study populations helped establish the distribution patterns of various C4 GCN groups. Low GCNs of C4T (C4T=2+3) and C4A deficiency (C4A=0+1) were strongly correlated with increased risk of IIM with OR equalled to 2.58 (2.28-2.91), p=5.0×10-53 for C4T, and 2.82 (2.48-3.21), p=7.0×10-57 for C4A deficiency. Contingency and regression analyses showed that among patients with C4A deficiency, the presence of HLA-DR3 became insignificant as a risk factor in IIM except for inclusion body myositis (IBM), by which 98.2% had HLA-DR3 with an OR of 11.02 (1.44-84.4). Intragroup analyses of patients with IIM for C4 protein levels and IIM-related autoantibodies showed that those with anti-Jo-1 or with anti-PM/Scl had significantly lower C4 plasma concentrations than those without these autoantibodies. CONCLUSIONS: C4A deficiency is relevant in dermatomyositis, HLA-DRB1*03 is important in IBM and both C4A deficiency and HLA-DRB1*03 contribute interactively to risk of polymyositis.

Impact of an augmented intervention on self-regulatory, dietary and physical activity outcomes in a diabetes prevention trial among adults with prediabetes.

Self-regulation can facilitate modifications in lifestyle to promote behavioral change. However, little is known about whether adaptive interventions promote improvement in self-regulatory, dietary, and physical activity outcomes among slow treatment responders. A stratified design with an adaptive intervention for slow responders was implemented and evaluated. Adults ≥ 21 years old with prediabetes were stratified to the standard Group Lifestyle Balance intervention (GLB; n = 79) or the adaptive GLB Plus intervention (GLB + ; n = 105) based on first-month treatment response. Intake of total fat was the only study measure that significantly differed between groups at baseline (P = 0.0071). GLB reported greater improvement in self-efficacy for lifestyle behaviors, goal satisfaction with weight loss, and very active minutes of activity than GLB + (all P < 0.01) at 4-months. Both groups reported significant improvement in self-regulatory outcomes and reduction in energy and fat intake (all P < 0.01). An adaptive intervention can improve self-regulation and dietary intake when tailored to early slow treatment responders.

The Effect of Donepezil on Problem-solving Ability in Individuals With Amnestic Mild Cognitive Impairment: A Pilot Study.

BACKGROUND: Clinical trials involving individuals with mild cognitive impairment (MCI) have reported mixed results for the effects of cholinesterase inhibitors on cognitive outcomes. Our previous work demonstrated that a visuospatial problem-solving task was sensitive to non-memory impairments in individuals with MCI. OBJECTIVE: To determine whether the same task is also sensitive to the effects of cholinesterase inhibitors in individuals with amnestic MCI (aMCI). METHOD: We gave 22 individuals with aMCI (clinical dementia rating of 0.5) and Mini-Mental State Examination (MMSE) scores of at least 24 the following measures at baseline and at follow-up 1 year later: Hopkins Verbal Learning Test, Boston Naming Test, Rey Complex Figures Test copying task, anagrams task, and visuospatial problem-solving task. The MMSE was also given at the 1-year follow-up. Twelve of the individuals were drug naïve, having never taken cholinesterase inhibitors before, and donepezil was initiated and titrated to 10 mg daily after baseline in an open-label manner. Ten of the individuals had already been taking donepezil, and there was no change in treatment. We compared the two groups for amount of performance change over 1 year. RESULTS: Individuals for whom donepezil was initiated performed significantly better on the visuospatial problem-solving task after 1 year compared with individuals who had already been taking donepezil. No difference was observed for any of the other variables. CONCLUSION: The visuospatial problem-solving task appeared to be more sensitive than memory measures to the effects of cholinesterase inhibitors in individuals with aMCI, perhaps due to the high attentional demand of the task.

Urinary Soluble CD163: a Novel Noninvasive Biomarker of Activity for Lupus Nephritis.

BACKGROUND: Clinical distinction between patients with lupus nephritis who have active inflammation or chronic kidney damage is challenging. Studies have shown soluble CD163, which derives from cleavage of the CD163 M2c macrophage receptor and can be quantified in urine, correlates with active lupus nephritis. METHODS: We measured urine CD163 at lupus nephritis flares in patients from a Mexican cohort and cross-sectional and longitudinal United States cohorts. We also performed serial urine CD163 measurements during the treatment of flares in a subset of patients from the Mexican and longitudinal United States cohorts, and assessed response to therapy at 12 months. In addition, we evaluated urinary CD163 agreement with histologic activity in 19 patients from the Mexican cohort who had repeated kidney biopsies on follow-up. RESULTS: Urinary CD163 levels were significantly higher in patients with active lupus nephritis than in patients with active extrarenal SLE, inactive SLE, and other glomerular diseases, and correlated with disease clinical severity, histologic class, and the histologic activity index. Urinary CD163 increased from 6 months preflare to flare, diminishing progressively in complete and partial responders, whereas it remained elevated in nonresponders. Urinary CD163 <370 ng/mmol at 6 months predicted complete renal response at 12 months with >87% sensitivity and >87% specificity. Urinary CD163 <370 ng/mmol or >370 ng/mmol perfectly agreed (κ=1.0) with a histologic activity index ≤1 or >1 in repeated biopsies, respectively. Evaluation of urinary CD163 in patients with persistent proteinuria at 6 months improved the prediction of who would achieve complete renal response at 12 months. CONCLUSIONS: Urinary CD163 reflects histologic inflammation in lupus nephritis and is a promising activity biomarker that varies over time with lupus nephritis activity and treatment.

Kidney biopsy-based management of maintenance immunosuppression is safe and may ameliorate flare rate in lupus nephritis.

The optimal duration of maintenance immunosuppressive therapy for patients with lupus nephritis who have achieved clinical remission has not been established. Furthermore, clinical and histologic remissions are often discordant. We postulated that continuing therapy for patients with persistent histologic activity on kidney biopsies done during maintenance and discontinuing therapy only for patients without histologic activity would minimize subsequent lupus nephritis flares. To test this, a cohort of 75 prospectively-followed patients with proliferative lupus nephritis was managed using kidney biopsies performed during maintenance therapy. These patients had been on immunosuppression for at least 42 months, had responded, and had maintained their clinical response for at least 12 months before the kidney biopsy was repeated. Maintenance therapy was withdrawn if the biopsy showed an activity index of zero, but was continued if the biopsy showed an activity index of one or more. A lupus nephritis flare developed in seven patients during the average 50 months from the third biopsy and the final clinic visit for a flare rate of 1.5/year; significantly less than reported flare rates. Baseline clinical parameters (serum creatinine, proteinuria) and serologic parameters (complement C3, C4 and anti-dsDNA) did not predict an activity index of zero on the third biopsy or who would have a lupus nephritis flare. No patients developed end-stage kidney disease. Four patients developed de novo chronic kidney disease. There were no serious adverse events related to biopsy. Thus, at an experienced center, biopsy-informed management of maintenance immunosuppression is safe and may improve the lupus nephritis flare rate compared to conventional clinical management.

Immunostaining for galactose-deficient immunoglobulin A is not specific for primary immunoglobulin A nephropathy.

BACKGROUND: Primary immunoglobulin A nephropathy (IgAN) is characterized by IgA1-dominant or codominant glomerular deposits, postulated to be galactose deficient (Gd). However, glomerular IgA deposition can also occur in nonrenal diseases such as liver cirrhosis, psoriasis and inflammatory bowel disease ('secondary IgAN') or be an incidental finding in biopsies with other pathologies. A glomerulonephritis resembling IgAN can develop in patients with bacterial, mainly staphylococcal infections [staphylococcal infection-associated glomerulonephritis (SAGN)]. There are no specific histological features to distinguish between these, but differentiation is critical for appropriate management. The aim of this study was to investigate whether a recently described antibody to Gd-IgA1 (KM-55) could aid in differentiating primary IgAN from other conditions with glomerular IgA deposition, especially SAGN. METHODS: We performed a retrospective cohort study of patients who underwent kidney biopsy for clinical indications and were found to have glomerular IgA deposits. RESULTS: We evaluated 100 biopsies, including primary IgAN (n = 44), secondary IgAN (n = 27), SAGN (n = 13), incidental IgA deposition (n = 8) and lupus nephritis (n = 8). There was no difference in Gd-IgA staining intensity or the proportion of positive cases between primary and secondary IgAN. SAGN and cases with incidental IgA deposits had significantly lower Gd-IgA staining intensity than primary IgAN, but up to 69% of SAGN cases were positive (albeit weaker). CONCLUSIONS: Gd-IgA staining is present not only in primary IgAN, but also in biopsies with secondary IgAN, SAGN and incidental IgA. Weak or negative staining may favor SAGN, especially in the setting of infection, or incidental IgA in the absence of nephritic symptoms or in the presence of other unrelated glomerular pathologies. However, positive staining for Gd-IgA alone is not specific enough for a diagnosis of primary IgAN.

A prospective observational cohort study highlights kidney biopsy findings of lupus nephritis patients in remission who flare following withdrawal of maintenance therapy.

One of the most difficult management issues in lupus nephritis (LN) is the optimal duration of maintenance immunosuppression after patients are in clinical remission. Most patients receive immunosuppression for years, based mainly on expert opinion. Prospective data are unavailable. Complicating this issue are data that patients in clinical remission can still have histologically active LN; however, the implications of this are unknown. To study this, the Lupus Flares and Histological Renal Activity at the end of Treatment study (ClinicalTrial.gov, NCT02313974) was designed to examine whether residual histologic activity predisposes to LN flares in class III and IV LN. Patients in complete clinical remission for at least 12 months who had received at least 36 months of immunosuppression were eligible. Patients consented to a second kidney biopsy, were tapered off maintenance immunosuppression and were then followed prospectively for LN flares over 24 months. Forty-four patients were enrolled, and 36 completed the study. LN flares occurred in 11 patients, and ten of these had residual histologic activity on the second biopsy. All patients with an NIH activity index over two flared. The activity index and duration of systemic lupus erythematosus at the second biopsy were independent predictors of flare. A predictive equation based on these variables discriminated between flare and no flare with a sensitivity of 100%, specificity of 88%, and a misclassification rate of 8.3%. Thus, a repeat kidney biopsy may be useful in managing maintenance immunosuppression in LN, and patients in histologic remission may be candidates for withdrawal of therapy.

Odds ratios from logistic, geometric, Poisson, and negative binomial regression models.

BACKGROUND: The odds ratio (OR) is used as an important metric of comparison of two or more groups in many biomedical applications when the data measure the presence or absence of an event or represent the frequency of its occurrence. In the latter case, researchers often dichotomize the count data into binary form and apply the well-known logistic regression technique to estimate the OR. In the process of dichotomizing the data, however, information is lost about the underlying counts which can reduce the precision of inferences on the OR. METHODS: We propose analyzing the count data directly using regression models with the log odds link function. With this approach, the parameter estimates in the model have the exact same interpretation as in a logistic regression of the dichotomized data, yielding comparable estimates of the OR. We prove analytically, using the Fisher information matrix, that our approach produces more precise estimates of the OR than logistic regression of the dichotomized data. We also show the gains in precision using simulation studies and real-world datasets. We focus on three related distributions for count data: geometric, Poisson, and negative binomial. RESULTS: In simulation studies, confidence intervals for the OR were 56-65% as wide (geometric model), 75-79% as wide (Poisson model), and 61-69% as wide (negative binomial model) as the corresponding interval from a logistic regression produced by dichotomizing the data. When we analyzed existing datasets using our approach, we found that confidence intervals for the OR could be up to 64% shorter (36% as wide) compared to if the data had been dichotomized and analyzed using logistic regression. CONCLUSIONS: More precise estimates of the OR can be obtained directly from the count data by using the log odds link function. This analytic approach is easy to implement in software packages that are capable of fitting generalized linear models or of maximizing user-defined likelihood functions.

Hemolytic disease of the fetus and newborn due to multiple maternal antibodies.

OBJECTIVE: The objective of the study was to determine whether women with combinations of red blood cell antibodies are more likely to develop significant hemolytic disease of the fetus and newborn than those with single antibodies. STUDY DESIGN: A retrospective exposure cohort study was conducted of pregnant women with red blood cell antibodies. The development of significant hemolytic disease of the fetus and newborn was then compared between patients with single antibodies and those with multiple antibodies. Data analysis was limited to pregnancies delivering since the year 2000. RESULTS: Thirteen percent of the patients referred to our program had multiple red blood cell antibodies. Odds of developing significant hemolytic disease of the fetus and newborn for patients with anti-Rh(D) combined with at least 1 additional red blood cell antibody were 3.65 times the odds for women with anti-Rh(D) antibodies in isolation (95% confidence interval, 1.84-7.33). In the setting of multiple antibodies including anti-Rh(D), Rh-positive fetuses/neonates have an increased odds of developing significant hemolytic disease even if the fetus is negative for the other corresponding red blood cell antigen. CONCLUSION: Women with multiple red blood cell antibodies are more likely to develop significant hemolytic disease of the fetus and newborn than those with a single antibody especially in the presence of anti-(Rh)D. This pathophysiology may suggest a more aggressive immune response in women who develop more than 1 red blood cell antibody.

A Randomized Controlled Trial Translating the Diabetes Prevention Program to a University Worksite, Ohio, 2012-2014.

INTRODUCTION: Working adults spend much time at the workplace, an ideal setting for wellness programs targeting weight loss and disease prevention. Few randomized trials have evaluated the efficacy of worksite diabetes prevention programs. This study evaluated the efficacy of a worksite lifestyle intervention on metabolic and behavioral risk factors compared with usual care. METHODS: A pretest-posttest control group design with 3-month follow-up was used. Participants with prediabetes were recruited from a university worksite and randomized to receive a 16-week lifestyle intervention (n = 35) or usual care (n = 34). Participants were evaluated at baseline, postintervention, and 3-month follow-up. Dietary intake was measured by a food frequency questionnaire and level of physical activity by accelerometers. Repeated measures analysis of variance compared the change in outcomes between and within groups. RESULTS: Mean (standard error [SE]) weight loss was greater in the intervention (-5.5% [0.6%]) than in the control (-0.4% [0.5%]) group (P < .001) postintervention and was sustained at 3-month follow-up (P < .001). Mean (SE) reductions in fasting glucose were greater in the intervention (-8.6 [1.6] mg/dL) than in the control (-3.7 [1.6] mg/dL) group (P = .02) postintervention; both groups had significant glucose reductions at 3-month follow-up (P < .001). In the intervention group, the intake of total energy and the percentage of energy from all fats, saturated fats, and trans fats decreased, and the intake of dietary fiber increased (all P < .01) postintervention. CONCLUSION: The worksite intervention improved metabolic and behavioral risk factors among employees with prediabetes. The long-term impact on diabetes prevention and program sustainability warrant further investigation.

Community Cognitive Screening Using the Self-Administered Gerocognitive Examination (SAGE).

This study investigated the functionality of the Self-Administered Gerocognitive Examination (SAGE) for cognitive screening in community settings and examined its characteristics as a cognitive screening assessment tool. From 45 community events, 1,047 individuals over age 50 were screened with SAGE. Cognitive impairment was identified in 28%. Principal-component and correlation analysis indicate that SAGE is an internally-consistent test that is very well balanced, with language, cognition, visuospatial, executive, and memory domains. Community cognitive screening using SAGE was found to be feasible and efficient in diverse settings with both small and large groups.

Self-administered gerocognitive examination (SAGE) aids early detection of cognitive impairment at primary care provider visits.

Introduction: Current estimates indicate that up to 50-75% of dementia cases are undiagnosed at an early stage when treatments are most effective. Conducting robust accurate cognitive assessments can be time-consuming for providers and difficult to incorporate into a time-limited Primary Care Provider (PCP) visit. We wanted to compare PCP visits with and without using the self-administered SAGE to determine differences in identification rates of new cognitive disorders. Methods: Three hundred patients aged 65-89 without diagnosed cognitive disorders completing a non-acute office visit were enrolled (ClinicalTrials.gov identifier: NCT04063371). Two PCP offices conducted routine visits for 100 consecutive eligible patients each. One office used the SAGE in an additional 100 subjects and asked available informants about cognitive changes over the previous year. Chart reviews were conducted 60 days later. One-way analysis of variance and Fisher exact tests were used to compare the groups and outcomes. Results: When SAGE was utilized, the PCP documented the detection of new cognitive conditions/concerns six times (9% versus 1.5%) as often (p = 0.003). The detection rate was nearly 4-fold for those with cognitively impaired SAGE scores (p = 0.034). Patients having impaired SAGE score and informant concerns were 15-fold as likely to have new cognitive conditions/concerns documented (p = 0.0007). Among providers using SAGE, 86% would recommend SAGE to colleagues. Discussion: SAGE was easily incorporated into PCP visits and significantly increased identification of new cognitive conditions/concerns leading to new diagnoses, treatment, or management changes. The detection rate increased 15-fold for those with impaired SAGE scores combined with informant reports.

Tau isoform composition influences rate and extent of filament formation.

The risk of developing tauopathic neurodegenerative disease depends in part on the levels and composition of six naturally occurring Tau isoforms in human brain. These proteins, which form filamentous aggregates in disease, vary only by the presence or absence of three inserts encoded by alternatively spliced exons 2, 3, and 10 of the Tau gene (MAPT). To determine the contribution of alternatively spliced segments to Tau aggregation propensity, the aggregation kinetics of six unmodified, recombinant human Tau isoforms were examined in vitro using electron microscopy assay methods. Aggregation propensity was then compared at the level of elementary rate constants for nucleation and extension phases. We found that all three alternatively spliced segments modulated Tau aggregation but through differing kinetic mechanisms that could synergize or compete depending on sequence context. Overall, segments encoded by exons 2 and 10 promoted aggregation, whereas the segment encoded by exon 3 depressed it with its efficacy dependent on the presence or absence of a fourth microtubule binding repeat. In general, aggregation propensity correlated with genetic risk reported for multiple tauopathies, implicating aggregation as one candidate mechanism rationalizing the correlation between Tau expression patterns and disease.

Weight loss maintenance following an augmented intervention for early slow weight loss responders: An adaptive trial.

Early slow weight loss during treatment is associated with less weight loss overall. The impact of an augmented intervention designed for early slow weight loss responders compared with a standard diabetes prevention intervention was evaluated following 12 months of treatment and 6 months of no contact. The impact of standard vs. augmented intervention sequences on weight and glycemia also was determined. Adults were ≥21 years old with overweight or obesity and prediabetes (n = 174). Slow responders were stratified to augmented treatment if they failed to achieve >2.5% weight loss (%WL) at Week 5. Matched within-sex pairs of participants were created based on %WL at Month 5 following the intensive intervention phase, and each person within the pair was randomly assigned to treatment for Months 5-12 during the extended intervention phase. Both 12-month interventions included a ≥7%WL goal. Mean 12-month %WL was 5.29% (95% CI: 4.27%-6.31%; P < .0001) and 18-month %WL was 3.34% (95% CI: 2.01%-4.66%; P < .0001) overall. %WL was greater for the standard (9.55%) than the augmented (4.0%) intervention (P = .0001); no differences occurred in weight regain between early and slow responders (P = .9476). No differences occurred in mean %WL at 12 months between the standard and augmented groups after controlling for %WL at Week 5 and sex (P = .23) nor in the change in glycemia (all P > .05). WL following the first month of treatment predicted 12- and 18-month WL success regardless of intervention sequence; however, even early slow responders achieved significant WL during treatment. Further research is needed to support effective WL maintenance for people with prediabetes.

Weight loss is a primary strategy for risk reduction in adults with prediabetes, and early weight loss may indicate weight loss success long-term. Early slow weight loss responders during behavioral treatment may benefit from alternate treatment compared with remaining in a standard diabetes prevention program. An intervention augmented with training in goal setting and problem-solving was implemented among slow weight loss responders following the first month of treatment in the current study. The change in percent weight loss observed in the augmented intervention compared with the standard diabetes prevention intervention was determined at 12 and 18 months from baseline. Both the standard and augmented interventions facilitated significant weight loss at 12 months. Participants who lost more than 2.5% of their weight during the first month of treatment (early responders) lost more weight overall during the study compared with people who were slower to respond. Percent weight loss following the first month of lifestyle intervention and sex predicted percent weight loss at 12 months. Participants regained some weight at 18 months regardless of the treatment group but weighed less than their baseline weight. Both early and slow weight loss responders may benefit from ongoing support following 12 months of treatment to achieve weight loss maintenance.

Sex Differences in Early Weight Loss Success During a Diabetes Prevention Intervention.

Objectives: Males often lose more weight than females during treatment, and early weight loss predicts weight loss longer-term. Yet, mechanisms for sex differences in early weight loss are unknown and were examined in this study.Methods: Adults≥21 years old with overweight or obesity and prediabetes (N=206) participated in a lifestyle intervention and completed baseline psychosocial questionnaires. Percent weight loss, session attendance, and number of days participants self-monitored dietary intake and weight were determined at week 5. Principal components, regression, and mediation analyses were conducted to determine whether weight loss differed by sex and potential mediators of weight change. Results: Mean (±SD) weight loss was greater for males (2.59±1.62%) than females (2.05±1.54%; p=.02). Attendance, self-monitoring, and beliefs regarding disease risk were independent predictors of weight loss (all p<.05) but did not explain sex differences. The association between attendance and weight loss was stronger for males than females (p<.05). Conclusions: Additional research is needed to identify mechanisms that explain sex differences in early weight loss. However, strengthening risk beliefs, attendance, and self-monitoring may promote greater early weight loss for all participants.

Randomized intervention and outpatient follow-up lowers 30-d readmissions for patients with hepatic encephalopathy, decompensated cirrhosis.

BACKGROUND: We previously reported national 30-d readmission rates of 27% in patients with decompensated cirrhosis (DC). AIM: To study prospective interventions to reduce early readmissions in DC at our tertiary center. METHODS: Adults with DC admitted July 2019 to December 2020 were enrolled and randomized into the intervention (INT) or standard of care (SOC) arms. Weekly phone calls for a month were completed. In the INT arm, case managers ensured outpatient follow-up, paracentesis, and medication compliance. Thirty-day readmission rates and reasons were compared. RESULTS: Calculated sample size was not achieved due to coronavirus disease 2019; 240 patients were randomized into INT and SOC arms. 30-d readmission rate was 33.75%, 35.83% in the INT vs 31.67% in the SOC arm (P = 0.59). The top reason for 30-d readmission was hepatic encephalopathy (HE, 32.10%). There was a lower rate of 30-d readmissions for HE in the INT (21%) vs SOC arm (45%, P = 0.03). There were fewer 30-d readmissions in patients who attended early outpatient follow-up (n = 17, 23.61% vs n = 55, 76.39%, P = 0.04). CONCLUSION: Our 30-d readmission rate was higher than the national rate but reduced by interventions in patients with DC with HE and early outpatient follow-up. Development of interventions to reduce early readmission in patients with DC is needed.

Remission of lupus nephritis: the trajectory of histological response in successfully treated patients.

OBJECTIVE: This study investigated changes in kidney histology over time in patients with lupus nephritis (LN) undergoing immunosuppressive treatment. METHODS: Patients with proliferative±membranous LN were studied. After a diagnostic kidney biopsy (Bx1), patients had protocol biopsy 2 (Bx2) at 9 (6-15) months and protocol biopsy 3 (Bx3) at 42 (28-67) months. Kidney histological activity and chronicity indices (AI, CI) were measured. RESULTS: AI declined in a biphasic fashion, falling rapidly between Bx1 and Bx2 and then more slowly between Bx2 and Bx3. Patients were divided into those who achieved histological remission, defined as an AI=0 at Bx3 (group 1), and those with persistent histological activity (AI >0) at Bx3 (group 2). The early decline in AI was 1.6 times greater (95% CI 1.30, 1.91) in group 1 than group 2 (p=0.01). Between Bx2 and Bx3, the AI decline was 2.19-fold greater (95% CI 2.09, 2.29) in group 1 versus group 2 (p=7.34×10-5). Individual histological components of the AI resolved at different rates. Inflammatory lesions like glomerular crescents, karyorrhexis and necrosis mostly resolved by Bx2, whereas endocapillary hypercellularity, subendothelial hyaline deposits and interstitial inflammation resolved slowly, accounting for residual histological activity at biopsy 3 in group 2. In contrast, CI increased rapidly, by 0.15 units/month between Bx1 and Bx2, then plateaued. There were no differences in the rate of accumulation of chronic damage between group 1 and group 2. The increase in CI was significantly related to the severity of glomerular crescents (p=0.044), subendothelial hyaline deposits (p=0.002) and interstitial inflammation (p=0.015) at Bx1. CONCLUSIONS: LN histological activity takes months to years to resolve, providing a rationale for the need of long-term, well-tolerated maintenance immunosuppression. Despite responding, LN kidneys accrue chronic damage early during treatment. This finding provides an explanation for the association of chronic progressive kidney disease with recurrent episodes of LN.

A composite urine biomarker reflects interstitial inflammation in lupus nephritis kidney biopsies.

The initial treatment of lupus nephritis is usually based on a renal biopsy. Subsequent disease flares, however, are often treated without the benefit of kidney pathology because repeat biopsies are infrequent. A noninvasive, real-time method to assess renal pathology would be useful to adjust treatment and improve outcome. To develop such a method we collected urine samples at or close to the time of 64 biopsies from 61 patients with lupus nephritis to identify potential biomarkers of tubulointerstitial inflammation and correlated these to biopsy parameters scored by a renal pathologist using a semiquantitative scale. Linear discriminant analysis was used to weight variables and derive composite biomarkers that identified the level of tubulointerstitial inflammation based on urine concentrations of monocyte chemotactic protein-1, hepcidin (a marker of active lupus), and liver fatty acid-binding protein. The discriminant function that described the most accurate composite biomarkers included urine monocyte chemotactic protein-1 and serum creatinine as the independent variables. This composite had sensitivity, specificity, positive predictive value, and negative predictive value of 100, 81, 67, and 100%, respectively. Only 14% of the biopsies were misclassified. Thus, specific renal pathologic lesions can be modeled by composite biomarkers to noninvasively follow and adjust the treatment of lupus nephritis reflecting renal injury.

Managing concurrency in cyclical projects under stochastic task environments: Vaccine development projects during pandemics.

Aggressive overlapping of stochastic activities during phases of vaccine development has been critical to making effective vaccines for COVID-19 available to the public, at "pandemic" speed. In cyclical projects wherein activities can be overlapped, downstream tasks may need rework on account of having commenced prior to receiving requisite information that is only available upon completion of upstream task(s). We provide a framework to understand the interplay between stochastic overlap duration and rework due to overlap, and its impact on minimizing expected completion time for a cyclical project. We motivate the problem using the new paradigm for planning vaccine development projects. It best exemplifies features and scenarios in our model that were not considered and are also not apparent in the examples for cyclical development projects in the literature focused on engineered and manufactured products. We find that planning overlapping in scenarios that may be deemed ineffective with an assumption of deterministic tasks, can actually be beneficial when analyzed using stochastic task duration. We determine optimal planned start times for stochastic tasks as a function of a parameter that proxies for the extent of net gain/loss from overlap to minimize expected completion time for the project. We show that in situations with a net gain from overlap it is optimal to start the downstream task concurrently unless the downstream task does not stochastically dominate the upstream task and the net gain from overlap is not low enough. However, in situations with a net loss from overlap it is always optimal to have some degree of overlap in a stochastic task environment. We find that project rescheduling flexibility is always beneficial in a scenario with net loss from overlap and only beneficial in a scenario with net gain from overlap when the downstream task does not stochastically dominate the upstream task and the net gain from overlap is high enough. Our results on overlapping in 1-to-1, 1-to-n, and n-to-1 stochastic task configurations guide the development of an effective heuristic. Our heuristic offers good solution quality and is scalable to large networks as its computational complexity is linear in the number of tasks.

Impact of a Novel Diabetes Prevention Intervention for Early Slow Weight Loss Responders Among Adults With Prediabetes: An Adaptive Trial.

OBJECTIVE: Some people are slower to respond during lifestyle interventions. An adaptive "rescue" intervention may improve outcomes among slow responders. The impact of a worksite rescue intervention for early slow responders was evaluated. RESEARCH DESIGN AND METHODS: Employees ≥21 years old with prediabetes were stratified to intervention using a 2.5% weight loss (%WL) threshold at week 5. Outcomes were assessed at baseline and at 4 months using mixed-effect and linear regression models. RESULTS: Significant improvement occurred in mean %WL, glycemia, total cholesterol, and triglycerides in the standard compared with the adaptive (Group Lifestyle Balance Plus [GLB+]) intervention (all P≤ 0.01). However, GLB+ participants also experienced a significant reduction in %WL and glycemia (all P < 0.01). The %WL at week 5 significantly predicted %WL at 4 months (P < 0.0001). The between-group difference of 4-month %WL was not significant for someone achieving 2.5%WL at week 5. CONCLUSIONS: Diabetes prevention programs should consider weight loss success following 1 month of treatment and offer a rescue intervention to early slow weight loss responders.