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Purpose/objective(s)In oncology, retrospective cohort studies are often used for comparative effectiveness research, studies that compare the efficacy of treatment A vs B. We examine the stability of these estimates using biostatistical methods for bias correction with varying sets of covariates. We hypothesize that retrospective comparative effectiveness research studies are sensitive to biostatistical analytic choices; by varying the methods, there will be significant instability and lack of consistency in conclusions.Materials/methodsWe evaluated three disease sites in oncology where the addition of local therapy over systemic therapy alone has been hypothesized to improve survival in the metastatic setting: lung, prostate, and female breast, using multivariable Cox regression analyses. Patient data were extracted from the National Cancer Database, 2004-2014. We employed various statistical techniques to adjust for selection bias and immortal time bias, including propensity score matching, left truncation adjustment, and landmark analysis. Further, we used combinations of covariates in regression models to generate hazard ratios (HRs) with 95% confidence intervals. We constructed plots of -log10(P-value) vs HR to quantify the variability of estimates.ResultsThere were 72,549 lung, 14,904 prostate, and 13,857 female breast cancer patients included. We ran > 300,000 regression models, where each model represents a publishable study. Without propensity score matching or immortal time bias adjustment, all multivariable models provided HRs that favored the addition of local therapy for all cancers, with HRs < 1, and all P-values < 0.001. Once propensity score matching was added to our analysis, higher HRs were observed, but most were still < 1. When landmark analysis and covariate combinations were used, we generated HRs that were < 1, equal to 1, and > 1, with 100-fold differences in -log10(P-values).ConclusionBy altering the biostatistical approach with varying combinations of covariates, we were able to generate contrary outcomes and statistical significance. Our results suggest that some retrospective observational studies may find a treatment helps, and another may find it does not, simply based on analytic choices. This paradox highlights the importance of randomized controlled trials, and may explain the discordance noted in prior studies comparing observational trials and randomized studies.

Asthma is a chronic lung disease that has a high prevalence. The therapeutic intervention of this disease can be made more effective if genetic variability in patients' response to medications is implemented. However, a clear picture of the genetic architecture of asthma intervention response remains elusive. We conducted a genome-wide association study (GWAS) to identify drug response-associated genes for asthma, in which 909 622 SNPs were genotyped for 120 randomized participants who inhaled multiple doses of glucocorticoids. By integrating pharmacodynamic properties of drug reactions, we implemented a mechanistic model to analyze the GWAS data, enhancing the scope of inference about the genetic architecture of asthma intervention. Our pharmacodynamic model observed associations of genome-wide significance between dose-dependent response to inhaled glucocorticoids (measured as %FEV1) and five loci (P=5.315 × 10(-7) to 3.924 × 10(-9)), many of which map to metabolic genes related to lung function and asthma risk. All significant SNPs detected indicate a recessive effect, at which the homozygotes for the mutant alleles drive variability in %FEV1. Significant associations were well replicated in three additional independent GWAS studies. Pooled together over these three trials, two SNPs, chr6 rs6924808 and chr11 rs1353649, display an increased significance level (P=6.661 × 10(-16) and 5.670 × 10(-11)). Our study reveals a general picture of pharmacogenomic control for asthma intervention. The results obtained help to tailor an optimal dose for individual patients to treat asthma based on their genetic makeup.

Many women experience depressive symptoms after birth, and rates among African Americans are as high as 40 percent. Spirituality and religiosity are valued in African American communities, but their relevance to new mothers has not been empirically tested. We examined effects of religiosity and spirituality on trajectories of depressive symptoms during the year following childbirth. Data were collected by the Eunice Kennedy Shriver NICHD Community and Child Health Network (CCHN) focused on maternal-child health disparities. The sample consisted of 702 low SES African American predominantly Christian women. Participants were interviewed in their homes throughout the year following a birth. Spirituality and religiosity each independently predicted changes in depressive symptoms with low levels predicting increases over time. Effects of religiosity were mediated by a woman's spirituality. Religiosity and spirituality functioned as significant, interrelated protective factors in this study which provides novel insight about lower income African American women following birth.

BackgroundRegular use of inhaled beta-adrenergic agonists may have adverse effects in some asthma patients. Polymorphisms of the beta(2)-adrenergic receptor (beta(2)-AR) can affect its regulation; however, results of smaller studies of the effects of such polymorphisms on response to beta-agonist therapy have been inconsistent.MethodsWe examined the possible effects of polymorphisms at codons 16 (beta(2)-AR-16) and 27 (beta(2)-AR-27) on response to albuterol by genotyping 190 asthmatics who had participated in a trial of regular versus as-needed albuterol use.ResultsDuring the 16-week treatment period, patients homozygous for arginine (Arg/Arg) at beta(2)-AR-16 who used albuterol regularly had a small decline in morning peak expiratory flow (AM PEF). This effect was magnified during a 4-week run-out period, when all patients returned to as-needed albuterol only. By the end of the study, Arg/Arg subjects who had used albuterol regularly had an AM PEF 30.5 +/- 12.1 liters/min lower (p = 0.012) than Arg/Arg patients who had used albuterol as needed only. Subjects homozygous for glycine at beta(2)-AR-16 showed no such decline. Evening PEF also declined in the Arg/Arg regular but not in as-need albuterol users. No significant differences between regular and as-needed treatment were associated with polymorphisms at beta(2)-AR-27.ConclusionsPolymorphisms of the beta(2)-AR may influence airway responses to regular inhaled beta-agonist treatment.

Inhaled beta-adrenergic agonists are the most commonly used medications for the treatment of asthma although there is evidence that regular use may produce adverse effects in some patients. Polymorphisms of the beta(2)-adrenergic receptor (beta(2)-AR) can affect regulation of the receptor. Smaller studies examining the effects of such polymorphisms on the response to beta-agonist therapy have produced inconsistent results. We examined whether polymorphisms at codon 16 (beta(2)-AR-16) and codon 27 (beta(2)-AR-27) of the beta(2)-AR might affect the response to regular versus as-needed use of albuterol by genotyping the 190 asthmatics who had participated in a trial examining the effects of regular versus as needed albuterol use. During the 16-wk treatment period there was a small decline in morning peak expiratory flow in patients homozygous for arginine at B(2)-AR-16 (Arg/Arg) who used albuterol regularly. This effect was magnified during a 4-wk run out period, during which all patients returned to using as-needed albuterol, so that by the end of the study Arg Arg patients who had regularly used albuterol had a morning peak expiratory flow 30. 5 +/- 12.1 L/min lower (p = 0.012) than Arg/Arg patients who had used albuterol on an as needed basis. There was no decline in peak flow with regular use of albuterol in patients who were homozygous for glycine at beta(2)-AR-16. Evening peak expiratory flow also declined in the Arg/Arg patients who used albuterol regularly but not in those who used albuterol on an as-needed basis. No significant differences in outcomes between regular and as-needed treatment were associated with polymorphisms at position 27 of the beta(2)-AR. No other differences in asthma outcomes that we investigated occurred in relation to these beta(2)-AR polymorphisms. Polymorphisms of the beta(2)-AR may influence airway responses to regular inhaled beta-agonist treatment.

Context: No consensus exists for adjusting inhaled corticosteroid therapy in patients with asthma. Approaches include adjustment at outpatient visits guided by physician assessment of asthma control (symptoms, rescue therapy, pulmonary function), based on exhaled nitric oxide, or on a day-to-day basis guided by symptoms.Objective: To determine if adjustment of inhaled corticosteroid therapy based on exhaled nitric oxide or day-to-day symptoms is superior to guideline-informed, physician assessment-based adjustment in preventing treatment failure in adults with mild to moderate asthma.Design, Setting, and Participants: A randomized, parallel, 3-group, placebo-controlled, multiply-blinded trial of 342 adults with mild to moderate asthma controlled by low-dose inhaled corticosteroid therapy (n = 114 assigned to physician assessment-based adjustment [101 completed], n = 115 to biomarker-based [exhaled nitric oxide] adjustment [92 completed], and n = 113 to symptom-based adjustment [97 completed]), the Best Adjustment Strategy for Asthma in the Long Term (BASALT) trial was conducted by the Asthma Clinical Research Network at 10 academic medical centers in the United States for 9 months between June 2007 and July 2010.Interventions: For physician assessment-based adjustment and biomarker-based (exhaled nitric oxide) adjustment, the dose of inhaled corticosteroids was adjusted every 6 weeks; for symptom-based adjustment, inhaled corticosteroids were taken with each albuterol rescue use.Main Outcome Measure: The primary outcome was time to treatment failure.Results: There were no significant differences in time to treatment failure. The 9-month Kaplan-Meier failure rates were 22% (97.5% CI, 14%-33%; 24 events) for physician assessment-based adjustment, 20% (97.5% CI, 13%-30%; 21 events) for biomarker-based adjustment, and 15% (97.5% CI, 9%-25%; 16 events) for symptom-based adjustment. The hazard ratio for physician assessment-based adjustment vs biomarker-based adjustment was 1.2 (97.5% CI, 0.6-2.3). The hazard ratio for physician assessment-based adjustment vs symptom-based adjustment was 1.6 (97.5% CI, 0.8-3.3).Conclusion: Among adults with mild to moderate persistent asthma controlled with low-dose inhaled corticosteroid therapy, the use of either biomarker-based or symptom-based adjustment of inhaled corticosteroids was not superior to physician assessment-based adjustment of inhaled corticosteroids in time to treatment failure.Trial Registration: clinicaltrials.gov Identifier: NCT00495157. [ABSTRACT FROM AUTHOR]

Rationale: To date, most studies aimed at discovering genetic factors influencing treatment response in asthma have focused on biologic candidate genes. Genome-wide association studies (GWAS) can rapidly identify novel pharmacogenetic loci.Objectives: To investigate if GWAS can identify novel pharmacogenetic loci in asthma.Methods: Using phenotypic and GWAS genotype data available through the NHLBI-funded Single-nucleotide polymorphism Health association-Asthma Resource Project, we analyzed differences in FEV(1) in response to inhaled corticosteroids in 418 white subjects with asthma. Of the 444,088 single nucleotide polymorphisms (SNPs) analyzed, the lowest 50 SNPs by P value were genotyped in an independent clinical trial population of 407 subjects with asthma.Measurements and Main Results: The lowest P value for the GWAS analysis was 2.09 × 10(-6). Of the 47 SNPs successfully genotyped in the replication population, three were associated under the same genetic model in the same direction, including two of the top four SNPs ranked by P value. Combined P values for these SNPs were 1.06 × 10(-5) for rs3127412 and 6.13 × 10(-6) for rs6456042. Although these two were not located within a gene, they were tightly correlated with three variants mapping to potentially functional regions within the T gene. After genotyping, each T gene variant was also associated with lung function response to inhaled corticosteroids in each of the trials associated with rs3127412 and rs6456042 in the initial GWAS analysis. On average, there was a twofold to threefold difference in FEV(1) response for those subjects homozygous for the wild-type versus mutant alleles for each T gene SNP.Conclusions: Genome-wide association has identified the T gene as a novel pharmacogenetic locus for inhaled corticosteroid response in asthma. [ABSTRACT FROM AUTHOR]

Rationale: Long-acting beta-agonists (LABAs) and inhaled corticosteroids administered together appear to be complementary in terms of effects on asthma control. The elements of asthma control achieved by LABAs (improved lung function) and leukotriene receptor antagonists (LTRAs; protection against exacerbations) may be complementary as well.Objective: We sought to determine whether the combination of the LTRA montelukast and the LABA salmeterol could provide an effective therapeutic strategy for asthma.Methods and Measurements: In a randomized, placebo-controlled, crossover study of 192 subjects with moderate asthma, we compared the clinical efficacy of regular treatment over 14 weeks with the combination of montelukast and salmeterol to that with the combination of beclomethasone and salmeterol in moderate asthma. The primary efficacy outcome was time to treatment failure.Main Results: Three months after the randomization of the last subject, the Data and Safety Monitoring Board determined that the primary research question had been answered and terminated the trial. The combination of montelukast and salmeterol was inferior to the combination of beclomethasone and salmeterol as judged by protection against asthma treatment failures (p = 0.0008), lung function (26 L/min difference in a.m. peak expiratory flow rate, p = 0.011), asthma control score (0.22 difference in Asthma Control Questionnaire score, p = 0.038), and markers of inflammation and airway reactivity.Conclusions: Patients with moderate asthma similar to those we studied should not substitute the combination of an LTRA and an LABA for the combination of inhaled corticosteroid and an LABA. [ABSTRACT FROM AUTHOR]

Background: Both the United States Medical Licensing Examination and the Orthopaedic In-Training Examination measure factual recall as well as interpretative and problem-solving skills. The former examination is used to a variable degree by postgraduate programs in resident selection. Orthopaedic In-Training Examination scores are one measure of the medical knowledge of residents and are used by all American orthopaedic residency programs on a yearly basis. This investigation was performed to retrospectively review Orthopaedic In-Training Examination scores of orthopaedic residents who took the examination in our program. In addition, we sought to determine whether a relationship existed between performance on the Orthopaedic In-Training Examination and the United States Medical Licensing Examinations taken while in medical school.Methods: The records of each orthopaedic resident who took the examination from November 1993 through November 2000 were reviewed. Correlation coefficients and 95% confidence intervals were calculated to assess the relationship, if any, between the Orthopaedic In-Training Examination percentiles and the three-digit scores on the Step-1 and Step-2 United States Medical Licensing Examination. In addition, examination scores were evaluated longitudinally from year-in-training 1 through 4.Results: A significant moderate-sized correlation was found between United States Medical Licensing Examination Step-2 scores and Orthopaedic In-Training Examination score percentiles (p < 0.05); however, with the numbers available, no correlation was seen between United States Medical Licensing Examination Step-1 scores and Orthopaedic In-Training Examination scores. The mean Orthopaedic In-Training Examination scores were in the 66th percentile for year-in-training 1, the 53rd percentile for year 2, the 57th percentile for year 3, and the 50th percentile for year 4. Residents in the laboratory for one year scored in the 88th percentile while in the laboratory (year 0), in the 86th percentile in year 1, and in the 48th percentile in year 4.Conclusion: Although Step-1 United States Medical Licensing Examination scores have been used by our department as a major factor in resident selection historically, our data failed to reveal a significant correlation with performance on the Orthopaedic In-Training Examination. The decrease in Orthopaedic In-Training Examination scores over time for our residents who worked in the laboratory is most likely attributable to multiple factors, including clinical workload hours. [ABSTRACT FROM AUTHOR]

Rationale: Several studies suggest that patients with asthma who are homozygous for arginine at the 16th position of the beta2-adrenergic receptor may not benefit from short-acting beta-agonists.Objectives: We investigated whether such genotype-specific effects occur when patients are treated with long-acting beta-agonists and whether such effects are modified by concurrent inhaled corticosteroid (ICS) use.Methods: We compared salmeterol response in patients with asthma homozygous for arginine at B16 (B16Arg/Arg) with those homozygous for glycine at B16 (B16Gly/Gly) in two separate cohorts. In the first, subjects were randomized to regular therapy with salmeterol while simultaneously discontinuing ICS therapy. In the second, subjects were randomized to regular therapy with salmeterol while continuing concomitant ICS.Results: In both trials, B16Arg/Arg subjects did not benefit compared with B16Gly/Gly subjects after salmeterol was initiated. In the first cohort, compared with placebo, the addition of salmeterol was associated with a 51.4 L/min lower A.M. peak expiratory flow (PEF; p = 0.005) in B16Arg/Arg subjects(salmeterol, n = 12; placebo, n = 5) as compared with B16Gly/Gly subjects (salmeterol, n = 13; placebo, n = 13). In the second cohort, B16Arg/Arg subjects treated with salmeterol and ICS concurrently (n = 8) had a lower A.M. PEF (36.8 L/min difference, p = 0.048) than B16Gly/Gly subjects (n = 22) treated with the same regimen. In addition, B16 Arg/Arg subjects in the second cohort had lower FEV1 (0.42 L, p = 0.003), increased symptom scores (0.2 units, p = 0.034), and increased albuterol rescue use (0.95 puffs/d, p = 0.004) compared with B16Gly/Gly subjects.Conclusions: Relative to B16Gly/Gly patients with asthma, B16Arg/Arg patients with asthma may have an impaired therapeutic response to salmeterol in either the absence or presence of concurrent ICS use. Investigation of alternate treatment strategies may benefit this group. [ABSTRACT FROM AUTHOR]

Context: Long-acting beta(2)-agonists are prescribed for patients with persistent asthma and are sometimes used without inhaled corticosteroids (ICSs). No evidence exists, however, to support their use as monotherapy in adults with persistent asthma.Objective: To examine the effectiveness of salmeterol xinafoate, a long-acting beta(2)-agonist, as replacement therapy in patients whose asthma is well controlled by low-dose triamcinolone acetonide, an ICS.Design and Setting: A 28-week, randomized, blinded, placebo-controlled, parallel group trial conducted at 6 National Institutes of Health-sponsored, university-based ambulatory care centers from February 1997 to January 1999.Participants: One hundred sixty-four patients aged 12 through 65 years with persistent asthma that was well controlled during a 6-week run-in period of treatment with inhaled triamcinolone (400 microg twice per day).Interventions: Patients were randomly assigned to continue triamcinolone therapy (400 microg twice per day; n = 54) or switch to salmeterol (42 microg twice per day; n = 54) or to placebo (n = 56) for 16 weeks, after which all patients received placebo for an additional 6-week run-out period.Main Outcome Measures: Change in morning and evening peak expiratory flow (PEF), forced expiratory volume in 1 second (FEV(1)), self-assessed asthma symptom scores, rescue albuterol use, asthma-specific quality-of-life scores, treatment failure, asthma exacerbation, bronchial reactivity, and markers of airway inflammation, compared among the 3 treatment groups.Results: During the 16-week randomized treatment period, no significant differences between the salmeterol and triamcinolone groups were observed for conventional outcomes of clinical studies of asthma therapy-morning PEF, evening PEF, asthma symptom scores, rescue albuterol sulfate use, or quality of life. Both active treatments were superior to placebo. However, the salmeterol group had more treatment failures than the triamcinolone group (13/54 [24%] vs 3/54 [6%]; P =.004), as well as more asthma exacerbations (11/54 [20%] vs 4/54 [7%]; P =.04), greater increases in median (interquartile range) sputum eosinophils (2.4% [0.0% to 10.6%] vs -0.1% [-0.7% to 0.3%]; P<.001), eosinophil cationic protein (71 [-2 to 430] U/L vs -4 [-31 to 56] U/L; P =.005), and tryptase (3.1 [2.1 to 7.6] ng/mL vs 0.0 [0.0 to 0.7] ng/mL; P<.001). The duration of benefit when patients were switched from active treatment to placebo after 22 weeks of randomized treatment was not significantly longer in the triamcinolone group than in the salmeterol group.Conclusions: Patients with persistent asthma well controlled by low doses of triamcinolone cannot be switched to salmeterol monotherapy without risk of clinically significant loss of asthma control. [ABSTRACT FROM AUTHOR]

Context: Inhaled long-acting beta(2)-agonists improve asthma control when added to inhaled corticosteroid (ICS) therapy.Objective: To determine whether ICS therapy can be reduced or eliminated in patients with persistent asthma after adding a long-acting beta(2)-agonist to their treatment regimen.Design and Setting: A 24-week randomized, controlled, blinded, double-dummy, parallel-group trial conducted at 6 National Institutes of Health-sponsored, university-based ambulatory care centers from February 1997 through January 1999.Participants: One hundred seventy-five patients aged 12 through 65 years with persistent asthma that was suboptimally controlled during a 6-week run-in period of treatment with inhaled triamcinolone acetonide (400 microg twice per day).Intervention: Patients continued triamcinolone therapy and were randomly assigned to receive add-on therapy with either placebo (placebo-minus group, n = 21) or salmeterol xinafoate, 42 microg twice per day (n = 154) for 2 weeks. The entire placebo-minus group was assigned and half of the salmeterol group (salmeterol-minus group) was randomly assigned to reduce by 50% (for 8 weeks) then eliminate (for 8 weeks) triamcinolone treatment. The other half of the salmeterol group (salmeterol-plus group) was randomly assigned to continue both salmeterol and triamcinolone for the remaining 16 weeks (active control group).Main Outcome Measure: Time to asthma treatment failure in patients receiving salmeterol.Results: Treatment failure occurred in 8.3% (95% confidence interval [CI], 2%-15%) of the salmeterol-minus group 8 weeks after triamcinolone treatment was reduced compared with 2.8% (95% CI, 0%-7%) of the salmeterol-plus group during the same period. Treatment failure occurred in 46.3% (95% CI, 34%-59%) of the salmeterol-minus group 8 weeks after triamcinolone therapy was eliminated compared with 13.7% (95% CI, 5%-22%) of the salmeterol-plus group. The relative risk (95% CI) of treatment failure at the end of the triamcinolone elimination phase in the salmeterol-minus group was 4.3 (2.0-9.2) compared with the salmeterol-plus group (P<.001).Conclusions: Our results indicate that in patients with persistent asthma suboptimally controlled by triamcinolone therapy alone but whose asthma symptoms improve after addition of salmeterol, a substantial reduction (50%) in triamcinolone dose can occur without a significant loss of asthma control. However, total elimination of triamcinolone therapy results in a significant deterioration in asthma control and, therefore, cannot be recommended. [ABSTRACT FROM AUTHOR]

Study Objectives: Several methods of utilizing peak expiratory flow (PEF) and other markers of disease activity have been suggested as useful in the management of asthma. It remains unclear, however, as to which surrogate markers of disease status are discriminative indicators of treatment failure, suitable for use in clinical trials.Design: We analyzed the operating characteristics of 66 surrogate markers of treatment failure using a receiver operating characteristic (ROC) curve analysis.Participants: Information regarding FEV(1), symptoms, beta(2)-agonist use, and PEF was available from 313 subjects previously enrolled in two Asthma Clinical Research Network trials, in which 71 treatment failures occurred (defined by a 20% fall in FEV(1) from baseline).Interventions: None.Measurements and Results: None of the measures had an acceptable ability to discriminate subjects with a > or % fall in FEV(1) from those without, regardless of the duration of the period of analysis or the criteria for test positivity employed. Areas under the ROC curves generated ranged from 0.51 to 0.79, but none were statistically superior. Sensitivity and specificity combinations were generally poor at all cutoff values; true-positive rates could not be raised without unacceptably elevating false-positive rates concurrently.Conclusions: Studies that seek to detect treatment failure defined by a significant fall in FEV(1) should not use such individual surrogate measures to estimate disease severity. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To examine how cumulative teenage sports histories and time-averaged teenage calcium intake are related to total body bone mineral gain between ages 12 and 18 years and to proximal femur bone mineral density (BMD) at age 18 years. Design. Longitudinal. Setting. University Hospital and local suburban community in Central Pennsylvania. STUDY PARTICIPANTS: Eighty-one white females in the ongoing Penn State Young Women's Health Study. OUTCOME MEASURES: Total body and proximal femur (hip) bone measurements by dual energy radiograph absorptiometry; nutrient intakes, including calcium, from 33 days of prospective food records collected at regular intervals between ages 12 and 18 years; and self-reported sports-exercise scores between ages 12 and 18 years. RESULTS: Cumulative sports-exercise scores between ages 12 and 18 years were associated with hip BMD at age 18 years (r = .42) but were not related to total body bone mineral gain. Time-averaged daily calcium intake, which ranged from 500 to 1500 mg/day in this cohort was not associated with hip BMD at age 18 years, or with total body bone mineral gain at age 12 through 18 years. CONCLUSIONS: The amount of physical activity that distinguishes a primarily sedentary teenager from one who engages in some form of exercise on a nearly daily basis is related to a significant increase in peak hip BMD. [ABSTRACT FROM AUTHOR]

Using a daily questionnaire, we prospectively studied 277 physicians from two hospital medical services for incidents of exposure to blood and body fluids and barrier use before and after the implementation of universal precautions. We found that implementation significantly increased the frequency of barrier use during exposure incidents from 54% before implementation to 73% after implementation of universal precautions. Implementation led to a decrease in the number of exposure incidents that resulted in direct contact with blood and body fluids (actual exposures), from 5.07 to 2.66 exposures per physician per patient care month, and to an increase in averted exposures in which direct contact was prevented by the use of barrier devices, from 3.41 exposures per patient care month before implementation to 5.90 exposures per patient care month after implementation. Implementation affected neither the types of body fluid or procedures involved nor the overall rate of exposure incidents (8.5 per patient care month) but, through an increase in barrier use, it did prevent direct contact with blood and body fluids and thus converted what would have been an actual exposure into an averted one. We conclude that universal precautions were effective in reducing the risk of occupational exposures among physicians on a medical service. [ABSTRACT FROM AUTHOR]

Background: Some studies suggest that patients with asthma who are homozygous for arginine at the 16th amino acid position of the beta2-adrenergic receptor (B16 Arg/Arg) benefit less from treatment with longacting beta2 agonists and inhaled corticosteroids than do those homozygous for glycine (B16 Gly/Gly). We investigated whether there is a genotype-specific response to treatment with a longacting beta2 agonist in combination with inhaled corticosteroid.Methods: In this multicentre, randomised, double-blind, placebo-controlled trial, adult patients with moderate asthma were enrolled in pairs matched for forced expiratory volume in 1 s and ethnic origin, according to whether they had the B16 Arg/Arg (n=42) or B16 Gly/Gly (n=45) genotype. Individuals in a matched pair were randomly assigned by computer-generated randomisation sequence to receive inhaled longacting beta2 agonist (salmeterol 50 microg twice a day) or placebo given in a double-blind, crossover design for two 18-week periods. Open-label inhaled corticosteroid (hydrofluoroalkane beclometasone 240 microg twice a day) was given to all participants during the treatment periods. The primary endpoint was morning peak expiratory flow (PEF). Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00200967.Findings: After 18 weeks of treatment, mean morning PEF in Arg/Arg participants was 21.4 L/min (95% CI 11.8-31.1) higher when participants were assigned to receive salmeterol than when assigned to receive placebo (p<0.0001). In Gly/Gly participants, morning PEF was 21.5 L/min (11.0-32.1) higher when participants were assigned to receive salmeterol than when assigned to receive placebo (p<0.0001). The improvement in PEF did not differ between genotypes (difference [Arg/Arg-Gly/Gly] -0.1, -14.4 to 14.2; p=0.99). In Gly/Gly participants, methacholine PC20 (20% reduction in forced expiratory volume in 1 s; a prespecified secondary outcome) was 2.4 times higher when participants were assigned to salmeterol than when assigned to placebo (p<0.0001). Responsiveness to methacholine did not differ between salmeterol and placebo in Arg/Arg participants (p=0.87). The 2.5 times higher genotype-specific difference in responsiveness to methacholine was significant (1.32 doubling dose difference between genotypes, 0.43-2.21, p=0.0038). Seven Arg/Arg participants (placebo, n=5; salmeterol, n=2) and six Gly/Gly participants (placebo, n=3; salmeterol, n=3) had an asthma exacerbation. Five serious adverse events were reported, one each during the pre-match and run-in phases on open-label inhaled corticosteroid, two during double-blind treatment with salmeterol/inhaled corticosteroid, and one during double-blind treatment with placebo/inhaled corticosteroid. None of the serious events was asthma-related or related to study drugs or procedures.Interpretation: In asthma patients with B16 Arg/Arg and B16 Gly/Gly genotypes, combination treatment with salmeterol and inhaled corticosteroid improved airway function when compared with inhaled corticosteroid therapy alone. These findings suggest that patients should continue to be treated with longacting beta2 agonists plus moderate-dose inhaled corticosteroids irrespective of B16 genotype. Further investigation is needed to establish the importance of the genotype-specific difference in responsiveness to methacholine.Funding: National Institutes of Health. [ABSTRACT FROM AUTHOR]

Background: Although guidelines recommend daily therapy for patients with mild persistent asthma, prescription patterns suggest that most such patients use these so-called controller therapies intermittently. In patients with mild persistent asthma, we evaluated the efficacy of intermittent short-course corticosteroid treatment guided by a symptom-based action plan alone or in addition to daily treatment with either inhaled budesonide or oral zafirlukast over a one-year period.Methods: In a double-blind trial, 225 adults underwent randomization. The primary outcome was morning peak expiratory flow (PEF). Other outcomes included the forced expiratory volume in one second (FEV1) before and after bronchodilator treatment, the frequency of exacerbations, the degree of asthma control, the number of symptom-free days, and the quality of life.Results: The three treatments produced similar increases in morning PEF (7.1 to 8.3 percent; approximately 32 liters per minute; P=0.90) and similar rates of asthma exacerbations (P=0.24), even though the intermittent-treatment group took budesonide, on average, for only 0.5 week of the year. As compared with intermittent therapy or daily zafirlukast therapy, daily budesonide therapy produced greater improvements in pre-bronchodilator FEV1 (P=0.005), bronchial reactivity (P<0.001), the percentage of eosinophils in sputum (P=0.007), exhaled nitric oxide levels (P=0.006), scores for asthma control (P<0.001), and the number of symptom-free days (P=0.03), but not in post-bronchodilator FEV1 (P=0.29) or in the quality of life (P=0.18). Daily zafirlukast therapy did not differ significantly from intermittent treatment in any outcome measured.Conclusions: It may be possible to treat mild persistent asthma with short, intermittent courses of inhaled or oral corticosteroids taken when symptoms worsen. Further studies are required to determine whether this novel approach to treatment should be recommended. [ABSTRACT FROM AUTHOR]

Introduction: Herpes zoster increases stroke and myocardial infarction risk. The objective of this study is to evaluate the impact of live attenuated zoster vaccination on stroke and myocardial infarction risk in patients at risk of zoster, including those with hypertension, diabetes mellites, obesity, hypercholesterolemia, chronic kidney disease, chronic obstructive pulmonary disease, emphysema, asthma, and chronic liver disease., Methods: This is a retrospective cohort study utilizing continuous de-identified claims data from the IBM MarketScan Commercial Claims and Encounters Database (collected from 2005-2018) containing data for 200 million commercially insured Americans. Participants included 27,093 adults vaccinated against zoster with at least 5 years of continuous enrollment, age and sex-matched 1:5 with unvaccinated controls. OR, risk difference, and the number needed to treat evaluated the effect of vaccination on stroke and myocardial infarction while controlling for relevant comorbidities., Results: Over the period of 5 years, proportions of myocardial infarction (1.29% vs 1.82%; p<0.05) and stroke (1.61% vs 2.20%; p<0.05) were lower in vaccinated versus unvaccinated individuals, respectively, controlling for age and sex, with the greatest benefit for people with diabetes (stroke OR=0.64, 95% CI=0.58, 0.71; myocardial infarction OR=0.63, 95% CI=0.57, 0.71). Although hypertension and chronic obstructive pulmonary disease had the highest odds of stroke and myocardial infarction, vaccination still provided significant risk-reduction (hypertension: stroke 0.75 [0.68, 0.83], myocardial infarction 0.73 [0.65, 0.81]; chronic obstructive pulmonary disease: stroke 0.75 [0.68, 0.83], myocardial infarction 0.74 [0.66, 0.83])., Conclusions: Live attenuated zoster vaccination is associated with lower risk of stroke and myocardial infarction in adults with at-risk comorbidities, controlling for age and sex. Vaccination may provide cardiovascular benefits beyond zoster prevention., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: The psychological impacts of skin disease are well documented, with patients reporting increased anxiety, depression and poorer quality of life. More recent studies suggest that adverse psychopathology is associated with re-direction of skin-disease-related social stigma towards oneself or internalized skin bias (ISB)., Objectives: To refine the Internalized Skin Bias Questionnaire (ISBQ) to reflect the construct of ISB with additional skin-specific biases as well as to evaluate its psychometric properties in a diverse sample of individuals with various skin conditions., Methods: Two-part observational design including consensus-building surveys among a dermatology expert group and a cross-sectional survey among participants with self-reported dermatological conditions to assess instrument psychometric properties. Eligible participants completed an online survey comprised of the revised ISBQ (ISBQ-R), the Questionnaire on Experiences with Skin Diseases-Short Form (QES-SF), the Dermatology Life Quality Index (DLQI), the Beck Depression Inventory-II (BDI-II) and the Burns Anxiety Inventory (BAI)., Results: Overall, 33 experts participated including 22 (66.7%) dermatologists or dermatology researchers and 11 (33.3%) patients. Except for three items in the first round, all items received high agreement for inclusion from the expert group. The revised survey was completed by 214 participants who identified mostly as female (n = 185; 86.9%), White (n = 182; 85.5%) and non-Hispanic/Latino (n = 200; 93.4%). Adding and modifying new items resulted in an instrument with stronger internal consistency (Cronbach's alpha = 0.92) and a stronger correlation with other existing stigma measures (QES-SF; ρ = 0.72)., Conclusions: The ISBQ-R is a modified instrument with stronger internal consistency and a stronger correlation with other existing stigma measures. Additionally, the study further expanded upon previous research by exploring a two-factor structure, suggesting that the ISBQ-R could be used as a single- or a dual-factor instrument depending on investigator goals., (© 2024 The Author(s). Journal of the European Academy of Dermatology and Venereology published by John Wiley & Sons Ltd on behalf of European Academy of Dermatology and Venereology.)

Background: The prevalence of Babesia coinfecting tick-borne zoonoses and mortality outcomes are not fully elucidated. The objective of the present study was to determine babesiosis coinfection prevalence rates and estimate the association with severe disease and mortality., Methods: We queried the TriNetX database between 2015 and 2022 for patients with babesiosis. The prevalence of Babesia coinfecting tick-borne zoonoses was estimated. The analysis focused on babesiosis coinfection with Borrelia burgdorferi , ehrlichiosis, and anaplasmosis. The exposure was coinfection, and the control group was the Babesia -only group. The primary outcome was 90-day mortality from the diagnosis of Babesia . Secondary outcomes were prevalence of coinfection, association of coinfection with acute respiratory distress syndrome, multiorgan failure, and disseminated intravascular coagulation. A multivariable logistic regression model was employed to estimate the disease severity and mortality risk associated with coinfections., Results: Of the 3521 patients infected with Babesia , the mean age (SD) was 56 (18) years, 51% were male, and 78% were White. The frequency of overall malignancies, lymphomas, and asplenia was 19%, 2%, and 2%, respectively. Temporal distribution of coinfections followed the overall babesiosis pattern, peaking in the summer months. The prevalence of 1 or more coinfections was 42% (95% CI, 40%-43%). The rate of coinfection with Borrelia burgdorferi was the highest at 41% (95% CI, 39%-42%), followed by ehrlichiosis at 3.7% (95% CI, 3.1%-4.4%) and anaplasmosis at only 0.3% (95% CI, 0.2%-0.6%). Doxycycline was more likely to be prescribed in the coinfection group than the Babesia -only group (25% vs 18%; P < .0001). Overall, 90-day mortality was 1.4% (95% CI, 1.0%-1.8%). After adjusting for potential confounding factors, compared with the babesiosis-only group, the likelihood of 90-day mortality was lower in the coinfection group (adjusted odds ratio, 0.43; 95% CI, 0.20-0.91). Severe disease did not differ significantly between the 2 groups., Conclusions: In this extensive study of >3000 patients with babesiosis in the United States, 4 in 10 patients had coinfecting tick-borne zoonoses. The prevalence rates of coinfection were highest with Borrelia burgdorferi, followed by ehrlichiosis, and lowest with anaplasmosis. Coinfection with other tick-borne infections was not associated with severe disease. It is plausible that this finding is due to the likelihood of treatment of coinfections with doxycycline. Future studies are needed to investigate the possible therapeutic benefits of doxycycline in babesiosis patients as, to date, no trials with doxycycline have been conducted in human patients with Babesia infections., Competing Interests: Potential conflicts of interest. All authors: no conflicts of interest to disclose., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

The purpose of the present study was to investigate the quality of patient/clinician communication as one potential factor that impacts colorectal cancer screening behavior. As part of a larger randomized controlled trial conducted between 2011 and 2016 in the setting of community and academic family medicine or internal medicine practices in Michigan, USA, patients completed a pre-encounter survey, completed their regularly scheduled visit with their primary care clinician (which was audio-recorded), completed a post-encounter survey, and allowed 6-month follow-up chart audit. We trained 10 coders to rate 216 of the audio-recorded conversations between 216 patients and their primary care physicians for 6 specific features of communication quality (using 7-point scales), including the extent to which participants enacted attention to medical content, engagement, emotional expression, relationships, face, and accommodation. At least 3 coders rated each conversation, and intraclass correlations (i.e., reliability assessment) were in the good to excellent range. We found that patient and clinician attention to face (an identity goal) was a significant predictor of colorectal cancer screening at 6 months follow up. Measuring communication in terms of attention to multiple goals reveals unexpected findings about the aspects of communication that impact colorectal cancer screening behavior. The focus of many interventions to improve colorectal cancer screening rates is on the content (i.e., task goals) of clinicians' communication (such as presenting the different options for screening), yet the content of communication was not a significant predictor of screening in the present study. Rather, clinicians' and patients' attention to identity goals predicted screening behavior, which suggests that interventions may not need to be overly complex and that simply improving the quality of attention to identity goals in clinician communication might be one of the most straightforward yet impactful ways to improve colorectal cancer screening uptake among patients., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

(1) Background: The incidence rate of early onset-cancer (<50) has increased since 1995. Among younger people, cancers in AYAs (aged 15-39 y) are often biologically distinct tumors from those treated in the pediatric and older adult population. The current study describes trends in the United States for the most recent years including the first year of the COVID-19 epidemic. We aimed to describe the recent incidence and mortality trends of cancers in AYAs (aged 15-39 y). (2) Methods: We used data from the Surveillance, Epidemiology, and End Results (SEER 22) from 1 January 2016 to 31 December 2021. Age-adjusted incidence and mortality rates were assessed by SEER*Stat 8.4.3 for major cancer types by sex, race/ethnicity, age, and metropolitan/nonmetropolitan status. Time trends of age-adjusted incidence and mortality rates were examined by sex and metropolitan/nonmetropolitan status. (3) Results: Age-adjusted overall cancer incidence and mortality rates were stable during this study period. The age-adjusted incidence rates declined significantly for ependymoma, melanoma, carcinomas of lung, bronchus, and trachea, unspecified malignant neoplasms, and non-Hodgkin's lymphoma. Significant increases were found for gastrointestinal tract cancers and non-Kaposi sarcomas. The age-adjusted mortality rate decreased for acute myeloid leukemia, melanoma, carcinomas of liver and intrahepatic bile ducts, kidney and, in women, leukemia. For some cancers, rates differed by sex, race, ethnicity, and geography. Monitoring the rates and time trends of AYA cancer emphasizes the distinct health concern for this age group.

Importance: Infection has been postulated as a driver in the sudden infant death syndrome (SIDS) cascade. Epidemiologic patterns of infection, including respiratory syncytial virus and influenza, were altered during the COVID-19 pandemic. Comparing month-to-month variation in both sudden unexpected infant death (SUID) and SIDS rates before and during the pandemic offers an opportunity to generate and expand existing hypotheses regarding seasonal infections and SUID and SIDS., Objective: To compare prepandemic and intrapandemic rates of SUID and SIDS, assessing for monthly variation., Design, Setting, and Participants: This cross-sectional study assessed US mortality data provided by the Centers for Disease Control and Prevention for January 1, 2018, through December 31, 2021. Events with International Statistical Classification of Diseases and Related Health Problems, Tenth Revision codes for SIDS (R95), unknown (R99), and accidental suffocation and strangulation in bed (W75) causes of death were examined. The data analysis was performed between November 2, 2023, and June 2, 2024., Exposure: COVID-19 pandemic., Main Outcomes and Measures: The primary and secondary outcomes were the monthly rates of SUID and SIDS during the COVID-19 pandemic (March 1, 2020, to December 31, 2021) compared with the prepandemic period (March 1, 2018, to December 31, 2019) as measured using generalized linear mixed-effects models. Seasonal trends in RSV and influenza rates were also examined., Results: There were 14 308 SUID cases from January 1, 2018, to December 31, 2021 (42% female infants). Compared with the prepandemic period, the risk of SUID increased during the intrapandemic period (intensity ratio [IR], 1.06; 95% CI, 1.05-1.07). Monthly assessments revealed an increased risk of SUID beyond the prepandemic baseline starting in July 2020, with a pronounced epidemiologic shift from June to December 2021 (ranging from 10% to 14%). Rates of SIDS were elevated throughout the intrapandemic period compared with the prepandemic baseline, with the greatest increase in July 2021 (IR, 1.18; 95% CI, 1.13-1.22) and August 2021 (IR, 1.17; 95% CI, 1.13-1.22). Seasonal shifts in RSV hospitalizations correlated with monthly changes in SUID observed during 2021., Conclusions and Relevance: This cross-sectional study found increased rates of both SUID and SIDS during the COVID-19 pandemic, with a significant shift in epidemiology from the prepandemic period noted in June to December 2021. These findings support the hypothesis that off-season resurgences in endemic infectious pathogens may be associated with SUID rates, with RSV rates in the US closely approximating this shift. Further investigation into the role of infection in SUID and SIDS is needed.

Background and Aims: Exercise is recommended for the management of metabolic dysfunction-associated steatotic liver disease (MASLD), yet effects on liver histology remain unknown, especially without significant weight loss. We aimed to examine changes in surrogate measures of liver histological response with exercise training., Methods: We conducted a post hoc pooled analysis of three randomised controlled trials (duration: 12-20 weeks) comparing aerobic exercise interventions with controls. The primary outcome measure was a ≥30% relative reduction in (MRI-measured) liver fat, as a surrogate measure of liver histological response (the threshold necessary for fibrosis improvement). Secondary outcome measures were changes in other biomarkers of liver fibrosis, anthropometry, body composition and aerobic fitness., Results: Eighty-eight adults (exercise: 54, control: 34; male: 67%) were included with mean (SD) age 51 (11) years and body mass index 33.3 (5.2) kg/m 2 . Following the intervention, exercise had ~5-fold (OR [95%CI]: 4.86 [1.72, 13.8], p = .002) greater odds of ≥30% relative reduction in MRI-measured liver fat compared with control. This paralleled the improvements in anthropometry (waist and hip circumference reduction), body composition (body fat, visceral and subcutaneous adipose tissue) and aerobic fitness (V̇O 2 peak, ventilatory threshold and exercise capacity). Importantly, these effects were independent of clinically significant body weight loss (<3% body weight)., Conclusion: Exercise training led to clinically meaningful improvements in surrogate serum- and imaging-based measures of liver histological change, without clinically meaningful body weight reduction. These data reinforce the weight-neutral benefit of exercise training and suggest that aerobic training may improve liver fibrosis in patients with MASLD., (© 2024 The Author(s). Liver International published by John Wiley & Sons Ltd.)

Background: The rate of spontaneous Intracerebral Hemorrhage (sICH) is rising among young Americans. Trends in acute seizure (AS) incidence in this age group is largely unknown. Further, the association of AS with mortality has not been reported in this age group. The aim of this study is to determine trends in AS among young individuals with sICH., Methods: The Merative MarketScan® Commercial Claims and Encounters database, for the years 2005 through 2015, served as the data source for this retrospective in-hospital population study. This period was chosen as spontaneous ICH incidence increased among young individuals between 2005 and 2015. Our study population included patients aged 18-64 years with ICH identified using the International Classification of Diseases, Ninth and Tenth Revision (ICD-9/10) codes 430, 431, 432.0, 432.1, 432.9, I61, I61.0, I61.1, I61.2, I61.3, I61.4, I61.5, I61.6, I61.8, and I61.9, excluding those with a prior diagnosis of seizures (ICD-9/10 codes 345.x,780.3x, G40, G41, and R56.8). We computed yearly AS incidence, mortality (in patients with and without seizures), and analyzed trends. We applied a logistic regression model to determine the independent association of AS with mortality accounting for demographic and clinical variables., Results: AS incidence increased linearly between 2005 (incidence rate: 8.1 %) and 2015 (incidence rate: 11.0 %), which represents a 26 % relative increase (P for trends <0.0001). In-hospital mortality rate was 14.3 % among those who developed AS and 11.5 % among those who did not have AS. Overall, between 2005 and 2015, in-hospital mortality decreased from 13.0 % to 9.7 % among patients without AS but remained unchanged among those with AS. Patients who developed AS were 10 % more likely to die than those who did not (OR: 1.10, 95 % confidence interval: 1.02-1.18)., Conclusions: Between 2005 and 2015, the incidence of AS increased by nearly 26 % among young Americans with sICH. In-patient mortality remained unchanged among those who developed seizures but declined among those who did not. The occurrence of AS was independently associated with a 10 % higher risk of in-hospital death., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Chemotherapy treatment-related side-effects are common and increase the risk of suboptimal outcomes. Exercise interventions during cancer treatment improve self-reported physical functioning, fatigue, anxiety, and depression, but it is unclear whether these interventions improve important clinical outcomes, such as chemotherapy relative dose intensity (RDI). The National Cancer Institute funded the Exercise and Nutrition to Improve Cancer Treatment-Related Outcomes (ENICTO) Consortium, to address this knowledge gap. This paper describes the mechanisms hypothesized to underpin intervention effects on clinically-relevant treatment outcomes, briefly outlines each project's distinct research aims, summarizes the scope and organizational structure of ENICTO, and provides an overview of the integrated common data elements used to pursue research questions collectively. In addition, the paper includes a description of consortium-wide activities and broader research community opportunities for collaborative research. Findings from the ENICTO Consortium have the potential to accelerate a paradigm shift in oncology care such that cancer patients could receive exercise and nutrition programming as the standard of care in tandem with chemotherapy to improve RDI for a curative outcome., (© The Author(s) 2024. Published by Oxford University Press.)

Introduction: Intracerebral hemorrhage represents 15 % of all strokes and it is associated with a high risk of post-stroke epilepsy. However, there are no reliable methods to accurately predict those at higher risk for developing seizures despite their importance in planning treatments, allocating resources, and advancing post-stroke seizure research. Existing risk models have limitations and have not taken advantage of readily available real-world data and artificial intelligence. This study aims to evaluate the performance of Machine-learning-based models to predict post-stroke seizures at 1 year and 5 years after an intracerebral hemorrhage in unselected patients across multiple healthcare organizations., Design/methods: We identified patients with intracerebral hemorrhage (ICH) without a prior diagnosis of seizures from 2015 until inception (11/01/22) in the TriNetX Diamond Network, using the International Classification of Diseases, Tenth Revision (ICD-10) I61 (I61.0, I61.1, I61.2, I61.3, I61.4, I61.5, I61.6, I61.8, and I61.9). The outcome of interest was any ICD-10 diagnosis of seizures (G40/G41) at 1 year and 5 years following the first occurrence of the diagnosis of intracerebral hemorrhage. We applied a conventional logistic regression and a Light Gradient Boosted Machine (LGBM) algorithm, and the performance of the model was assessed using the area under the receiver operating characteristics (AUROC), the area under the precision-recall curve (AUPRC), the F1 statistic, model accuracy, balanced-accuracy, precision, and recall, with and without seizure medication use in the models., Results: A total of 85,679 patients had an ICD-10 code of intracerebral hemorrhage and no prior diagnosis of seizures, constituting our study cohort. Seizures were present in 4.57 % and 6.27 % of patients within 1 and 5 years after ICH, respectively. At 1-year, the AUROC, AUPRC, F1 statistic, accuracy, balanced-accuracy, precision, and recall were respectively 0.7051 (standard error: 0.0132), 0.1143 (0.0068), 0.1479 (0.0055), 0.6708 (0.0076), 0.6491 (0.0114), 0.0839 (0.0032), and 0.6253 (0.0216). Corresponding metrics at 5 years were 0.694 (0.009), 0.1431 (0.0039), 0.1859 (0.0064), 0.6603 (0.0059), 0.6408 (0.0119), 0.1094 (0.0037) and 0.6186 (0.0264). These numerical values indicate that the statistical models fit the data very well., Conclusion: Machine learning models applied to electronic health records can improve the prediction of post-hemorrhagic stroke epilepsy, presenting a real opportunity to incorporate risk assessments into clinical decision-making in post-stroke care clinical care and improve patients' selection for post-stroke epilepsy research., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Most patients with metabolic dysfunction-associated steatotic liver disease are unable to achieve clinically significant body weight loss with traditional in-person approaches. Digital therapeutic (DTx)-delivered interventions offer promise to remove barriers to weight loss success inherent to traditional resource-heavy in-person programs and at a population level, but their efficacy remains relatively unknown., Methods: Published studies were identified through May 2023 by searching the following electronic databases: PubMed and Embase (Ovid). DTx intervention was compared to standard of care. The primary outcome was a change in body weight. Secondary outcomes included clinically significant body weight loss (≥5%) and change in liver enzymes., Results: Eight studies comprising 1001 patients met inclusion criteria (mean age: 47 y; body mass index: 33.2 kg/m2). The overall rate of clinically significant body weight loss was 33%, with DTx lifestyle interventions ranging from 4 to 24 months in length. DTx lifestyle intervention achieved statistically significant body weight loss (absolute change -3.4 kg, 95% CI: -4.8 to -2.0 kg, p < 0.01, relative change -3.9%, 95% CI: -6.6 to -1.3, p < 0.01) as well as clinically significant body weight loss of ≥5% (risk ratio: 3.0, 95% CI: 1.7-5.5, p < 0.01) compared to standard of care. This was seen alongside improvement in liver enzymes., Conclusions: DTx-delivered lifestyle intervention programs lead to greater amounts of body weight loss than traditional in-person lifestyle counseling. These results further support the role of DTx in delivering lifestyle intervention programs to patients with metabolic dysfunction-associated steatotic liver disease and suggest that this scalable intervention offers promise to benefit the billions of patients worldwide with this condition., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Association for the Study of Liver Diseases.)

Objective: The purpose of this study was to examine the multimorbidity burden of clinical trial participants and assess its association with treatment response., Methods: We conducted a reanalysis of patient level data. There were 29,954 participants from 8 clinical trials containing 11 comparisons between an intervention and control condition. Patients were classified by Charlson Comorbidity Index (CCI) score. The primary outcomes were the primary study endpoints as originally specified for each trial. A Cox model that included the CCI score groups, the randomized group, and their interaction, was used to compare the primary outcome between randomized groups. The interaction term between randomized group and comorbidity index allowed the treatment effect to differ by level of comorbidity index and comprised the primary effect of interest. Hazard ratios and risk differences were reported for all comparisons., Results: The mean CCI scores of trial populations ranged from 2.1 to 3.9 points, and the percentage of patients with scores ≥5 from 3% to 39%. Tests of interaction terms in models yielded P values ≤ .10 for 4/11 comparisons and ≤ .05 for 2/11 comparisons. In 3 additional comparisons, potentially important treatment variation on an absolute scale was observed despite interaction tests with P values > .10 on the relative scale., Conclusions: These trials were mainly composed of patient populations with CCI scores ≤4. Despite this, biologically plausible treatment interactions were commonly suggested. These results are hypothesis generating; confirmation of results would require larger studies or studies targeted specifically toward patients with higher levels of multimorbidity., (Copyright © 2024. Published by Elsevier Inc.)

In clinical and observational studies, secondary outcomes are frequently collected alongside the primary outcome for each subject, yet their potential to improve the analysis efficiency remains underutilized. Moreover, missing data, commonly encountered in practice, can introduce bias to estimates if not appropriately addressed. This article presents an innovative approach that enhances the empirical likelihood-based information borrowing method by integrating missing-data techniques, ensuring robust data integration. We introduce a plug-in inverse probability weighting estimator to handle missingness in the primary analysis, demonstrating its equivalence to the standard joint estimator under mild conditions. To address potential bias from missing secondary outcomes, we propose a uniform mapping strategy, imputing incomplete secondary outcomes into a unified space. Extensive simulations highlight the effectiveness of our method, showing consistent, efficient, and robust estimators under various scenarios involving missing data and/or misspecified secondary models. Finally, we apply our proposal to the Uniform Data Set from the National Alzheimer's Coordinating Center, exemplifying its practical application., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Recently renamed, metabolic dysfunction-associated steatotic liver disease remains a leading cause of chronic liver disease worldwide. Regular physical activity is recommended as a treatment for all with this condition because it is highly efficacious, especially when exercise training is undertaken with a specific goal in mind. Despite decades of research demonstrating exercise's efficacy, key questions remain about the mechanism of benefit and most efficacious dose, as well as the independent impact on liver histology. To answer these questions, we present the design of a 16-week randomized controlled clinical trial of 45 adults aged 18-69 years with metabolic dysfunction-associated steatohepatitis. The primary aim of this study is to better understand the dose required and mechanisms to explain how exercise impacts multiple clinical end points in metabolic dysfunction-associated steatohepatitis. The primary outcome is MRI-measured liver fat. Secondary outcomes include other biomarkers of liver fibroinflammation, liver histology, and mechanistic pathways, as well as cardiometabolic risk and quality of life. This is the first study to compare different doses of exercise training to determine if there is a differential impact on imaging and serum biomarkers as well as liver histology., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Association for the Study of Liver Diseases.)

Background: The association between angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin II receptor blockers (ARBs) and severe acute respiratory syndrome coronavirus 2 susceptibility, particularly via ACE-2 receptor upregulation in the kidneys, raises concerns about potential kidney disease risks in long coronavirus disease (COVID) patients. This study explores the association of ACEI/ARB therapy on acute kidney injury (AKI), chronic kidney disease (CKD) and all-cause mortality in patients with and without long COVID., Methods: A retrospective cohort study using TriNetX datasets was conducted, with diagnoses of long COVID via International Classification of Diseases, Tenth Revision (ICD-10) codes and prescription for ACEI/ARB as the classification of four cohorts: long COVID ACEI/ARB users (LCAUs), long COVID ACEI/ARB non-users (LCANs), non-long COVID ACEI/ARB users (NLCAUs) and non-long COVID ACEI/ARB non-users (NLCANs). Multivariable stratified Cox proportional hazards regression models assessed the adjusted hazard ratios (aHRs) across groups. Additional analyses were conducted, including time-dependent exposure analysis and comparison with an active comparator, calcium channel blockers., Results: Our study included 18 168 long COVID and 181 680 propensity score-matched non-long COVID patients from October 2021 to October 2023. ACEI/ARB use did not significantly affect the risk of AKI or CKD when comparing LCAUs with LCANs and NLCAUs with NLCANs. However, a protective effect against all-cause mortality was observed {aHR 0.79 [95% confidence interval (CI) 0.65-0.93]} in the NLCAU group compared with the NLCAN group. Conversely, long COVID was associated with increased risks of CKD [aHR 1.49 (95% CI 1.03-2.14)] and all-cause mortality [aHR 1.49 (95% CI 1.00-2.23)] when comparing LCANs with NLCANs. The additional analyses support the primary findings., Conclusions: ACEI/ARB treatment does not increase the incidence of CKD or AKI, regardless of long COVID status. However, long COVID itself is associated with increasing risks of kidney diseases and all-cause mortality., Competing Interests: None declared., (© The Author(s) 2024. Published by Oxford University Press on behalf of the ERA.)