RESUMO
We pay tribute to Marshall Joffe, PhD, and his substantial contributions to the field of causal inference with focus in biostatistics and epidemiology. By compiling narratives written by us, his colleagues, we not only present highlights of Marshall's research and their significance for causal inference but also offer a portrayal of Marshall's personal accomplishments and character. Our discussion of Marshall's research notably includes (but is not limited to) handling of posttreatment variables such as noncompliance, employing G-estimation for treatment effects on failure-time outcomes, estimating effects of time-varying exposures subject to time-dependent confounding, and developing a causal framework for case-control studies. We also provide a description of some of Marshall's unpublished work, which is accompanied by a bonus anecdote. We discuss future research directions related to Marshall's research. While Marshall's impact in causal inference and the world outside of it cannot be wholly captured by our words, we hope nonetheless to present some of what he has done for our field and what he has meant to us and to his loved ones.
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Bioestatística , Humanos , Masculino , Causalidade , Estudos de Casos e ControlesRESUMO
PURPOSE: This study tested the hypothesis that ecological momentary assessment (EMA) of pelvic pain (PP) and urinary urgency (UU) would reveal unique Urologic Chronic Pelvic Pain Syndrome (UCPPS) phenotypes that would be associated with disease specific quality of life (QOL) and illness impact metrics (IIM). MATERIALS AND METHODS: A previously validated smart phone app (M-app) was provided to willing Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) participants. M-app notifications were sent 4-times daily for 14 days inquiring about PP and UU severity. A clustering algorithm that accounted for variance placed participants into PP and UU variability? clusters. Associations between clusters and QOL and IIM were then determined. RESULTS: A total of 204 participants enrolled in the M-app study (64% female). M-app compliance was high (median 63% of surveys). Cluster analysis revealed k = 3 (high, low, none) PP clusters and k = 2 (high, low) UU clusters. When adjusting for baseline pain severity, high PP variability, but not UU variability, was strongly associated with QOL and IIM; specifically worse mood, worse sleep and higher anxiety. UU and PP clusters were associated with each other (p < 0.0001), but a large percentage (33%) of patients with high PP variability had low UU variability. CONCLUSIONS: PP variability is an independent predictor of worse QOL and more severe IIM in UCPPS participants after controlling for baseline pain severity and UU. These findings suggest alternative pain indices, such as pain variability and unpredictability, may be useful adjuncts to traditional measures of worst and average pain when assessing UCPPS treatment responses.
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Dor Crônica , Qualidade de Vida , Humanos , Feminino , Masculino , Avaliação Momentânea Ecológica , Dor Crônica/diagnóstico , Dor Pélvica/diagnóstico , Medição da DorRESUMO
PURPOSE: In patients with urologic chronic pelvic pain syndrome (UCPPS), the presence of widespread pain appears to identify a distinct phenotype, with a different symptom trajectory and potentially different response to treatment than patients with pelvic pain only. MATERIALS AND METHODS: A 76-site body map was administered four times, at weekly intervals, to 568 male and female UCPPS participants in the MAPP Network protocol. The 76 sites were classified into 13 regions (1 pelvic region and 12 nonpelvic regions). The degree of widespread pain was scored from 0 to 12 based on the number of reported nonpelvic pain regions. This continuous body map score was regressed over other measures of widespread pain, with UCPPS symptom severity, and with psychosocial variables to measure level of association. These models were repeated using an updated body map score (0-12) that incorporated a threshold of pain ≥ 4 at each site. RESULTS: Body map scores showed limited variability over the 4 weekly assessments, indicating that a single baseline assessment was sufficient. The widespread pain score correlated highly with other measures of widespread pain and correlated with worsened UCPPS symptom severity and psychosocial functioning. Incorporating a pain severity threshold ≥4 resulted in only marginal increases in these correlations. CONCLUSIONS: These results support the use of this 13-region body map in the baseline clinical assessment of UCPPS patients. It provides reliable data about the presence of widespread pain and does not require measurement of pain severity, making it relatively simple to use for clinical purposes.
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Dor Crônica , Cistite Intersticial , Prostatite , Humanos , Masculino , Feminino , Dor Pélvica/diagnóstico , Dor Pélvica/psicologia , Dor Crônica/diagnóstico , Dor Crônica/psicologia , Síndrome , Limiar da Dor , Medição da Dor , Cistite Intersticial/diagnósticoRESUMO
PURPOSE: Symptom heterogeneity in interstitial cystitis/bladder pain syndrome and chronic prostatitis/chronic pelvic pain syndrome, collectively termed urological chronic pelvic pain syndrome, has resulted in difficulty in defining appropriate clinical trial endpoints. We determine clinically important differences for 2 primary symptom measures, pelvic pain severity and urinary symptom severity, and evaluate subgroup differences. MATERIALS AND METHODS: The Multidisciplinary Approach to the Study of Chronic Pelvic Pain Symptom Patterns Study enrolled individuals with urological chronic pelvic pain syndrome. We defined clinically important differences by associating changes in pelvic pain severity and urinary symptom severity over 3 to 6 months with marked improvement on a global response assessment using regression and receiver operating characteristic curves. We evaluated clinically important differences for absolute and percent change and examined differences in clinically important differences by sex-diagnosis, presence of Hunner lesions, pain type, pain widespreadness, and baseline symptom severity. RESULTS: An absolute change of -4 was clinically important in pelvic pain severity among all patients, but clinically important difference estimates differed by pain type, presence of Hunner lesions, and baseline severity. Pelvic pain severity clinically important difference estimates for percent change were more consistent across subgroups and ranged from 30% to 57%. The absolute change urinary symptom severity clinically important difference was -3 for female participants and -2 for male participants with chronic prostatitis/chronic pelvic pain syndrome only. Patients with greater baseline severity required larger decreases in symptoms to feel improved. Estimated clinically important differences had lower accuracy among participants with low baseline symptoms. CONCLUSIONS: A reduction of 30%-50% in pelvic pain severity is a clinically meaningful endpoint for future therapeutic trials in urological chronic pelvic pain syndrome. Urinary symptom severity clinically important differences are more appropriately defined separately for male and female participants.
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Dor Crônica , Cistite Intersticial , Prostatite , Humanos , Masculino , Feminino , Prostatite/complicações , Prostatite/diagnóstico , Dor Pélvica/diagnóstico , Dor Pélvica/etiologia , Dor Crônica/diagnóstico , Dor Crônica/etiologia , Cistite Intersticial/complicações , Cistite Intersticial/diagnóstico , Depressão/diagnósticoRESUMO
Chronic inflammation is highly prevalent among patients receiving maintenance hemodialysis and is associated with morbidity and mortality. Inhibiting inflammation with anti-cytokine therapy has been proposed but not well studied in this population. Therefore, we conducted the ACTION trial, a pilot, multicenter, randomized, placebo-controlled trial of an IL-1 receptor antagonist, anakinra, to evaluate safety, tolerability, and feasibility, and explore efficacy. Eighty hemodialysis patients with plasma concentrations of high sensitivity C-reactive protein (hsCRP) 2 mg/L and above were randomized 1:1 to placebo or anakinra 100 mg, three times per week via the hemodialysis circuit for 24 weeks, with an additional 24 weeks of post-treatment safety monitoring. Efficacy outcomes included changes in hsCRP (primary), cytokines, and patient-reported outcomes. Rates of serious adverse events and deaths were similar with anakinra and placebo (serious adverse events: 2.71 vs 2.74 events/patient-year; deaths: 0.12 vs 0.22 events/patient-year). The rate of adverse events of interest (including infections and cytopenias) was significantly lower with anakinra than placebo (0.48 vs 1.40 events/patient-year). Feasibility was demonstrated by attaining the enrollment target, a retention rate of 80%, and administration of 72% of doses. The median decrease in hsCRP from baseline to Week 24 was 41% in the anakinra group and 6% in the placebo group, a between-group difference that was not statistically significant. For IL-6, the median decreases were significant: 25% and 0% in the anakinra and placebo groups, respectively. An effect of anakinra on patient-reported outcomes was not evident. Thus, anakinra was well tolerated and did not increase infections or cytopenias. The promising safety data and potential efficacy on CRP and IL-6 provide support for conducting definitive trials of IL-1 inhibition to improve outcomes in hemodialysis patients.
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Inflamação , Proteína Antagonista do Receptor de Interleucina 1 , Diálise Renal , Humanos , Proteína C-Reativa , Método Duplo-Cego , Inflamação/tratamento farmacológico , Inflamação/etiologia , Proteína Antagonista do Receptor de Interleucina 1/uso terapêutico , Interleucina-1 , Interleucina-6 , Projetos Piloto , Receptores de Interleucina-1/antagonistas & inibidores , Diálise Renal/efeitos adversos , Resultado do TratamentoRESUMO
PURPOSE: We assessed the reliability and validity of an efficient severity assessment for pelvic pain and urinary symptoms in urological chronic pelvic pain syndrome, which consists of interstitial cystitis/bladder pain syndrome and chronic prostatitis/chronic pelvic pain syndrome. MATERIALS AND METHODS: A total of 578 patients were assessed using brief, empirically derived self-report scales for pelvic pain severity (PPS) and urinary symptom severity (USS) 4 times during a 1-month period and baseline clinic visit that included urological, pain and illness-impact measures. Mild, moderate and severe categories on each dimension were examined for measurement stability and construct validity. RESULTS: PPS and USS severity categories had adequate reliability and both discriminant validity (differential relationships with specific clinical and self-report measures) and convergent validity (common association with nonurological somatic symptoms). For example, increasing PPS was associated with pelvic tenderness and widespread pelvic pain, whereas USS was associated with urgency during a bladder filling test and increased sensory sensitivity. PPS and USS categories were independently associated with nonurological pain and emotional distress. A descriptive analysis identified higher likelihood characteristics associated with having moderate to severe PPS or USS or both. Lack of sex interactions indicated that the measures are comparable in interstitial cystitis/bladder pain syndrome and chronic prostatitis/chronic pelvic pain syndrome. CONCLUSIONS: Women and men with urological chronic pelvic pain syndrome can be reliably subgrouped using brief self-report measures of mild, moderate or severe pelvic pain and urinary symptoms. Comparisons with a broad range of clinical variables demonstrate the validity and potential clinical utility of these classifications, including use in clinical trials, health services and biological research.
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Dor Crônica , Cistite Intersticial , Prostatite , Dor Crônica/complicações , Dor Crônica/etiologia , Cistite Intersticial/complicações , Cistite Intersticial/diagnóstico , Cistite Intersticial/psicologia , Feminino , Humanos , Masculino , Dor Pélvica/complicações , Dor Pélvica/etiologia , Prostatite/complicações , Prostatite/diagnóstico , Prostatite/psicologia , Reprodutibilidade dos Testes , SíndromeRESUMO
BACKGROUND: CKD is a heterogeneous condition with multiple underlying causes, risk factors, and outcomes. Subtyping CKD with multidimensional patient data holds the key to precision medicine. Consensus clustering may reveal CKD subgroups with different risk profiles of adverse outcomes. METHODS: We used unsupervised consensus clustering on 72 baseline characteristics among 2696 participants in the prospective Chronic Renal Insufficiency Cohort (CRIC) study to identify novel CKD subgroups that best represent the data pattern. Calculation of the standardized difference of each parameter used the cutoff of ±0.3 to show subgroup features. CKD subgroup associations were examined with the clinical end points of kidney failure, the composite outcome of cardiovascular diseases, and death. RESULTS: The algorithm revealed three unique CKD subgroups that best represented patients' baseline characteristics. Patients with relatively favorable levels of bone density and cardiac and kidney function markers, with lower prevalence of diabetes and obesity, and who used fewer medications formed cluster 1 (n=1203). Patients with higher prevalence of diabetes and obesity and who used more medications formed cluster 2 (n=1098). Patients with less favorable levels of bone mineral density, poor cardiac and kidney function markers, and inflammation delineated cluster 3 (n=395). These three subgroups, when linked with future clinical end points, were associated with different risks of CKD progression, cardiovascular disease, and death. Furthermore, patient heterogeneity among predefined subgroups with similar baseline kidney function emerged. CONCLUSIONS: Consensus clustering synthesized the patterns of baseline clinical and laboratory measures and revealed distinct CKD subgroups, which were associated with markedly different risks of important clinical outcomes. Further examination of patient subgroups and associated biomarkers may provide next steps toward precision medicine.
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Insuficiência Renal Crônica/classificação , Adulto , Idoso , Algoritmos , Densidade Óssea , Estudos de Coortes , Progressão da Doença , Feminino , Testes de Função Cardíaca , Humanos , Estimativa de Kaplan-Meier , Testes de Função Renal , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos , Insuficiência Renal Crônica/fisiopatologia , Fatores de Risco , Aprendizado de Máquina não Supervisionado , Adulto JovemRESUMO
OBJECTIVE: To use the phenotyping data from the MAPP-II Symptom Patterns Study (SPS) to compare the systemic features between urologic chronic pelvic pain syndrome (UCPPS) with Hunner lesion (HL) versus those without HL. METHODS: We performed chart review on 385 women and 193 men with UCPPS who enrolled in the MAPP-II SPS. 223 had cystoscopy and documentation of HL status. Among them, 12.5% had HL and 87.5% did not. RESULTS: UCPPS participants with HL were older, had increased nocturia, higher Interstitial Cystitis Symptom and Problem Indexes, and were more likely to report "painful urgency" compared with those without HL. On the other hand, UCPPS without HL reported more intense nonurologic pain, greater distribution of pain outside the pelvis, greater numbers of comorbid chronic overlapping pain conditions, higher fibromyalgia-like symptoms, and greater pain centralization, and were more likely to have migraine headache than those with HL. UCPPS without HL also had higher anxiety, perceived stress, and pain catastrophizing than those with HL. There were no differences in sex distribution, UCPPS symptom duration, intensity of urologic pain, distribution of genital pain, pelvic floor tenderness on pelvic examination, quality of life, depression, pain characteristics (nociceptive pain vs. neuropathic pain), mechanical hypersensitivity in the suprapubic area during quantitative sensory testing, and 3-year longitudinal pain outcome and urinary outcome between the two groups. CONCLUSIONS: UCPPS with HL displayed more bladder-centric symptom profiles, while UCPPS without HL displayed symptoms suggesting a more systemic pain syndrome. The MAPP-II SPS phenotyping data showed that Hunner lesion is a distinct phenotype from non-Hunner lesion.
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Dor Crônica/genética , Dor Pélvica/genética , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , FenótipoRESUMO
BACKGROUND: Single-center trials and retrospective case series have reported promising outcomes using kidneys from donors with hepatitis C virus (HCV) infection. However, multicenter trials are needed to determine if those findings are generalizable. METHODS: We conducted a prospective trial at seven centers to transplant 30 kidneys from deceased donors with HCV viremia into HCV-uninfected recipients, followed by 8 weeks of once-daily coformulated glecaprevir and pibrentasvir, targeted to start 3 days posttransplant. Key outcomes included sustained virologic response (undetectable HCV RNA 12 weeks after completing treatment with glecaprevir and pibrentasvir), adverse events, and allograft function. RESULTS: We screened 76 patients and enrolled 63 patients, of whom 30 underwent kidney transplantation from an HCV-viremic deceased donor (median kidney donor profile index, 53%) in May 2019 through October 2019. The median time between consent and transplantation of a kidney from an HCV-viremic donor was 6.3 weeks. All 30 recipients achieved a sustained virologic response. One recipient died of complications of sepsis 4 months after achieving a sustained virologic response. No severe adverse events in any patient were deemed likely related to HCV infection or treatment with glecaprevir and pibrentasvir. Three recipients developed acute cellular rejection, which was borderline in one case. Three recipients developed polyomavirus (BK) viremia near or >10,000 copies/ml that resolved after reduction of immunosuppression. All recipients had good allograft function, with a median creatinine of 1.2 mg/dl and median eGFR of 57 ml/min per 1.73 m2 at 6 months. CONCLUSIONS: Our multicenter trial demonstrated safety and efficacy of transplantation of 30 HCV-viremic kidneys into HCV-negative recipients, followed by early initiation of an 8-week regimen of glecaprevir and pibrentasvir.
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Ácidos Aminoisobutíricos/uso terapêutico , Antivirais/uso terapêutico , Benzimidazóis/uso terapêutico , Ciclopropanos/uso terapêutico , Hepacivirus , Hepatite C/prevenção & controle , Transplante de Rim , Lactamas Macrocíclicas/uso terapêutico , Leucina/análogos & derivados , Prolina/análogos & derivados , Quinoxalinas/uso terapêutico , RNA Viral/sangue , Sulfonamidas/uso terapêutico , Adulto , Aloenxertos/fisiologia , Aloenxertos/virologia , Ácidos Aminoisobutíricos/efeitos adversos , Antivirais/efeitos adversos , Benzimidazóis/efeitos adversos , Ciclopropanos/efeitos adversos , Combinação de Medicamentos , Feminino , Taxa de Filtração Glomerular , Hepatite C/sangue , Humanos , Rim/fisiologia , Lactamas Macrocíclicas/efeitos adversos , Leucina/efeitos adversos , Leucina/uso terapêutico , Masculino , Prolina/efeitos adversos , Prolina/uso terapêutico , Estudos Prospectivos , Pirrolidinas , Quinoxalinas/efeitos adversos , Sulfonamidas/efeitos adversos , Resposta Viral SustentadaRESUMO
PURPOSE: We evaluated and identified baseline factors associated with change in health related quality of life among patients with interstitial cystitis/bladder pain syndrome and chronic prostatitis/chronic pelvic pain syndrome. MATERIALS AND METHODS: A total of 191 men and 233 women with interstitial cystitis/bladder pain syndrome or chronic prostatitis/chronic pelvic pain syndrome (collectively referred to as urologic chronic pelvic pain syndrome) were followed for 12 months with bimonthly completion of the Short Form 12 to assess general mental and physical health related quality of life, and with biweekly assessment of condition specific health related quality of life using the Genitourinary Pain Index. A functional clustering algorithm was used to classify participants as improved, stable or worsened for each health related quality of life measure. Ordinal logistic regression was used to determine baseline factors associated with change. RESULTS: Physical health related quality of life improved in 22% of the participants, mental health related quality of life improved in 25% and condition specific health related quality of life improved in 47%. Better baseline physical health related quality of life, older age and the presence of nonurological symptoms were associated with lower likelihood of improvement in physical health related quality of life. Better baseline mental health related quality of life, female sex, and greater baseline depression and stress were associated with a lower likelihood of improvement in mental health related quality of life. Better baseline condition specific health related quality of life and more severe baseline urologic chronic pelvic pain syndrome pain symptoms were associated with a lower likelihood of improvement in condition specific health related quality of life. CONCLUSIONS: While several nonurologic chronic pelvic pain syndrome factors influenced the trajectory of general health related quality of life over time, only condition specific baseline health related quality of life and urologic chronic pelvic pain syndrome symptoms were associated with urologic chronic pelvic pain syndrome specific health related quality of life change. Significant differences in how urologic chronic pelvic pain syndrome impacts various aspects of health related quality of life suggest a multidisciplinary approach to assessment and treatment of these patients.
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Cistite Intersticial , Prostatite , Qualidade de Vida , Pesquisa Biomédica , Correlação de Dados , Feminino , Humanos , Masculino , Estudos Prospectivos , Fatores de TempoRESUMO
A major goal of phylogenetic systematics is to understand both the patterns of diversification and the processes by which these patterns are formed. Few studies have focused on the ancient, species-rich Magnoliales clade and its diversification pattern. Within Magnoliales, the pantropically distributed Annonaceae are by far the most genus-rich and species-rich family-level clade, with c. 110 genera and c. 2,400 species. We investigated the diversification patterns across Annonaceae and identified traits that show varied associations with diversification rates using a time-calibrated phylogeny of 835 species (34.6% sampling) and 11,211 aligned bases from eight regions of the plastid genome (rbcL, matK, ndhF, psbA-trnH, trnL-F, atpB-rbcL, trnS-G, and ycf1). Twelve rate shifts were identified using BAMM: in Annona, Artabotrys, Asimina, Drepananthus, Duguetia, Goniothalamus, Guatteria, Uvaria, Xylopia, the tribes Miliuseae and Malmeeae, and the Desmos-Dasymaschalon-Friesodielsia-Monanthotaxis clade. TurboMEDUSA and method-of-moments estimator analyses showed largely congruent results. A positive relationship between species richness and diversification rate is revealed using PGLS. Our results show that the high species richness in Annonaceae is likely the result of recent increased diversification rather than the steady accumulation of species via the 'museum model'. We further explore the possible role of selected traits (habit, pollinator trapping, floral sex expression, pollen dispersal unit, anther septation, and seed dispersal unit) in shaping diversification patterns, based on inferences of BiSSE, MuSSE, HiSSE, and FiSSE analyses. Our results suggest that the liana habit, the presence of circadian pollinator trapping, androdioecy, and the dispersal of seeds as single-seeded monocarp fragments are closely correlated with higher diversification rates; pollen aggregation and anther septation, in contrast, are associated with lower diversification rates.
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Annonaceae/classificação , Annonaceae/genética , Biodiversidade , Genoma de Planta , Filogenia , Plastídeos/genéticaRESUMO
PURPOSE: To correlate the presence of fungi with symptom flares, pain and urinary severity in a prospective, longitudinal study of women with IC/BPS enrolled in the MAPP Research Network. METHODS: Flare status, pelvic pain, urinary severity, and midstream urine were collected at baseline, 6 and 12 months from female IC/BPS participants with at least one flare and age-matched participants with no reported flares. Multilocus PCR coupled with electrospray ionization/mass spectrometry was used for identification of fungal species and genus. Associations between "mycobiome" (species/genus presence, relative abundance, Shannon's/Chao1 diversity indices) and current flare status, pain, urinary severity were evaluated using generalized linear mixed models, permutational multivariate analysis of variance, Wilcoxon's rank-sum test. RESULTS: The most specific analysis detected 13 fungal species from 8 genera in 504 urine samples from 202 females. A more sensitive analysis detected 43 genera. No overall differences were observed in fungal species/genus composition or diversity by flare status or pain severity. Longitudinal analyses suggested greater fungal diversity (Chao1 Mean Ratio 3.8, 95% CI 1.3-11.2, p = 0.02) and a significantly greater likelihood of detecting any fungal species (OR = 5.26, 95% CI 1.1-25.8, p = 0.04) in high vs low urinary severity participants. Individual taxa analysis showed a trend toward increased presence and relative abundance of Candida (OR = 6.63, 95% CI 0.8-58.5, p = 0.088) and Malassezia (only identified in 'high' urinary severity phenotype) for high vs low urinary symptoms. CONCLUSION: This analysis suggests the possibility that greater urinary symptom severity is associated with the urinary mycobiome urine in some females with IC/BPS.
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Cistite Intersticial/urina , DNA Fúngico/análise , Fungos/genética , Sistema Urinário/microbiologia , Adulto , Cistite Intersticial/microbiologia , Feminino , Seguimentos , Humanos , Fenótipo , Estudos Prospectivos , Fatores de TempoRESUMO
BACKGROUND AND PURPOSE: Increasing evidence has demonstrated that aquaporin-4 (AQP4) immunoglobulin G causes damage to the kidney in neuromyelitis optica spectrum disorder (NMOSD). However, changes in urinalysis in NMOSD have not been investigated thus far. Our objective was to evaluate the changes in urinalysis in NMOSD patients. METHODS: Case data were collected from 44 patients with AQP4 antibody-positive NMOSD, 53 patients with multiple sclerosis (MS) and 79 age- and sex-matched healthy controls. Analyses of early morning urine and 24-h urine samples comparing NMOSD with MS patients were conducted. RESULTS: In the acute phase, urine pH levels (P < 0.001) and urine specific gravity levels (P < 0.001) from NMOSD patients were significantly higher and lower, respectively, than for MS patients. 24-h urine sodium and 24-h urine volume from NMOSD patients were significantly higher than for MS patients (both P = 0.001). A 24-h urine volume higher than 2500 ml (odds ratio 11.7, 95% confidence interval 1.863-73.066) and a 24-h urine sodium higher than 200 mmol (odds ratio 16.0, 95% confidence interval 2.122-120.648) are more likely to occur in NMOSD patients in the acute phase than in MS patients. CONCLUSIONS: The urinalysis results were significantly different between NMOSD patients and MS patients. The pathophysiological changes in AQP4 antibody-positive NMOSD patients were not limited to the central nervous system.
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Neuromielite Óptica/urina , Urinálise , Adulto , Aquaporina 4/imunologia , Autoanticorpos , Feminino , Humanos , Imunoglobulina G/imunologia , Masculino , Pessoa de Meia-Idade , Neuromielite Óptica/imunologia , Estudos Prospectivos , Adulto JovemRESUMO
AIMS: The Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) Research Network initiated a second observational cohort study-the Symptom Patterns Study (SPS)-to further investigate the underlying pathophysiology of Urologic Chronic Pelvic Pain Syndrome (UCPPS) and to discover factors associated with longitudinal symptom changes and responses to treatments. METHODS: This multisite cohort study of males and females with UCPPS features a run-in period of four weekly web-based symptom assessments before a baseline visit, followed by quarterly assessments up to 36 months. Controls were also recruited and assessed at baseline and 6 months. Extensive clinical data assessing urological symptoms, nonurological pain, chronic overlapping pain syndromes, and psychosocial factors were collected. Diverse biospecimens for biomarker and microbiome studies, quantitative sensory testing (QST) data under multiple stimuli, and structural and functional neuroimaging scans were obtained under a standardized protocol. RESULTS: Recruitment was initiated (July 2015) and completed (February 2019) at six discovery sites. A total of 620 males and females with UCPPS and 73 Controls were enrolled, including 83 UCPPS participants who re-enrolled from the first MAPP Network cohort study (2009-2012). Baseline neuroimaging scans, QST measures, and biospecimens were obtained on 578 UCPPS participants. The longitudinal follow-up of the cohort is ongoing. CONCLUSIONS: This comprehensive characterization of a large UCPPS cohort with extended follow-up greatly expands upon earlier MAPP Network studies and provides unprecedented opportunities to increase our understanding of UCPPS pathophysiology, factors associated with symptom change, clinically relevant patient phenotypes, and novel targets for future interventions.
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Dor Crônica/diagnóstico , Dor Pélvica/diagnóstico , Fenótipo , Adulto , Biomarcadores , Dor Crônica/fisiopatologia , Estudos de Coortes , Feminino , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Neuroimagem , Dor Pélvica/fisiopatologiaRESUMO
BACKGROUND: Data from clinical trials to inform practice in maintenance hemodialysis are limited. Incorporating randomized trials into dialysis clinical care delivery should help generate practice-guiding evidence, but the feasibility of this approach has not been established. METHODS: To develop approaches for embedding trials into routine delivery of maintenance hemodialysis, we performed a cluster-randomized, pragmatic trial demonstration project, the Time to Reduce Mortality in ESRD (TiME) trial, evaluating effects of session duration on mortality (primary outcome) and hospitalization rate. Dialysis facilities randomized to the intervention adopted a default session duration ≥4.25 hours (255 minutes) for incident patients; those randomized to usual care had no trial-driven approach to session duration. Implementation was highly centralized, with no on-site research personnel and complete reliance on clinically acquired data. We used multiple strategies to engage facility personnel and participating patients. RESULTS: The trial enrolled 7035 incident patients from 266 dialysis units. We discontinued the trial at a median follow-up of 1.1 years because of an inadequate between-group difference in session duration. For the primary analysis population (participants with estimated body water ≤42.5 L), mean session duration was 216 minutes for the intervention group and 207 minutes for the usual care group. We found no reduction in mortality or hospitalization rate for the intervention versus usual care. CONCLUSIONS: Although a highly pragmatic design allowed efficient enrollment, data acquisition, and monitoring, intervention uptake was insufficient to determine whether longer hemodialysis sessions improve outcomes. More effective strategies for engaging clinical personnel and patients are likely required to evaluate clinical trial interventions that are fully embedded in care delivery.
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Causas de Morte , Falência Renal Crônica/mortalidade , Falência Renal Crônica/terapia , Avaliação de Resultados em Cuidados de Saúde , Diálise Renal/mortalidade , Diálise Renal/métodos , Assistência Ambulatorial/métodos , Análise por Conglomerados , Feminino , Humanos , Falência Renal Crônica/diagnóstico , Masculino , Taxa de Sobrevida , Fatores de Tempo , Estados UnidosRESUMO
The safety and efficacy of spironolactone is uncertain in end-stage renal disease. We randomized 129 maintenance hemodialysis patients to placebo (n=51) or spironolactone 12.5 mg (n=27), 25 mg (n=26), or 50 mg (n=25) daily for 36 weeks in a double-blind, placebo-controlled, multiple dosage trial to assess safety, tolerability and feasibility and to explore cardiovascular efficacy. The primary safety endpoints were hyperkalemia (potassium > 6.5 mEq/L) and hypotension requiring emergency department visit or hospitalization. Diastolic function was assessed by Doppler echocardiography. 125 participants (97%) completed dose escalation, with no significant difference in permanent study drug discontinuation between the groups (27.5% in placebo versus 16.7% in the combined spironolactone groups and 28% in the 50 mg group). Hyperkalemia frequency was similar between spironolactone and placebo (0.49 versus 0.50 events per patient-year) but demonstrated a significant linear trend due primarily to an increased event rate at the 50 mg dose (0.89 events per patient-year). The primary hypotension outcome was infrequent and similar with spironolactone and placebo (0.11 versus 0 events per patient-year). Gynecomastia was rare and did not differ significantly between groups. Change in diastolic function was similar with spironolactone and placebo. Spironolactone appears safe in carefully monitored maintenance hemodialysis patients, but did not affect cardiovascular parameters in this small study. Hyperkalemia occurs more frequently as dosage increases to 50 mg daily.
Assuntos
Doenças Cardiovasculares/prevenção & controle , Hiperpotassemia/epidemiologia , Hipotensão/epidemiologia , Falência Renal Crônica/terapia , Antagonistas de Receptores de Mineralocorticoides/efeitos adversos , Espironolactona/efeitos adversos , Adulto , Idoso , Aldosterona/metabolismo , Doenças Cardiovasculares/diagnóstico por imagem , Diástole/efeitos dos fármacos , Relação Dose-Resposta a Droga , Método Duplo-Cego , Ecocardiografia Doppler , Estudos de Viabilidade , Feminino , Ginecomastia/induzido quimicamente , Ginecomastia/epidemiologia , Humanos , Hiperpotassemia/sangue , Hiperpotassemia/induzido quimicamente , Hipotensão/induzido quimicamente , Falência Renal Crônica/complicações , Falência Renal Crônica/metabolismo , Masculino , Pessoa de Meia-Idade , Antagonistas de Receptores de Mineralocorticoides/administração & dosagem , Placebos/administração & dosagem , Placebos/efeitos adversos , Potássio/sangue , Diálise Renal , Espironolactona/administração & dosagemRESUMO
BACKGROUND: Serum testosterone concentrations decrease as men age, but benefits of raising testosterone levels in older men have not been established. METHODS: We assigned 790 men 65 years of age or older with a serum testosterone concentration of less than 275 ng per deciliter and symptoms suggesting hypoandrogenism to receive either testosterone gel or placebo gel for 1 year. Each man participated in one or more of three trials--the Sexual Function Trial, the Physical Function Trial, and the Vitality Trial. The primary outcome of each of the individual trials was also evaluated in all participants. RESULTS: Testosterone treatment increased serum testosterone levels to the mid-normal range for men 19 to 40 years of age. The increase in testosterone levels was associated with significantly increased sexual activity, as assessed by the Psychosexual Daily Questionnaire (P<0.001), as well as significantly increased sexual desire and erectile function. The percentage of men who had an increase of at least 50 m in the 6-minute walking distance did not differ significantly between the two study groups in the Physical Function Trial but did differ significantly when men in all three trials were included (20.5% of men who received testosterone vs. 12.6% of men who received placebo, P=0.003). Testosterone had no significant benefit with respect to vitality, as assessed by the Functional Assessment of Chronic Illness Therapy-Fatigue scale, but men who received testosterone reported slightly better mood and lower severity of depressive symptoms than those who received placebo. The rates of adverse events were similar in the two groups. CONCLUSIONS: In symptomatic men 65 years of age or older, raising testosterone concentrations for 1 year from moderately low to the mid-normal range for men 19 to 40 years of age had a moderate benefit with respect to sexual function and some benefit with respect to mood and depressive symptoms but no benefit with respect to vitality or walking distance. The number of participants was too few to draw conclusions about the risks of testosterone treatment. (Funded by the National Institutes of Health and others; ClinicalTrials.gov number, NCT00799617.).
Assuntos
Fadiga/tratamento farmacológico , Terapia de Reposição Hormonal , Comportamento Sexual/efeitos dos fármacos , Testosterona/uso terapêutico , Caminhada/fisiologia , Idoso , Depressão/tratamento farmacológico , Método Duplo-Cego , Humanos , Libido/efeitos dos fármacos , Masculino , Antígeno Prostático Específico/sangue , Valores de Referência , Comportamento Sexual/fisiologia , Testosterona/efeitos adversos , Testosterona/sangueRESUMO
BACKGROUND: Insulin resistance contributes to the metabolic syndrome, which is associated with the development of kidney disease. However, it is unclear if insulin resistance independently contributes to an increased risk of chronic kidney disease (CKD) progression or CKD complications. Additionally, predisposing factors responsible for insulin resistance in the absence of diabetes in CKD are not well described. This study aimed to describe factors associated with insulin resistance and characterize the relationship of insulin resistance to CKD progression, cardiovascular events and death among a cohort of non-diabetics with CKD. METHODS: Data was utilized from Chronic Renal Insufficiency Cohort Study participants without diabetes (N = 1883). Linear regression was used to assess associations with insulin resistance, defined using the Homeostasis Model Assessment of Insulin Resistance (HOMA-IR). The relationship of HOMA-IR, fasting glucose, hemoglobin A1c (HbA1c), and C-peptide with CKD progression, cardiovascular events, and all-cause mortality was examined with Cox proportional hazards models. RESULTS: Novel positive associations with HOMA-IR included serum albumin, uric acid, and hemoglobin A1c. After adjustment, HOMA-IR was not associated with CKD progression, cardiovascular events, or all-cause mortality. There was a notable positive association of one standard deviation increase in HbA1c with the cardiovascular endpoint (HR 1.16, 95% CI: 1.00-1.34). CONCLUSION: We describe potential determinants of HOMA-IR among a cohort of non-diabetics with mild-moderate CKD. HOMA-IR was not associated with renal or cardiovascular events, or all-cause mortality, which adds to the growing literature describing an inconsistent relationship of insulin resistance with CKD-related outcomes.
Assuntos
Glicemia , Doenças Cardiovasculares/epidemiologia , Resistência à Insulina , Rim , Insuficiência Renal Crônica , Glicemia/análise , Glicemia/metabolismo , Causas de Morte , Estudos de Coortes , Progressão da Doença , Feminino , Humanos , Rim/metabolismo , Rim/fisiopatologia , Masculino , Pessoa de Meia-Idade , Mortalidade , Insuficiência Renal Crônica/diagnóstico , Insuficiência Renal Crônica/metabolismo , Insuficiência Renal Crônica/mortalidade , Insuficiência Renal Crônica/fisiopatologia , Fatores de Risco , Estados Unidos/epidemiologiaRESUMO
BACKGROUND: Patient portals are frequently used in modern health care systems as an engagement and communication tool. An increased focus on the potential value of these communication channels to improve health outcomes is warranted. OBJECTIVE: This paper aimed to quantify the impact of portal use on patients' preventive health behavior and chronic health outcomes. METHODS: We conducted a retrospective, observational cohort study of 10,000 patients aged 50 years or older who were treated at the University of Pennsylvania Health System (UPHS) from September 1, 2014, to October 31, 2016. The data were sourced from the UPHS electronic health records. We investigated the association between patient portal use and patients' preventive health behaviors or chronic health outcomes, controlling for confounders using a novel cardinality matching approach based on propensity scoring and a subsequent bootstrapping method to estimate the variance of association estimates. RESULTS: Patient-level characteristics differed substantially between portal users, comprising approximately 59.32% (5932/10000) of the cohort, and nonusers. On average, users were more likely to be younger (63.46 years for users vs 66.08 years for nonusers), white (72.77% [4317/5932] for users vs 52.58% [2139/4068] for nonusers), have commercial insurance (60.99% [3618/5932] for users vs 40.12% [1632/4068] for nonusers), and have higher annual incomes (US $74,172/year for users vs US $62,940/year for nonusers). Even after adjusting for these potential confounders, patient portal use had a positive and clinically meaningful impact on patients' preventive health behaviors but not on chronic health outcomes. CONCLUSIONS: This paper contributes to the understanding of the impact of patient portal use on health outcomes and is the first study to identify a meaningful subgroup of patients' health behaviors that improved with portal use. These findings may encourage providers to promote portal use to improve patients' preventive health behaviors.
Assuntos
Registros Eletrônicos de Saúde/normas , Comportamentos Relacionados com a Saúde/fisiologia , Portais do Paciente/normas , Idoso , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos RetrospectivosRESUMO
STUDY QUESTION: Can a novel targeted next generation sequencing (tNGS) platform accurately detect whole chromosome aneuploidy in a trophectoderm biopsy and provide additional information to improve testing? SUMMARY ANSWER: Karyotypes obtained by tNGS were concordant with other validated platforms and single nucleotide polymorphism genotyping information obtained can be used for improved detection and quality control. WHAT IS KNOWN ALREADY: qPCR-based whole chromosome aneuploidy screening is highly accurate in comparison to other common methods and has been shown to improve IVF success in two randomized clinical trials. With aneuploidy screening becoming standard of care in many IVF centres, there is a need to develop platforms with high throughput, low cost capabilities. STUDY DESIGN SIZE, DURATION: Twelve well-characterized cell lines were obtained from a commercial cell line repository and 31 discarded human blastocysts were obtained from 17 IVF patients who underwent comprehensive chromosome screening (CCS). PARTICIPANTS/MATERIAL, SETTING, METHODS: All samples were processed using a unique amplification strategy which directly incorporated sequencing library adapters and barcodes. Sequencing was performed on an Ion Torrent Proton. A custom bioinformatics pipeline was used to determine the karyotype for each sample. The consistency of tNGS diagnoses with either conventional karyotyping of cell lines or quantitative real-time PCR based CCS of blastocyst biopsies was evaluated. MAIN RESULTS AND THE ROLE OF CHANCE: Overall consistency per sample of tNGS based CCS in 5-cell samples from a variety of cell lines was 99.2%. In the blinded analysis of rebiopsies of aneuploid blastocysts, an overall targeted tNGS CCS consistency of 98.7% was observed per sample. These data demonstrate the ability of tNGS based CCS to provide an accurate and high throughput evaluation of aneuploidy in the human blastocyst. LARGE SCALE DATA: Not applicable. LIMITATIONS REASONS FOR CAUTION: This study is limited to whole chromosome aneuploidy, as mosaicism and segmental aneuploidy have not been investigated. WIDER IMPLICATIONS OF THE FINDINGS: These data show an accurate, high throughput method, and with the greater depth of each amplicon sequenced in comparison to commercial kits, there is greater application available for single nucleotide polymorphism based analysis for quality control. STUDY FUNDING/COMPETING INTERESTS: This study was funded through intramural research funds provided by the Foundation for Embryonic Competence. There are no competing interests.