PrEP Uptake and Methamphetamine Use Patterns in a 4-Year U.S. National Prospective Cohort Study of Sexual and Gender Minority People, 2017-2022.

Methamphetamine use is on the rise among sexual and gender minority people who have sex with men (SGMSM), escalating their HIV risk. Despite pre-exposure prophylaxis (PrEP) being an effective biomedical HIV prevention tool, its uptake in relation to methamphetamine use patterns in SGMSM has not been studied. In a U.S. cohort study from 2017 to 2022, 6,253 HIV-negative SGMSM indicated for but not using PrEP were followed for four years. Methamphetamine use was categorized (i.e., newly initiated, persistently used, never used, used but quit), and PrEP uptake assessed using generalized estimating equation (GEE), adjusted for attrition. Participants had a median age of 29, with 51.9% White, 11.1% Black, 24.5% Latinx, and 12.5% other races/ethnicities. Over the four years, PrEP use increased from 16.3 to 27.2%. GEE models identified risk factors including housing instability and food insecurity. In contrast, older age, health insurance, clinical indications, and prior PrEP use increased uptake. Notably, Latinx participants were more likely to use PrEP than Whites. Regarding methamphetamine use, those who newly initiated it were more likely to use PrEP compared to non-users. However, those who quit methamphetamine and those who persistently used it had PrEP usage rates comparable to those of non-users. Though PrEP uptake increased, it remained low in SGMSM. Methamphetamine use was associated with PrEP uptake. Healthcare providers should assess methamphetamine use for harm reduction. Prioritizing younger, uninsured SGMSM and addressing basic needs can enhance PrEP uptake and reduce HIV vulnerabilities.

Determinants of continuing mental health service use among older persons diagnosed with depressive disorders in general hospitals: latent class analysis and GEE.

BACKGROUND: Prevalence of depression in older persons was a leading cause of disability. This group has the lowest access to service and retention in care compared to other age groups. This study aimed to explore continuing mental health service use and examined the predictive power of the mental health service delivery system and individual factors on mental health service use among older persons diagnosed with depressive disorders. METHODS: We employed an analytic cross-sectional study design of individual and organizational variables in 12 general hospitals selected using multi-stratified sampling. There were 3 clusters comprising community hospitals, advanced and standard hospitals, and university hospitals. Participants in each group were 150 persons selected by purposive sampling. We included older persons with a first or recurring diagnosis of a depressive disorder in the last 6 to 12 months of the data collection date. Data at the individual level included socio-demographic characteristics, Charlson Comorbidity Index, Attitude toward Depression and its treatment, and perceived social support. Data at the organizational level had hospital level, nurse competency, nurse-patient ratio, and appointment reminders. Descriptive statistics, Pearson chi-square test, latent class analysis (LCA), and marginal logistic regression model using generalized estimating equation (GEE) were used to analyze the data. RESULTS: The continuing mental health service use among older persons diagnosed with depressive disorders was 54%. The latent class analysis of four variables in the mental health services delivery organization yielded distinct and interpretable findings in two groups: high and low resource organization. The marginal logistic multivariable regression model using GEE found that organizational group and attitude toward depression and its treatment were significantly associated with mental health service use (p-value = 0.046; p-value = 0.003). CONCLUSIONS: The findings suggest that improving continuing mental health services use in older persons diagnosed with depressive disorders should emphasize specialty resources of the mental health services delivery system and attitude toward depression and its treatment.

Relative efficiency of equal versus unequal cluster sizes in cluster randomized trials with a small number of clusters.

To calculate sample sizes in cluster randomized trials (CRTs), the cluster sizes are usually assumed to be identical across all clusters for simplicity. However, equal cluster sizes are not guaranteed in practice, especially when the number of clusters is limited. Therefore, it is important to understand the relative efficiency (RE) of equal versus unequal cluster sizes when designing CRTs with a limited number of clusters. In this paper, we are interested in the RE of two bias-corrected sandwich estimators of the treatment effect in the Generalized Estimating Equation (GEE) models for CRTs with a small number of clusters. Specifically, we derive the RE of two bias-corrected sandwich estimators for binary, continuous, or count data in CRTs under the assumption of an exchangeable working correlation structure. We consider different scenarios of cluster size distributions and investigate RE performance through simulation studies. We conclude that the number of clusters could be increased by as much as 42% to compensate for efficiency loss due to unequal cluster sizes. Finally, we propose an algorithm of increasing the number of clusters when the coefficient of variation of cluster sizes is known and unknown.

A prospective pilot study of the effect on catecholamines of mindfulness training vs pharmacological prophylaxis in patients with chronic migraine and medication overuse headache.

AIM: To address whether, in patients with chronic migraine and medication overuse headache, mindfulness-based treatment is associated with changes in plasma levels of catecholamines and elusive amines that are similar to those observed in patients undergoing pharmacological prophylaxis. METHODS: In this non-randomized, clinic-based effectiveness study, patients aged 18-65, with a history of chronic migraine ≥ 10 years and overuse of triptans or non-steroidal anti-inflammatory drugs ≥ 5 years, were enrolled. Upon completion of a structured withdrawal program, patients received either pharmacological prophylaxis or six weekly sessions of mindfulness-based treatment and were followed for 12 months. Daily headache diaries were used to record headache frequency and medication intake; catecholamines (noradrenaline, epinephrine and dopamine) and levels of elusive amines were assayed from poor platelet plasma. RESULTS: Complete follow-up data were available for 15 patients in the pharmacological prophylaxis-group (14 females, average age 44.1) and 14 in the mindfulness treatment-group (all females, average age 46.4), and all variables were comparable between groups at baseline. At 12 months, significant improvement ( p < .001) was found in the pharmacological prophylaxis group for headache frequency and medication intake (by 51% and 48.7%, respectively), noradrenaline, epinephrine and dopamine (by 98.7%, 120.8% and 501.9%, respectively); patients in the mindfulness treatment-group performed similarly. For elusive amines, no longitudinal changes were found. CONCLUSIONS: The similar improvement trends observed in the two groups of patients further support the utility of mindfulness-based treatment in migraine care, and reinforce the hypothesis that alteration and normalization of tyrosine metabolism are implicated in migraine chronification and in remission of chronic migraine.

Optimal designs in three-level cluster randomized trials with a binary outcome.

Cluster randomized trials (CRTs) were originally proposed for use when randomization at the subject level is practically infeasible or may lead to a severe estimation bias of the treatment effect. However, recruiting an additional cluster costs more than enrolling an additional subject in an individually randomized trial. Under budget constraints, researchers have proposed the optimal sample sizes in two-level CRTs. CRTs may have a three-level structure, in which two levels of clustering should be considered. In this paper, we propose optimal designs in three-level CRTs with a binary outcome, assuming a nested exchangeable correlation structure in generalized estimating equation models. We provide the variance of estimators of three commonly used measures: risk difference, risk ratio, and odds ratio. For a given sampling budget, we discuss how many clusters and how many subjects per cluster are necessary to minimize the variance of each measure estimator. For known association parameters, the locally optimal design is proposed. When association parameters are unknown but within predetermined ranges, the MaxiMin design is proposed to maximize the minimum of relative efficiency over the possible ranges, that is, to minimize the risk of the worst scenario.

Identifying factors influencing contraceptive use in Bangladesh: evidence from BDHS 2014 data.

BACKGROUND: Birth control is the conscious control of the birth rate by methods which temporarily prevent conception by interfering with the normal process of ovulation, fertilization, and implantation. High contraceptive prevalence rate is always expected for controlling births for those countries that are experiencing high population growth rate. The factors that influence contraceptive prevalence are also important to know for policy implication purposes in Bangladesh. This study aims to explore the socio-economic, demographic and others key factors that influence the use of contraception in Bangladesh. METHODS: The contraception data are extracted from the 2014 Bangladesh Demographic and Health Survey (BDHS) data which were collected by using a two stage stratified random sampling technique that is a source of nested variability. The nested sources of variability must be incorporated in the model using random effects in order to model the actual parameter effects on contraceptive prevalence. A mixed effect logistic regression model has been implemented for the binary contraceptive data, where parameters are estimated through generalized estimating equation by assuming exchangeable correlation structure to explore and identify the factors that truly affect the use of contraception in Bangladesh. RESULTS: The prevalence of contraception use by currently married 15-49 years aged women or their husbands is 62.4%. Our study finds that administrative division, place of residence, religion, number of household members, woman's age, occupation, body mass index, breastfeeding practice, husband's education, wish for children, living status with wife, sexual activity in past year, women amenorrheic status, abstaining status, number of children born in last five years and total children ever died were significantly associated with contraception use in Bangladesh. CONCLUSIONS: The odds of women experiencing the outcome of interest are not independent due to the nested structure of the data. As a result, a mixed effect model is implemented for the binary variable 'contraceptive use' to produce true estimates for the significant determinants of contraceptive use in Bangladesh. Knowing such true estimates is important for attaining future goals including increasing contraception use from 62 to 75% by 2020 by the Bangladesh government's Health, Population & Nutrition Sector Development Program (HPNSDP).

The pervasive effect of youth self-report of hunger on depression over 6 years of follow up.

PURPOSE: We used longitudinal data to clarify the association between self-report of hunger and subsequent depression risk among youth and young adults, accounting for other risk factors. METHODS: Youth self-report of ever experiencing hunger data were collected from cycles 4-6 of the National Longitudinal Survey of Children and Youth cohort of Canadian youth 16 years and older (n = 4139). Data on depressive symptoms (CES-D 12) were collected over three cycles (2004-2009, cycles 6-8). We used multivariable regression based on generalized estimating equations (GEE) to examine prior youth hunger on later depression risk, adjusting for time-stable, time-varying, and lagged variables (e.g., depressive symptoms in previous cycle), thereby clarifying the temporal relationship. RESULTS: The prevalence of youth hunger experience and depression risk reached 5.9 and 15.0%, respectively. The adjusted odds ratio of depression for participants reporting hunger was 2.31 (95% CI 1.54, 3.46) and changed little [2.17 (95% CI 1.29, 3.67)] after accounting for previous CES-D 12 scores, suggesting a temporal relationship in which hunger contributes to depression risk. Unlike never-hungry youth, depression in ever-hungry youth remained comparatively elevated over time. CONCLUSIONS: Our models support an independent and temporal relationship between youth self-report of hunger and depression in adolescence and young adulthood.

Novel Application of Cultured Epithelial Autografts (CEA) with Expanded Mesh Skin Grafting Over an Artificial Dermis or Dermal Wound Bed Preparation.

Cultured epithelial autografts (CEA) with highly expanded mesh skin grafts were used for extensive adult burns covering more than 30% of the total body surface area. A prospective study on eight patients assessed subjective and objective findings up to a 12-month follow-up. The results of wound healing for over 1:6 mesh plus CEA, gap 1:6 mesh plus CEA, and 1:3 mesh were compared at 3, 6, and 12 months using extensibility, viscoelasticity, color, and transepidermal water loss by a generalized estimating equation (GEE) or generalized linear mixed model (GLMM). No significant differences were observed among the paired treatments at any time point. At 6 and 12 months, over 1:6 mesh plus CEA achieved significantly better expert evaluation scores by the Vancouver and Manchester Scar Scales (p < 0.01). Extended skin grafting plus CEA minimizes donor resources and the quality of scars is equal or similar to that with conventional low extended mesh slit-thickness skin grafting such as 1:3 mesh. A longitudinal analysis of scars may further clarify the molecular changes of scar formation and pathogenesis.

Accounting for interactions and complex inter-subject dependency in estimating treatment effect in cluster-randomized trials with missing outcomes.

Semi-parametric methods are often used for the estimation of intervention effects on correlated outcomes in cluster-randomized trials (CRTs). When outcomes are missing at random (MAR), Inverse Probability Weighted (IPW) methods incorporating baseline covariates can be used to deal with informative missingness. Also, augmented generalized estimating equations (AUG) correct for imbalance in baseline covariates but need to be extended for MAR outcomes. However, in the presence of interactions between treatment and baseline covariates, neither method alone produces consistent estimates for the marginal treatment effect if the model for interaction is not correctly specified. We propose an AUG-IPW estimator that weights by the inverse of the probability of being a complete case and allows different outcome models in each intervention arm. This estimator is doubly robust (DR); it gives correct estimates whether the missing data process or the outcome model is correctly specified. We consider the problem of covariate interference which arises when the outcome of an individual may depend on covariates of other individuals. When interfering covariates are not modeled, the DR property prevents bias as long as covariate interference is not present simultaneously for the outcome and the missingness. An R package is developed implementing the proposed method. An extensive simulation study and an application to a CRT of HIV risk reduction-intervention in South Africa illustrate the method.

COPD-Related Mortality before and after Mass COVID-19 Vaccination in Northern Italy.

BACKGROUND/OBJECTIVE: Little is known about the impact of the COVID-19 pandemic on mortality from COPD at the population level. The objective was to investigate COPD-related mortality throughout different epidemic waves in Italy before and after the vaccination campaign, which started in late December 2020 and initially targeted the population aged ≥80 years. METHODS: Death certificates of residents in Veneto (Northeastern Italy) aged ≥40 years between 2008 and 2021 were analyzed. Age-standardized morality rates were computed for death certificates with any mention of COPD. Generalized estimating equation (GEE) models were fitted to estimate the expected mortality during the pandemic. The results were stratified by age groups of 40-79 and ≥80 years, main comorbidities, and place of death. RESULTS: COPD was mentioned in 3478 death certificates in 2020 (+14% compared to the 2018-2019 average) and in 3133 in 2021 (+3%). Age-standardized mortality rates increased in all age and sex groups in 2020; in 2021, mortality returned to pre-pandemic levels among the elderly but not in the population aged 40-79 years (+6%). GEE models confirmed this differential trend by age. COPD-related mortality peaks were observed, especially in the first pandemic waves, with COVID-19 identified as the underlying cause of death in a relevant proportion (up to 35% in November 2020-January 2021). Mortality with comorbid diabetes and hypertensive diseases slightly increased during the pandemic. CONCLUSION: COPD-related mortality increased at the beginning of the pandemic, due to deaths from COVID-19. The start of the vaccination campaign was associated with an important decline in COPD-related mortality, especially among the elderly, who first benefited from COVID-19 vaccines. The study findings show the role of mass vaccination in reducing COPD-related deaths during the later phases of the pandemic.

Risk factors of involuntary referral by police to ER psychiatric services for patients with a severe mental illness: A GEE analysis.

This study aimed to identify risk factors for involuntary referral by police to emergency room (ER) psychiatric services for community-based patients with a mental illness via a generalized estimating equation (GEE) analysis. The analysis was based on data from the Management Information System of Psychiatric Care (MISPC) system for patients with a severe mental illness in Taipei, Taiwan and registered referral records of the police. Data on 6378 patients aged ≥20 years were used in this study, including 164 patients who were involuntarily referred to the ER by the police and 6214 patients who were not during the period of January 1, 2018 to December 31, 2020. GEEs were utilized to explore possible risk factors of repeated involuntary referral to ER psychiatric services for patients with a severe mental illness. The logistic regressions indicated that patients defined as "severe" according to the Mental Health Act of Taiwan (crude odds ratio (OR): 3.840, 95 % confidence interval (CI): 2.407-6.126), with a disability (crude OR: 3.567, 95 % CI: 1.339-9.501), with two or more family members with a psychiatric disorder (crude OR: 1.598, 95 % CI: 1.002-2.548), with a history of a suicide attempt (crude OR: 25.582, 95 % CI: 17.608-37.167), and with a history of domestic violence (crude OR: 16.141, 95 % CI: 11.539-22.579) were positively associated with involuntary referral to ER psychiatric services. However, age (crude OR: 0.971, 95 % CI: 0.960-0.983) and the MISPC score (crude OR: 0.834, 95 % CI: 0.800-0.869) were inversely associated with involuntary referral to ER psychiatric services. After adjusting for demographics and potential confounders, we found that patients defined as "severe" (Exp (ß): 3.236), with a disability (Exp (ß): 3.715), with a history of a suicide attempt (Exp (ß): 8.706), and with a history of domestic violence (Exp (ß): 8.826), as well as age (Exp (ß): 0.986) and the MISPC score (Exp (ß): 0.902) remained significantly associated with repeated involuntary referral to ER psychiatric services. In conclusion, community-based mentally ill patients with a history of a suicide attempt, with a history of domestic violence, with a severe illness, and with a profound level of disability were highly associated with involuntary referral to ER psychiatric services. We suggest that community mental health case managers identify significant factors associated with involuntary referral to ER psychiatric services to accordingly arrange case management plans.

Community-based care for autistic youth: community providers' reported use of treatment practices in the United States.

Introduction: To illustrate the landscape of community-based care for autistic youth in the United States, we identified transdisciplinary psychosocial intervention practice sets that community providers report utilizing to care for this population, and examined characteristics associated with provider-reported utilization. Methods: The Usual Care for Autism Study (UCAS) Survey assessed provider demographics and provider-reported use of transdisciplinary practices for common ASD co-occurring problems: social difficulties, externalizing behaviors, and anxiety. Community practitioners (N = 701) from allied health, behavioral, education, medical, mental health and other disciplines who treat or work with autistic youth (7-22 years) participated. Results: Exploratory factor analysis yielded four factors: Consequence-Based Strategies (CBS), Cognitive-Behavioral and Therapy Strategies (CBTS), Antecedent-Based Strategies (ABS), and Teaching Strategies (TS). Providers across disciplines reported utilizing ABS more often than other sets. Providers from behavioral disciplines, with less than 4-year or Master degrees, or with more experience reported the most use of ABS, CBS and CBTS. Medical and behavioral providers reported the most use of TS. Setting and child characteristics were associated with practice set use, indicating variability by disability and client socioeconomic status. Discussion: Findings reflect the complexity and inconsistency of the service landscape for autistic youth across the U.S. Only by understanding the service landscape and predictors of practice utilization, can researchers, policymakers, provider groups, and the autistic community facilitate effective implementation strategy development and use to ultimately improve community-based care.

Factors associated with the healthcare expenditures of patients with multiple sclerosis in urban areas of China estimated by a generalized estimating equation.

Background: Multiple sclerosis (MS) has a significant healthcare burden. This study examined the medical cost and out-of-pocket (OOP) expenses, and quantified the impact factors contributing to the costs. Methods: This is a retrospective study in 77 Chinese urban cites from 2013 to 2015. The data included the details of the utilization of medical resources, cost, and reimbursement ratio of all patients with a diagnosis of MS. A generalized estimating equation model was used to estimate the factors influencing the direct medical cost and OOP expenses for in- and outpatients. Results: A total of 267 patients with MS were identified. The mean cost per in- and outpatient was respectively 16996.2 and 2294.2 renminbi ($2768.12 and $373.65, €2087.16 and €281.73). Approximately 27% of the expenses were paid by the patients OOP. Factors contributing to high cost and high OOP expenses for inpatients were tertiary hospital admission, length of stay and residence in the east regions of China. Females and outpatients with resident insurance paid more OOP. Conclusion: This study illustrates the medical costs and burden of MS in Chinese patients and provides real-world data on MS that are essential for the improvement of health policies.

Polypharmacy and Utilization of Health Care Services: A Cohort Study of People Aged Over 50 Years in Taiwan.

This study aimed to understand the changes and correlation in the long-term trends of polypharmacy and the utilization of health care services in a population over the age of 50 years through the use of a national database. A total of 2813 subjects who participated in surveys in 1999, 2003, and 2007 were selected as the samples. Each subject was followed-up for the period of 9 years. From 1999 to 2007, the proportion of mild and severe polypharmacy cases increased from 41.5% (1999) to 51.3% (2003) and 57.1% (2007), respectively. This study found that the more severe the polypharmacy was, the higher the risk of health care service utilization would be. The Generalized Estimating Equation model of multivariate analysis showed that the incidence rate ratio of medical utilization increased with the severity of polypharmacy, as did the use of advanced medical resources (ie, the number of hospitalizations). In particular, the increase in incidence rate ratio was more significant in 3 aspects: (1) number of pharmacy visits; (2) number of emergency room admissions; and (3) number of hospitalizations. The government should establish policies and guidance for the safe use of medicines to ensure reduced risk for older people.

Stress and career aspirations: a longitudinal study with medical students.

Background: The psychological well-being of medical students has often been studied in relation to various factors and typically exhibits poorer scores than comparable student groups. This diminished well-being can have far-reaching implications, like impact on career or academic engagement. While there are some studies on specialty choice or academic performance few studies have examined the effects of stress at the beginning of medical school on career ambitions and the associated interest in research. Given the anticipated future shortage of healthcare professionals and the goal of gender equality in higher positions, it is crucial to examine this relationship as early as medical education. The question arises whether medical education and the demands of studying influence the career ambitions of different student groups. Method: As part of a longitudinal survey, students from a medical cohort are surveyed over three consecutive years. A total of 297 students participated in the surveys, of which 66.4% were women. Stress experiences during medical school and career aspirations are assessed and analyzed using Generalized Estimating Equation (GEE) modeling. Results: The results indicate that early academic stress is a negative predictor of the career ambitions of medical students (B = 1.637; p = 0.009). Also, female students report lower career goals than male students (B = 1.168; p = 0.018). In addition, gender moderates the impact of stress on career ambitions (p = 0.046). Finally, stress levels are highest when starting the medical program (p = 0.022) and decrease over time. Discussion: Stress during the initial medical training impedes students to pursue higher career ambitions. Future research as well as medical programs need to elaborate more on and consider structural stress prevention interventions in order to promote well-being and strengthen also scientific career goals at an early stage, specifically for female students.

Effects of family planning factors on the awareness of sexual and reproductive healthcare rights among married women of reproductive age in China: a cross sectional study.

OBJECTIVES: Although family planning in China has changed gradually since 1994, there are few studies about family planning and women's reproductive rights. The main objective of this study was to examine awareness of sexual and reproductive healthcare rights (SRHCRs), and learn how factors related to family planning influence awareness of SRHCRs among married women of reproductive age in China. METHODS AND PARTICIPANTS: Inner Mongolia, Chongqing, Guangdong and Henan were selected for the study, and a total of 2504 married women of reproductive age were recruited. A self-administered anonymous questionnaire was used to collect information on participants' awareness of SRHCRs. RESULTS: There were a total of 10 843 (≤6×2504) responses, with a response rate of 72.17% (10 843/15 024) on average among participants regarding SRHCRs (a multiple response set). The highest response rate was for choice (Right 3) (90.64%, 95% CI 89.47%, 91.81%), followed by privacy (Right 5) (86.11%, 95% CI 84.72%, 87.50%) and information (Right 1) (84.47%, 95% CI 83.02%, 85.93%). Only 43.39% (95% CI 41.40%, 45.38%) of participants gave responses to safety (Right 4). Participants without children showed more interest in Right 1, in access (Right 2) and in Right 4. Those who utilised tests for fetal sex determination paid more attention to Rights 2 and 4. Women who accepted informed choice were more likely to be aware of all six rights except for Right 3 and dignity (Right 6). Those individuals who were satisfied or very satisfied with comprehensive sexual and reproductive health counselling services were more likely to show interest in all six rights. CONCLUSIONS: Awareness of SRHCRs among reproductive aged women in China is still inadequate. Family planning service providers might strengthen the service awareness of sex and reproductive health rights according to the different needs of women.

Effect of lavender inhalation on the symptoms of primary dysmenorrhea and the amount of menstrual bleeding: A randomized clinical trial.

OBJECTIVE: The purpose of this study was to explore the effect of Lavandula angustifolia (lavender) inhalation on the symptoms of dysmenorrhea and the amount of menstrual bleeding in female students with primary dysmenorrhea. DESIGN: This study is an experimental clinical trial. The subjects were 96 female students residing in dormitory at Tehran University of Medical Sciences in 2011 and suffering from level two or three dysmenorrhea according to the verbal multi-dimensional scoring system. The inclusion criteria were as: being single, suffering from primary dysmenorrhea, having no genital organs disorder, having no systemic disease, having regular menstrual cycles, using no contraceptives, etc. The follow-up time was 4 menstrual cycles. INTERVENTIONS: The subjects were randomized into two groups: experimental (n=48) who inhaled lavender based on sesame oil, and placebo (n=48) who inhaled sesame oil only. MAIN OUTCOME MEASURES: The severity of dysmenorrhea symptoms was measured through a questionnaire, and the amount of menstrual bleeding was measured by sanitary towel usage. METHODS: Ordinal logistic regression and generalized estimating equation (GEE) were used to analyze the data. RESULTS: The symptoms of dysmenorrhea were significantly lowered in the lavender group compared to the placebo group (p<0.001). The amount of menstrual bleeding in the lavender group was reduced in comparison to the placebo group but the difference was not statistically significant (p=0.25). No significant difference was observed for blood clot among the students (p=0.666). CONCLUSIONS: This study showed that lavender inhalation was effective in alleviating dysmenorrhea symptoms, suggesting that it could be applied by midwives in a safe manner because of no side effects, simplicity and cost-effectiveness for all patients.