Outcomes of New York City Care Calls: A Prospective Randomized Controlled Effectiveness Trial of Telephone-Delivered Type 2 Diabetes Self-Management Support.

PURPOSE: The purpose of the 12-month randomized controlled trial was to evaluate the effectiveness of a Telephonic Self-Management Support (T-SMS) program among adults with type 2 diabetes (T2D). METHODS: Eight hundred twelve adults with T2D participated in NYC Care Calls (mean age = 59.2, SD = 10.8; female = 57%; mean A1C = 9.3, SD = 1.8; Latino = 86%) and were randomly assigned to T-SMS or enhanced usual care (EUC). A1C (primary outcome), blood pressure, and body mass index (secondary outcomes) were extracted from electronic medical records. Secondary patient-reported outcomes, including depressive symptoms, diabetes distress, medication adherence, and self-management activities, were assessed by telephone in English or Spanish. For T-SMS, the number of assigned phone calls was based on baseline A1C, depressive symptoms, and/or diabetes distress. Analyses were conducted under the intention-to-treat principle. RESULTS: A1C decreased over 12 months in both T-SMS (0.72% percentage points; 95% CI, 0.53-0.91) and EUC (0.66% percentage points; 95% CI, 0.46-0.85; Ps < .001). Diabetes distress and self-management also improved over time in both arms (Ps < .05). Compared to EUC, participants in the T-SMS arm did not differ in outcomes. CONCLUSIONS: The T-SMS and EUC groups were found not to have an appreciable outcome difference. It is unclear whether improvements in A1C across both conditions represent a secular trend or indicate that print-based educational intervention may have a positive impact on self-management and well-being.

Facilitation of team-based care to improve HTN management and outcomes: a protocol for a randomized stepped wedge trial.

BACKGROUND: There are well-established guidelines for treating hypertension (HTN), yet only half of patients with HTN meet the defined target of < 140/90. Team-based care (TBC) is an evidence-based strategy for improving blood pressure (BP) management and control. TBC is defined as the provision of health services by at least two health professionals "who work collaboratively with patients and their caregivers to accomplish shared goals to achieve coordinated, high-quality care". However, primary care practices experience challenges to implementing TBC principles and care processes; these are more pronounced in small independent practice settings (SIPs). Practice facilitation (PF) is an implementation strategy that may overcome barriers to adopting evidence-based TBC to improve HTN management in SIPs. METHODS: Using a stepped wedge randomized controlled trial design, we will test the effect of PF on the adoption of TBC to improve HTN management in small practices (< 5 FTE clinicians) in New York City, and the impact on BP control compared with usual care. We will enroll 90 SIPs and randomize them into one of three 12-month intervention waves. Practice facilitators will support SIPs to adopt TBC principles to improve implementation of five HTN management strategies (i.e., panel management, population health, measuring BP, supporting medication adherence, self-management). The primary outcome is the adoption of TBC for HTN management measured at baseline and 12 months. Secondary outcomes include the rate of BP control and sustainability of TBC and BP outcomes at 18 months. Aggregated data on BP measures are collected every 6 months in all clusters so that each cluster provides data points in both the control and intervention conditions. Using a mixed methods approach, we will also explore factors that influence the effectiveness of PF at the organization and team level. DISCUSSION: This study will provide much-needed guidance on how to optimize adoption and sustainability of TBC in independent primary care settings to reduce the burden of disease related to suboptimal BP control and advance understanding of how facilitation works to improve implementation of evidence-based interventions. TRIAL REGISTRATION: ClinicalTrials.gov; NCT05413252 .

Practice facilitation for scale up of clinical decision support for hypertension management: study protocol for a cluster randomized control trial.

BACKGROUND: Only half of patients with hypertension have adequately controlled blood pressure. Clinical decision support (CDS) has the potential to overcome barriers to delivering guideline-recommended care and improve hypertension management. However, optimal strategies for scaling CDS have not been well established, particularly in small, independent primary care practices which often lack the resources to effectively change practice routines. Practice facilitation is an implementation strategy that has been shown to support process changes. Our objective is to evaluate whether practice facilitation provided with hypertension-focused CDS can lead to improvements in blood pressure control for patients seen in small primary care practices. METHODS/DESIGN: We will conduct a cluster randomized control trial to compare the effect of hypertension-focused CDS plus practice facilitation on BP control, as compared to CDS alone. The practice facilitation intervention will include an initial training in the CDS and a review of current guidelines along with follow-up for coaching and integration support. We will randomize 46 small primary care practices in New York City who use the same electronic health record vendor to intervention or control. All patients with hypertension seen at these practices will be included in the evaluation. We will also assess implementation of CDS in all practices and practice facilitation in the intervention group. DISCUSSION: The results of this study will inform optimal implementation of CDS into small primary care practices, where much of care delivery occurs in the U.S. Additionally, our assessment of barriers and facilitators to implementation will support future scaling of the intervention. CLINICALTRIALS: gov Identifier: NCT05588466.

Diabetes-Related Quality of Life: Learning From Individuals Making Lifestyle Changes to Improve Type 2 Diabetes Control.

PURPOSE: The purpose of this study was to explore how treatment adherence and lifestyle changes required for glycemic control in type 2 diabetes (T2D) are related to quality of life (QoL) among predominantly ethnic minority and socioeconomically disadvantaged adults engaged in making changes to improve T2D self-management. METHODS: Adults with T2D in New York City were recruited for the parent study based on recent A1C (≥7.5%) and randomly assigned to 1 of 2 arms, receiving educational materials and additional self-management support calls, respectively. Substudy participants were recruited from both arms after study completion. Participants (N = 50; 62% Spanish speaking) were interviewed by phone using a semistructured guide and were asked to define QoL and share ways that T2D, treatment, self-management, and study participation influenced their QoL. Interviews were analyzed using thematic analysis. RESULTS: QoL was described as a multidimensional health-related construct with detracting and enhancing factors related to T2D. Detracting factors included financial strain, symptom progression and burden, perceived necessity to change cultural and lifestyle traditions, and dietary and medical limitations. Enhancing factors included social support, diabetes education, health behavior change, sociocultural connection. CONCLUSION: QoL for diverse and socioeconomically disadvantaged adults with T2D is multifaceted and includes aspects of health, independence, social support, culture, and lifestyle, which may not be captured by existing QoL measures. Findings may inform the development of a novel QoL measure for T2D.

Design and methods of NYC care calls: An effectiveness trial of telephone-delivered type 2 diabetes self-management support.

Although problems with type 2 diabetes (T2D) self-management and treatment adherence often co-occur with emotional distress, few translatable intervention approaches are available that can target these related problems in primary care practice settings. The New York City (NYC) Care Calls study is a randomized controlled trial that tests the effectiveness of structured support for diabetes self-management and distress management, delivered via telephone by health educators, in improving glycemic control, self-management and emotional well-being among predominantly ethnic minority and socioeconomically disadvantaged adults with suboptimally controlled T2D. English- and Spanish-speaking adults treated for T2D in NYC primary care practices were recruited based on having an A1C ≥ 7.5% despite being prescribed medications for diabetes. Participants (N = 812) were randomly assigned to a telephonic intervention condition with a stepped protocol of 6-12 phone calls over 1 year, delivered by a health educator, or to a comparison condition of enhanced usual care. The primary outcome is change in A1C over one year, measured at baseline and again approximately 6- and 12-months later. Secondary outcomes measured on the same schedule include blood pressure, patient-reported emotional distress, treatment adherence and self-management behaviors. A comprehensive effectiveness evaluation is guided by the RE-AIM framework (Reach, Effectiveness, Adoption, Implementation, Maintenance) to gather data that can inform dissemination and implementation of the intervention, if successful. This paper describes the study rationale, trial design, and methodology.

Impact of a Telephonic Intervention to Improve Diabetes Control on Health Care Utilization and Cost for Adults in South Bronx, New York.

OBJECTIVE: Self-management education and support are essential for improved diabetes control. A 1-year randomized telephonic diabetes self-management intervention (Bronx A1C) among a predominantly Latino and African American population in New York City was found effective in improving blood glucose control. To further those findings, this current study assessed the intervention's impact in reducing health care utilization and costs over 4 years. RESEARCH DESIGN AND METHODS: We measured inpatient (n = 816) health care utilization for Bronx A1C participants using an administrative data set containing all hospital discharges for New York State from 2006 to 2014. Multilevel mixed modeling was used to assess changes in health care utilization and costs between the telephonic diabetes intervention (Tele/Pr) arm and print-only (PrO) control arm. RESULTS: During follow-up, excess relative reductions in all-cause hospitalizations for the Tele/Pr arm compared with PrO arm were statistically significant for odds of hospital use (odds ratio [OR] 0.89; 95% CI 0.82, 0.97; P < 0.01), number of hospital stays (rate ratio [RR] 0.90; 95% CI 0.81, 0.99; P = 0.04), and hospital costs (RR 0.90; 95% CI 0.84, 0.98; P = 0.01). Reductions in hospital use and costs were even stronger for diabetes-related hospitalizations. These outcomes were not significantly related to changes observed in hemoglobin A1c during individuals' participation in the 1-year intervention. CONCLUSIONS: These results indicate that the impact of the Bronx A1C intervention was not just on short-term improvements in glycemic control but also on long-term health care utilization. This finding is important because it suggests the benefits of the intervention were long-lasting with the potential to not only reduce hospitalizations but also to lower hospital-associated costs.

Heart Age, Cardiovascular Disease Risk, and Disparities by Sex and Race/Ethnicity Among New York City Adults.

OBJECTIVES: Cardiovascular disease (CVD) is the leading cause of mortality in the United States. The risk for developing CVD is usually calculated and communicated to patients as a percentage. The calculation of heart age-defined as the predicted age of a person's vascular system based on the person's CVD risk factor profile-is an alternative method for expressing CVD risk. We estimated heart age among adults aged 30-74 in New York City and examined disparities in excess heart age by race/ethnicity and sex. METHODS: We applied data from the 2011, 2013, and 2015 New York State Behavioral Risk Factor Surveillance System to the non-laboratory-based Framingham risk score functions to calculate 10-year CVD risk and heart age by sex, race/ethnicity, and selected sociodemographic groups and risk factors. RESULTS: Of 6117 men and women in the study sample, the average heart age was 5.7 years higher than the chronological age, and 2631 (43%) adults had a predicted heart age ≥5 years older than their chronological age. Mean excess heart age increased with age (from 0.7 year among adults aged 30-39 to 11.2 years among adults aged 60-74) and body mass index (from 1.1 year among adults with normal weight to 11.8 years among adults with obesity). Non-Latino white women had the lowest mean excess heart age (2.3 years), and non-Latino black men and women had the highest excess heart age (8.4 years). CONCLUSIONS: Racial/ethnic and sex disparities in CVD risk persist among adults in New York City. Use of heart age at the population level can support public awareness and inform targeted programs and interventions for population subgroups most at risk for CVD.

Supportive Housing and Its Relationship With Diabetes Diagnosis and Management Among Homeless Persons in New York City.

Supportive housing addresses a fundamental survival need among homeless persons, which can lead to reduced risk of diabetes mellitus and improved diabetes care. We tested the association between supportive housing and diabetes outcomes among homeless adults who were eligible for New York City's supportive housing program in 2007-2012. We used multiple administrative data sources, identifying 7,525 Medicaid-eligible adults. The outcomes included receiving medical evaluation and management services, hemoglobin A1C and lipid testing (n = 1,489 persons with baseline diabetes), and incidence of new diabetes diagnoses (n = 6,036 persons without baseline diabetes) in the 2 years postbaseline. Differences in these outcomes by placement were estimated using inverse-probability-of-treatment weighting. Placed persons were more likely to receive evaluation and management services (relative risk (RR) = 1.03, 95% confidence interval (CI): 1.01, 1.04) than unplaced persons. For those with baseline diabetes, placed persons were more likely to receive hemoglobin A1C tests (RR = 1.10, 95% CI: 1.02, 1.19) and lipid tests (RR = 1.09, 95% CI: 1.02, 1.17). For those without baseline diabetes, placement was also associated with lower risk of new diabetes diagnoses (RR = 0.87, 95% CI: 0.76, 0.99). These findings show that benefits of supportive housing may be extended to diabetes care and prevention.

Primary Care Practices' Abilities And Challenges In Using Electronic Health Record Data For Quality Improvement.

Federal value-based payment programs require primary care practices to conduct quality improvement activities, informed by the electronic reports on clinical quality measures that their electronic health records (EHRs) generate. To determine whether EHRs produce reports adequate to the task, we examined survey responses from 1,492 practices across twelve states, supplemented with qualitative data. Meaningful-use participation, which requires the use of a federally certified EHR, was associated with the ability to generate reports-but the reports did not necessarily support quality improvement initiatives. Practices reported numerous challenges in generating adequate reports, such as difficulty manipulating and aligning measurement time frames with quality improvement needs, lack of functionality for generating reports on electronic clinical quality measures at different levels, discordance between clinical guidelines and measures available in reports, questionable data quality, and vendors that were unreceptive to changing EHR configuration beyond federal requirements. The current state of EHR measurement functionality may be insufficient to support federal initiatives that tie payment to clinical quality measures.

Using Indirect Measures to Identify Geographic Hot Spots of Poor Glycemic Control: Cross-sectional Comparisons With an A1C Registry.

OBJECTIVE: Focusing health interventions in places with suboptimal glycemic control can help direct resources to neighborhoods with poor diabetes-related outcomes, but finding these areas can be difficult. Our objective was to use indirect measures versus a gold standard, population-based A1C registry to identify areas of poor glycemic control. RESEARCH DESIGN AND METHODS: Census tracts in New York City (NYC) were characterized by race, ethnicity, income, poverty, education, diabetes-related emergency visits, inpatient hospitalizations, and proportion of adults with diabetes having poor glycemic control, based on A1C >9.0% (75 mmol/mol). Hot spot analyses were then performed, using the Getis-Ord Gi* statistic for all measures. We then calculated the sensitivity, specificity, positive and negative predictive values, and accuracy of using the indirect measures to identify hot spots of poor glycemic control found using the NYC A1C Registry data. RESULTS: Using A1C Registry data, we identified hot spots in 42.8% of 2,085 NYC census tracts analyzed. Hot spots of diabetes-specific inpatient hospitalizations, diabetes-specific emergency visits, and age-adjusted diabetes prevalence estimated from emergency department data, respectively, had 88.9%, 89.6%, and 89.5% accuracy for identifying the same hot spots of poor glycemic control found using A1C Registry data. No other indirect measure tested had accuracy >80% except for the proportion of minority residents, which had 86.2% accuracy. CONCLUSIONS: Compared with demographic and socioeconomic factors, health care utilization measures more accurately identified hot spots of poor glycemic control. In places without a population-based A1C registry, mapping diabetes-specific health care utilization may provide actionable evidence for targeting health interventions in areas with the highest burden of uncontrolled diabetes.

Associations of Residential Socioeconomic, Food, and Built Environments With Glycemic Control in Persons With Diabetes in New York City From 2007-2013.

In the present study, we examined the longitudinal associations between residential environmental factors and glycemic control in 182,756 adults with diabetes in New York City from 2007 to 2013. Glycemic control was defined as a hemoglobin A1c (HbA1c) level less than 7%. We constructed residential-level measures and performed principle component analysis to formulate a residential composite score. On the basis of this score, we divided residential areas into quintiles, with the lowest and highest quintiles reflecting the least and most advantaged residential environments, respectively. Several residential-level environmental characteristics, including more advantaged socioeconomic conditions, greater ratio of healthy food outlets to unhealthy food outlets, and residential walkability were associated with increased glycemic control. Individuals who lived continuously in the most advantaged residential areas took less time to achieve glycemic control compared with the individuals who lived continuously in the least advantaged residential areas (9.9 vs. 11.5 months). Moving from less advantaged residential areas to more advantaged residential areas was related to improved diabetes control (decrease in HbA1c = 0.40%, 95% confidence interval: 0.22, 0.55), whereas moving from more advantaged residential areas to less advantaged residential areas was related to worsening diabetes control (increase in HbA1c = 0.33%, 95% confidence interval: 0.24, 0.44). These results show that residential areas with greater resources to support healthy food and residential walkability are associated with improved glycemic control in persons with diabetes.

Poorly Controlled Diabetes in New York City: Mapping High-Density Neighborhoods.

OBJECTIVE: To identify geographic areas in New York City (NYC) for implementing programming focused on reducing the burden attributed to poor glycemic control and improving the health of New Yorkers. DESIGN: We geocoded addresses of NYC residents in the NYC Hemoglobin A1c (HbA1C) Registry with high (>9%) HbA1c test values from 2011 to 2013 on an NYC base map. The ArcGIS point density spatial analysis tool was applied to create a map of NYC residents with diabetes in poor glycemic control. SETTING: The setting for HbA1c testing was medical facilities within NYC. PARTICIPANTS: The study population included NYC residents (excluding undomiciled persons and addresses corresponding to prisons, hospitals, or nursing homes) 18 years or older who underwent HbA1c testing from 2011 to 2013. MAIN OUTCOME MEASURES: A map depicting point density of NYC residents with poor glycemic control was developed each year from 2011 to 2013 (2011: n = 70 359; 2012: n = 75 643; 2013: n = 78 694). RESULTS: Particularly, high densities of persons in poor glycemic control were identified in Flatbush, East Harlem, Washington Heights/Inwood, and the South Bronx. The 2 highest-density gradients (out of 9) covered approximately 1.7% of the total habitable area in NYC, while accounting for more than 1 in 10 (10.5%) persons in poor glycemic control. The 3 highest-density gradients covered 4.1% of NYC's habitable area and accounted for more than 1 in 5 (21.9%) persons in poor glycemic control. CONCLUSION: The point density analysis highlighted several defined geographic areas representing a meaningful proportion of the population in poor glycemic control. This analysis could be used to raise community awareness and guide potential programming focused on reducing the burden of poor glycemic control such as the placement of diabetes self-management education classes, community health workers, and farmers' markets. Given the geographic breadth of NYC and limited resources, focused efforts on these defined areas would reach a sizeable number of the at-risk population.

Testing the use of practice facilitation in a cluster randomized stepped-wedge design trial to improve adherence to cardiovascular disease prevention guidelines: HealthyHearts NYC.

BACKGROUND: HealthyHearts NYC (HHNYC) will evaluate the effectiveness of practice facilitation as a quality improvement strategy for implementing the Million Hearts' ABCS treatment guidelines for reducing cardiovascular disease (CVD) among high-risk patients who receive care in primary care practices in New York City. ABCS refers to (A) aspirin in high-risk individuals; (B) blood pressure control; (C) cholesterol management; and (S) smoking cessation. The long-term goal is to create a robust infrastructure for implementing and disseminating evidence-based practice guidelines (EBPG) in primary care practices. METHODS/DESIGN: We are using a stepped-wedge cluster randomized controlled trial design to evaluate the implementation process and the impact of practice facilitation (PF) versus usual care on ABCS outcomes in 250 small primary care practices. Randomization is at the practice site level, all of which begin as part of the control condition. The intervention consists of one year of PF that includes a combination of one-on-one onsite visits and shared learning across practice sites. PFs will focus on helping sites implement evidence-based components of patient-centered medical home (PCMH) and the chronic care model (CCM), which include decision support, provider feedback, self-management tools and resources, and linkages to community-based services. DISCUSSION: We hypothesize that practice facilitation will result in superior clinical outcomes compared to usual care; that the effects of practice facilitation will be mediated by greater adoption of system changes in accord with PCMH and CCM; and that there will be increased adaptive reserve and change capacity. TRIAL REGISTRATION: NCT02646488.

Strengthening public health and primary care collaboration through electronic health records.

Electronic health records (EHRs) have great potential to serve as a catalyst for more effective coordination between public health departments and primary care providers (PCP) in maintaining healthy communities. As a system for documenting patient health data, EHRs can be harnessed to improve public health surveillance for communicable and chronic illnesses. EHRs facilitate clinical alerts informed by public health goals that guide primary care physicians in real time in their diagnosis and treatment of patients. As health departments reassess their public health agendas, the use of EHRs to facilitate this agenda in primary care settings should be considered. PCPs and EHR vendors, in turn, will need to configure their EHR systems and practice workflows to align with public health priorities as these agendas include increased involvement of primary care providers in addressing public health concerns.

Impact of integrating public health clinical decision support alerts into electronic health records on testing for gastrointestinal illness.

Laboratory testing by clinicians is essential to outbreak investigations. Electronic health records may increase testing through clinical decision support that alerts providers about existing outbreaks and facilitates laboratory ordering. The impact on laboratory testing was evaluated for foodborne disease outbreaks between 2006 and 2009. After controlling for standard public health messaging and season, decision support resulted in a significant increase in laboratory testing and may be useful in enhancing public health messaging and provider action.

Patient experiences at primary care practices using electronic health records.

We assessed patient experiences before and one year after electronic health record (EHR) implementation among primary care practices in New York City. These practices represented an ethnically diverse population in lower-income, urban communities. Surveys, available in English, Spanish, and Chinese languages, were administered at 10 sites. Generally, patients reported positive responses during both periods. After EHR implementation, patients were more likely to want e-mail communication with their doctors' office. The 70% of patients with Internet access were generally more satisfied with their experience and more likely to recognize benefits of EHRs. However, older patients and those with lower education levels or chronic diseases were significantly less likely than their counterparts to use the Internet. Therefore, disparities in Internet access could potentially lead to unequal access and use of healthcare if not addressed. Practices should routinely record patient communication preferences within the EHR, to tailor communications and improve patient experiences.

Syndromic surveillance during pandemic (H1N1) 2009 outbreak, New York, New York, USA.

We compared emergency department and ambulatory care syndromic surveillance systems during the pandemic (H1N1) 2009 outbreak in New York City. Emergency departments likely experienced increases in influenza-like-illness significantly earlier than ambulatory care facilities because more patients sought care at emergency departments, differences in case definitions existed, or a combination thereof.

Reducing medication errors and improving systems reliability using an electronic medication reconciliation system.

BACKGROUND: Medication reconciliation (MedRecon) has been a Joint Commission National Patient Safety Goal since 2006. However, there is scant literature on the evaluation of electronic MedRecon systems in reducing medication errors and on improving reliability of the MedRecon process. METHODS: An electronic MedRecon system was designed and implemented in an acute inpatient care facility. Two analyses were performed: (1) one based on a 2-week pilot evaluation of the system based on 120 MedRecon events, and (2) a more comprehensive 17-month evaluation of the system, based on 19,356 MedRecon events. RESULTS: The unintended discrepancy rate between a patient's home medications and admission medication orders was reduced from 20% during the pilot phase to 1.4%. The omission of a home medication was the most common type of discrepancy. Nighttime admission (8 P.M.-8 A.M.), total home medications > four, patient age > 65 years, and resident physician performing the medication reconciliation were found to have a significant positive correlation (p < .05) with the discrepancy rate. Using computerized alerts improved compliance with the MedRecon process from 34% to 98%-100%. DISCUSSION: Using a multidisciplinary process based on an electronic system substantially reduced medication errors on admission, suggesting that an electronic MedRecon system can be an important tool in improving patient safety. The use of an interactive reminder alert in the MedRecon system improved systems reliability by ensuring physician compliance with MedRecon performance. Although computerized physician order entry (CPOE) decision support tools are an important component of medication error prevention strategies, they alone are not sufficient to prevent errors of prescribing.

Effect of quality improvement organization activities on outpatient diabetes care in eastern New York State.

BACKGROUND: Quality improvement organizations (QIOs) are contracted to improve the quality of care delivered to Medicare beneficiaries. The purpose of this study was to determine whether provider participation in New York State QIO activities resulted in significant improvements in the quality of diabetes care during the recent contract cycle with the Centers for Medicare & Medicaid Services. RESEARCH DESIGN: A retrospective analysis between participating and nonparticipating providers on their performance in 3 quality measures (biennial ophthalmology examination, biennial lipid profile monitoring, annual hemoglobin A1c monitoring) was used. Data of New York State Medicare beneficiaries before and after QIO intervention activities were examined to determine change in performance. General linear models were created to examine the effect QIO participation had on the change in performance for each measure. RESULTS: Providers who participated in QIO activities had significant absolute improvements in lipid monitoring compared with nonparticipating providers at high baseline performance for low (3.10%, P < 0.001), medium (2.57%, P < 0.001), and high (1.51%, P = 0.002) baseline patient volume, and medium baseline performance for low (2.38%, P < 0.001), and medium (1.85%, P < 0.001) baseline patient volume. The same trend was seen for hemoglobin A1c monitoring (4.28%, P < 0.001; 3.57%, P < 0.001; 2.15%, P < 0.001; 2.63%, P = 0.001; 1.92%, P = 0.006). For ophthalmology examination, participation resulted in significant changes at low (2.28%, P = 0.003) and medium (1.73%, P = 0.009) baseline patient volume. CONCLUSION: The study results suggest QIO activities can improve outpatient diabetes care; however, limitations in the study design preclude any definitive remarks.