Safety and functional outcomes of early antiplatelet therapy within 24 hours following mechanical thrombectomy for secondary prevention in emergent large-vessel occlusion strokes: a registry study.

OBJECTIVE: The aim of this study was to demonstrate the safety and functional outcomes of antiplatelet use within 24 hours following mechanical thrombectomy (MT). METHODS: A retrospective review of prospectively collected data for consecutive patients who underwent MT for acute ischemic stroke (AIS) between 2016 and 2020 was performed. Patient demographics, comorbidities, Alberta Stroke Program Early CT Score (ASPECTS), antiplatelet use, neurological status, and tissue plasminogen activator use were collected. Patients were stratified into two groups, early (< 24 hours) or late (> 24 hours), based on when antiplatelet therapy was initiated post-MT. The primary outcome was safety, determined based on the rate of symptomatic intracranial hemorrhage (sICH) and inpatient mortality. The secondary outcome was functional independence (defined as modified Rankin Scale [mRS] score ≤ 2) at discharge and 30 days and 90 days postoperatively. The two cohorts were compared using univariate analysis. Multiple imputations were used to create complete data sets for missing data. Multivariable analysis was used to identify predictors for sICH and functional outcomes. RESULTS: A total of 190 patients met inclusion criteria (95 per group). Significant differences between the early and late groups included sex, preoperative intravenous thrombolysis, angioplasty, stent placement, and thrombectomy site. ICH (symptomatic and asymptomatic) and inpatient mortality were not significantly different between the groups. The mRS score was significantly lower at discharge (p < 0.001), 30 days (p = 0.011), and 90 days (p = 0.024) following MT in the early group. Functional independence was significantly higher in the early antiplatelet group at discharge (p = 0.015) and at 30 days (p = 0.006). Early antiplatelet use was independently associated with significantly increased odds of achieving functional independence at discharge (OR 3.07, p = 0.007) and 30 days (OR 5.78, p = 0.004). Early antiplatelet therapy was not independently associated with increased odds of sICH. CONCLUSIONS: Early antiplatelet initiation after MT in patients with AIS was independently associated with significantly increased odds of improved postoperative functional outcomes without increased odds of developing sICH.

The Effect of Preoperative Symptom Duration on Patient-Reported Outcomes After Anterior Cervical Discectomy and Fusion in Nonmyelopathic Patients: Analyses From the Michigan Spine Surgery Improvement Collaborative (MSSIC).

BACKGROUND: The effect of preoperative symptom duration (PSD) on patient-reported outcomes (PROs) in anterior cervical discectomy and fusion (ACDF) for radiculopathy is unclear. OBJECTIVE: To determine whether PSD is a predictor for PRO after ACDF for radiculopathy. METHODS: The Michigan Spine Surgery Improvement Collaborative registry was queried between March, 2014, and July, 2019, for patients who underwent ACDF without myelopathy and PROs (baseline, 90 days, 1 year, 2 years). PROs were measured by numerical rating scales for neck/arm pain, Patient-Reported Outcomes Measurement Information System Short Form-Physical Function (PROMIS-PF), EuroQol-5D (EQ5D), and North American Spine Society satisfaction. Univariate analyses were used to evaluate the proportion of patients reaching minimal clinically important differences (MCID). PSD was <3 months, 3 month-1 year, or >1 years. Multiple logistic regression models were used to estimate the association between PSD and PRO reaching MCID. The discriminative ability of the model was evaluated by receiver operating characteristic curve. RESULTS: We included 2233 patients who underwent ACDF with PSD <3 months (278, 12.4%), 3 month-1 year (669, 30%), and >1 years (1286, 57.6%). Univariate analyses demonstrated a greater proportion of patients achieving MCID in <3-month cohort for arm numerical rating scales, PROMIS-PF, EQ5D, and North American Spine Society Satisfaction. Multivariable analyses demonstrated using <3 months PSD as a reference, PSD >1 years was associated with decreased odds of achieving MCID for EQ5D (odds ratio 0.5, CI 0.32-0.80, P = .004). Private insurance and increased baseline PRO were associated with significantly higher odds for achieving PROMIS-PF MCID and EQ5D-MCID. CONCLUSION: Preoperative symptom duration greater than 1 year in patients who underwent ACDF for radiculopathy was associated with worse odds of achieving MCID for multiple PROs.

Radiographic and Patient-Reported Outcomes of Lordotic Versus Non-lordotic Static Interbody Devices in Minimally Invasive Transforaminal Lumbar Interbody Fusion: A Longitudinal Comparative Cohort Study.

Introduction Minimally invasive transforaminal lumbar interbody fusion (MI-TLIF) is increasingly used to treat lumbar degenerative pathology. Its effect on sagittal parameters remains controversial. Static and expandable lordotic interbody devices (cages) were developed to improve segmental and overall lumbar lordosis. This study aimed to compare the radiographic and patient-reported outcomes (PROs) between static lordotic and non-lordotic titanium cages in patients undergoing 1-2 level MI-TLIF for degenerative conditions.  Methods We reviewed consecutive eligible patients who underwent 1-2 level MI-TLIF (7/2017-11/2019) at a single institution by multiple surgeons. Standing X-rays and PROs were collected at preoperative, 1-month, and 6-month postoperative intervals. Using univariate analyses, we compared the two cohorts regarding confounders, radiographic parameters, and proportions of patients reaching minimal clinically important difference (MCID) for PROs. Results One-hundred-twenty-five patients were reviewed. Forty-seven had lordotic and seventy-eight non-lordotic cages. The lordotic cohort was significantly younger than the non-lordotic (55.9 years vs. 60.7 years, p= 0.042). The baseline radiographic parameters were not significantly different between cohorts. At the preoperative-6-month interval, the lordotic cohort had significant improvement in lumbar lordosis versus non-lordotic cohort (2.95° ± 7.2° vs. -0.3° ± 7.1°, p=0.024). Both cohorts showed improvement in segmental lordosis, anterior and posterior interspace height, and low subsidence grade with no significant difference between cohorts at all intervals. Overall, 69.1-83.8% of patients achieved MCID in all PROs with no significant difference between cohorts. Conclusions The use of a static lordotic titanium cage in 1-2 level MI-TLIF did not result in significantly different radiographic improvements or PROs compared with a non-lordotic cage.

The effect of ketorolac on posterior minimally invasive transforaminal lumbar interbody fusion: an interim analysis from a randomized, double-blinded, placebo-controlled trial.

BACKGROUND CONTEXT: Postoperative pain control following posterior lumbar fusion continues to be challenging and often requires high doses of opioids for pain relief. The use of ketorolac in spinal fusion is limited due to the risk of pseudarthrosis. However, recent literature suggests it may not affect fusion rates with short-term use and low doses. PURPOSE: We sought to demonstrate noninferiority regarding fusion rates in patients who received ketorolac after undergoing minimally invasive (MIS) posterior lumbar interbody fusion. Additionally, we sought to demonstrate ketorolac's opioid-sparing effect on analgesia in the immediate postoperative period. STUDY DESIGN/SETTING: This is a prospective, randomized, double-blinded, placebo-controlled trial. We are reporting our interim analysis. PATIENT SAMPLE: Adults with degenerative spinal conditions eligible to undergo a one to three-level MIS transforaminal lumbar interbody fusion (TLIF). OUTCOME MEASURES: Six-month and 1-year radiographic fusion as determined by Suk criteria, postoperative opioid consumption as measured by intravenous milligram morphine equivalent, length of stay, and drug-related complications. Self-reported and functional measures include validated visual analog scale, short-form 12, and Oswestry Disability Index. METHODS: A double-blinded, randomized placebo-controlled, noninferiority trial of patients undergoing 1- to 3-level MIS TLIF was performed with bone morphogenetic protein (BMP). Patients were randomized to receive a 48-hour scheduled treatment of either intravenous ketorolac (15 mg every 6 hours) or saline in addition to a standardized pain regimen. The primary outcome was fusion. Secondary outcomes included 48-hour and total postoperative opioid use demonstrated as milligram morphine equivalence, pain scores, length of stay (LOS), and quality-of-life outcomes. Univariate analyses were performed. The present study provides results from a planned interim analysis. RESULTS: Two hundred and forty-six patients were analyzed per protocol. Patient characteristics were comparable between the groups. There was no significant difference in 1-year fusion rates between the two treatments (p=.53). The difference in proportion of solid fusion between the ketorolac and placebo groups did not reach inferiority (p=.072, 95% confidence interval, -.07 to .21). There was a significant reduction in total/48-hour mean opioid consumption (p<.001) and LOS (p=.001) for the ketorolac group while demonstrating equivalent mean pain scores in 48 hours postoperative (p=.20). There was no significant difference in rates of perioperative complications. CONCLUSIONS: Short-term use of low-dose ketorolac in patients who have undergone MIS TLIF with BMP demonstrated noninferior fusion rates. Ketorolac safely demonstrated a significant reduction in postoperative opioid use and LOS while maintaining equivalent postoperative pain control.

Age as a Risk Factor for Complications Following Anterior Cervical Discectomy and Fusion: Analysis From the Michigan Spine Surgery Improvement Collaborative (MSSIC).

STUDY DESIGN: Retrospective analysis of prospectively collected registry data using multivariable analyses of imputed data. OBJECTIVE: We sought to demonstrate that age would not be associated with complications in patients undergoing anterior cervical discectomy and fusion (ACDF). SUMMARY OF BACKGROUND DATA: Elderly patients (≥70 yrs) undergoing ACDF are considered a higher risk for complications. However, conclusive evidence is lacking. The Michigan Spine Surgery Improvement Collaborative (MSSIC) is a quality improvement collaborative with 30 hospitals across Michigan. METHODS: The study included all patients who had 1 to 4 level ACDF (September 2015-August 2019) for 90-day complications. Major and minor complications were defined using a validated classification. Multiple imputations were used to generate complete covariate datasets. Generalized estimating equation model was used to identify associations with complications using the whole cohort and elderly subgroup analyses. Bonferroni correction was used. RESULTS: Nine thousand one hundred thirty five patients (11.1% ≥ 70 yrs and 88.9% <70 yrs) with 2266 complications were analyzed. Comparing elderly versus non-elderly, the elderly had a significantly higher rate of any complications (31.5% vs. 24.0%, P < 0.001) and major complications (14.1% vs. 7.0%, P < 0.001). On multivariable analysis, age was not independently associated with any complication. POD#0 ambulation and preop independent ambulation were independently associated with significantly decreased odds of any complication. In the elderly, independent preoperative ambulation was protective for any complication (odds ratio [OR] 0.53, 0.39-0.73 95% confidence interval [CI]), especially major complications (OR 0.41, 0.27-0.61 95% CI). CONCLUSION: Age was not an independent risk factor for complications in patients that underwent ACDF. In the elderly, independent preoperative ambulation was especially protective for major complications.Level of Evidence: 3.

The Effect of Morbid Obesity on Complications, Readmission, and Patient-Reported Outcomes Following Minimally Invasive Transforaminal Lumbar Interbody Fusion: An Inverse Propensity Score Weighted Analysis.

STUDY DESIGN: Retrospective review of prospectively collected data at a single institution. OBJECTIVE: To compare perioperative and clinical outcomes in morbidly obese patients who underwent minimally invasive transforaminal lumbar interbody fusion (MiTLIF). SUMMARY OF BACKGROUND DATA: Obesity remains a serious public health concern. Obese patients who undergo lumbar fusion have historically thought to be at higher risk for complications and fare worse regarding quality-of-life outcomes. However, recent literature may demonstrate comparable risk and outcomes in obese patients. An increasing number of patients are categorized as morbidly obese (body mass index [BMI] ≥ 40 kg/m2). Perioperative and patient-reported outcomes (PROs) are lacking in this patient population. METHODS: The authors retrospectively reviewed a prospectively collected database of all morbidly obese and non-obese patients that underwent MiTLIF between 2015 and 2018 for degenerative conditions who had minimum 1-year follow-up for outcome assessment. An inverse propensity/probability of treatment weighting was utilized to create a synthetic weighted sample in which covariates were independent of obesity designation to adjust for imbalance between groups. Generalized estimating equations (GEE) was used to estimate the association of morbid obesity and complications and 1-year PROs. RESULTS: A total of 292 patients were analyzed with 234 non-obese patients and 58 morbidly obese patients. Multivariate analysis failed to demonstrate any association between morbid obesity and achieving minimal clinically important difference (MCID) for Oswestry disability index (ODI), visual analog scale (VAS), or short form-12 (SF-12) physical component score. However, morbid obesity was associated with significant decrease in odds of achieving MCID for SF-12 mental component score (P = 0.001). Increased surgery duration was significantly associated with morbid obesity (P = 0.001). Morbid obesity exhibited no statistically significant association with postoperative complications, readmission, pseudarthrosis, or adjacent segment disease (ASD). CONCLUSION: Morbidly obese patients who undergo MiTLIF can achieve meaningful clinical improvement comparable to nonobese patients. Morbid obesity was associated with longer surgical times but was not associated with postoperative complications, readmission, or ASD.Level of Evidence: 3.

Age as a Predictor for Complications and Patient-reported Outcomes in Multilevel Transforaminal Lumbar Interbody Fusions: Analyses From the Michigan Spine Surgery Improvement Collaborative (MSSIC).

STUDY DESIGN: Retrospective review of a multi-institutional data registry. OBJECTIVE: The authors sought to determine the association between age and complications & patient-reported outcomes (PRO) in patients undergoing multilevel transforaminal interbody lumbar fusion (MTLIF). SUMMARY OF BACKGROUND DATA: Elderly patients undergoing MTLIF are considered high risk. However, data on complications and PRO are lacking. Additionally, safety of multilevel lumbar fusion in the elderly remains uncertain. METHODS: Patients ≥50-year-old who underwent MTLIF for degenerative lumbar spine conditions were analyzed. Ninety-day complications and PROs (baseline, 90-d, 1-y, 2-y) were queried using the MSSIC database. PROs were measured by back & leg visual analog scale (VAS), Patient-reported Outcomes Measurement Information System (PROMIS), EuroQol-5D (EQ-5D), and North American Spine Society (NASS) Patient Satisfaction Index. Univariate analyses were used to compare among elderly and complication cohorts. Generalized estimating equation (GEE) was used to identify predictors of complications and PROs. RESULTS: A total of 3120 patients analyzed with 961 (31%) ≥ 70-y-o and 2159 (69%) between 50-69. A higher proportion of elderly experienced postoperative complications (P = .003) including urinary retention (P = <.001) and urinary tract infection (P = .002). Multivariate analysis demonstrated that age was not independently associated with complications. Number of operative levels was associated with any (P = .001) and minor (P = .002) complication. Incurring a complication was independently associated with worse leg VAS and PROMIS scores (P = <.001). Preoperative independent ambulation was independently associated with improved PROMIS, and EQ5D (P = <.001). Within the elderly, preoperative independent ambulation and lower BMI were associated with improved PROMIS (P = <.001). Complications had no significant effect on PROs in the elderly. CONCLUSIONS: Age was not associated with complications nor predictive of functional outcomes in patients who underwent MTLIF. Age alone, therefore, may not be an appropriate surrogate for risk. Furthermore, baseline preoperative independent ambulation was associated with better clinical outcomes and should be considered during preoperative surgical counseling.Level of Evidence: 3.

Big data registries in spine surgery research: the lurking dangers.

Spine surgery research has improved considerably over the last few decades. Its' most recent growth is in large part due to the mounting increase in studies conducted using national databases and registries. With easy access to a large number of patients, the benefit of these registries has become evident. However, as with any research, this type of data must be used responsibly with the appropriate strengths and limitations kept in mind. Inappropriate use of these registries continues to be a growing concern as potentially false or inaccurate conclusions can adversely impact clinical practice. It is, therefore, the author and the readers' responsibility to acknowledge and understand the limitations of this type of data. Knowledge of methodological requirements in the use and analyses of registry data is essential to ensuring quality evidence with proper interpretation.

Patient Satisfaction with Neurosurgery Telemedicine Visits During the Coronavirus Disease 2019 Pandemic: A Prospective Cohort Study.

BACKGROUND: Telemedicine refers to various modalities for remote care, including telephone calls, imaging review, and real-time video teleconferencing visits. Although it has not been widely used in outpatient neurosurgery settings, the COVID-19 (coronavirus disease 2019) pandemic has necessitated a broader adoption. Our goal is to show the level of patient satisfaction with their telemedicine care. METHODS: We prospectively studied consecutive telemedicine patients who scheduled outpatient neurosurgery visits from May 15 to June 8, 2020. Patients were seen by the surgeon via real-time video conferencing using Google Meet, and then completed a telemedicine satisfaction survey. Our primary outcome was telemedicine satisfaction scores. We compared satisfaction scores between new and established patients and between patients within and outside of a 15-mile radius of the nearest clinic location. Sensitivity analyses were performed to account for the nonrespondents. Descriptive and univariate analyses were performed. A P value of <0.05 was considered significant. RESULTS: Five-hundred and ninety patients completed a telemedicine visit during the study period. One patient from out of state was excluded. Three-hundred and ten patients (52.6%) responded. The average age was 60.9 ± 13.60 years; 59% were female, 20.6% were new patients; the average distance to the clinic was 28.03 ± 36.09 km (17.42 ± 22.43 miles). The mean overall satisfaction score was 6.32 ± 1.27. Subgroup analyses by new/established patient status and distance from their home to the clinic showed no significant difference in mean satisfaction scores between groups. CONCLUSIONS: Telemedicine provided a viable and satisfactory option for neurosurgical patients in the outpatient setting during the COVID-19 pandemic.

Efficacy and safety of cilostazol-nimodipine combined therapy on delayed cerebral ischaemia after aneurysmal subarachnoid haemorrhage: a prospective, randomised, double-blinded, placebo-controlled trial protocol.

INTRODUCTION: Delayed cerebral ischaemia (DCI) due to cerebral vasospasm (cVS) remains the foremost contributor to morbidity and mortality following aneurysmal subarachnoid haemorrhage (aSAH). Past efforts in preventing and treating DCI have failed to make any significant progress. To date, our most effective treatment involves the use of nimodipine, a calcium channel blocker. Recent studies have suggested that cilostazol, a platelet aggregation inhibitor, may prevent cVS. Thus far, no study has evaluated the effect of cilostazol plus nimodipine on the rate of DCI following aSAH. METHODS AND ANALYSIS: This is a multicentre, double-blinded, randomised, placebo-controlled superiority trial investigating the effect of cilostazol on DCI. Data concerning rates of DCI, symptomatic and radiographic vasospasm, length of intensive care unit stay, and long-term functional and quality-of-life (QoL) outcomes will be recorded. All data will be collected with the aim of demonstrating that the use of cilostazol plus nimodipine will safely decrease the incidence of DCI, and decrease the rates of both radiographic and symptomatic vasospasm with subsequent improvement in long-term functional and QoL outcomes when compared with nimodipine alone. ETHICS AND DISSEMINATION: Ethical approval was obtained from all participating hospitals by the Ascension Providence Hospital Institutional Review Board. The results of this study will be submitted for publication in peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT04148105.

Recent update on basic mechanisms of spinal cord injury.

Spinal cord injury (SCI) is a life-shattering neurological condition that affects between 250,000 and 500,000 individuals each year with an estimated two to three million people worldwide living with an SCI-related disability. The incidence in the USA and Canada is more than that in other countries with motor vehicle accidents being the most common cause, while violence being most common in the developing nations. Its incidence is two- to fivefold higher in males, with a peak in younger adults. Apart from the economic burden associated with medical care costs, SCI predominantly affects a younger adult population. Therefore, the psychological impact of adaptation of an average healthy individual as a paraplegic or quadriplegic with bladder, bowel, or sexual dysfunction in their early life can be devastating. People with SCI are two to five times more likely to die prematurely, with worse survival rates in low- and middle-income countries. This devastating disorder has a complex and multifaceted mechanism. Recently, a lot of research has been published on the restoration of locomotor activity and the therapeutic strategies. Therefore, it is imperative for the treating physicians to understand the complex underlying pathophysiological mechanisms of SCI.

Minimally Invasive Sacroiliac Joint Fusion Using Triangular Titanium versus Cylindrical Threaded Implants: A Comparison of Patient-Reported Outcomes.

BACKGROUND: Minimally invasive fusion of the sacroiliac (SI) joint has gained popularity for the treatment of refractory dysfunction. The purpose of this study was to compare the clinical outcomes of minimally invasive SI joint fusion between cylindrical threaded implants (CTIs) and triangular dowel implants (TDIs). METHODS: We retrospectively reviewed consecutive patients who underwent SI joint fusions with either CTIs or TDIs. Data collected included patient demographics, perioperative data, and all patient-reported outcomes (PROs) including postoperative visual analog scale (VAS), Oswestry Disability Index, and Short Form-12 at 6 months and 1 year. The change from baseline PROs between the cohorts was analyzed as the primary outcome. Secondary outcomes included revision rates and time to revision between the two cohorts. A P value <0.05 was considered significant. RESULTS: One hundred fifty-six consecutive patients underwent SI joint fusion, 74 patients with CTIs and 82 with TDIs. There was a significant difference in procedure length with CTI averaging 60.0 minutes (confidence interval: 55.7-64.3) and TDI averaging 41.2 minutes (confidence interval: 38.4-43.9, P < 0.0005). In both cohorts, there was a significant improvement in all PROs at 6 months when compared with preoperative values. However, when compared, there was no significant difference between the cohorts at 6-month follow-up or 1-year follow-up for either VAS-back, VAS-leg, Oswestry Disability Index, or Short Form-12. A 6.1% revision rate in the CTI cohort was observed compared with a 2.4% revision rate in the TDI cohort (P = 0.11). CONCLUSIONS: SI joint fusions with TDI or CTI offer a significant improvement in pain, disability, and quality of life. However, no difference was observed between devices to suggest superior clinical outcomes. Increased revision rates in the Rialto group warrants further investigation.

Elderly as a Predictor for Perioperative Complications in Patients Undergoing Multilevel Minimally Invasive Transforaminal Lumbar Interbody Fusion: A Regression Modeling Study.

STUDY DESIGN: This was a single-institute retrospective study. OBJECTIVE: To describe perioperative and postoperative complications in elderly who underwent multilevel minimally invasive transforaminal lumbar interbody fusion (MIS TLIF) while identifying predictors of complications. SUMMARY OF BACKGROUND DATA: The number of elderly patients undergoing spinal fusion is rising. Spinal surgery in the elderly is considered high risk with high rates of complications. Perioperative and postoperative complications in elderly undergoing multilevel MIS TLIF is, however, not known. METHODS: A retrospective analysis was performed on 467 consecutive patients who underwent multilevel MIS TLIF at a single institution from 2013 to 2017. Two cohorts, 70 years or older and 50 to 69 years old were analyzed. Multiple logistic regressions with minor and major complication rates as the dependent variables were performed to identify predictors of complication based on previously cited risk factors. A p-value of 0.008 or less was considered significant. RESULTS: One hundred fifty-two elderly and 315 nonelderly patients underwent multilevel MIS TLIFs. The average age was 76.4 and 60.4 years for the elderly and nonelderly cohorts. We observed 13 major (8.44%) and 72 minor (47.4%) complications in the elderly. No difference was noted in complication rates between the cohorts, except for urinary tract infection (P = .004) and urinary retention (P = .014). There were no myocardial infarctions; hardware complications; visceral, vascular, and neural injuries; or death. Length of stay, comorbidity, and length of surgery were predictive of major and minor complications. CONCLUSION: Elderly may undergo multilevel MIS TLIF with comparable complication rates. Age was not a predictor of complications. Rather, attention should focus on evaluation of comorbidity and limiting operative times. LEVEL OF EVIDENCE: 3.

The effect of ketorolac on posterior thoracolumbar spinal fusions: a prospective double-blinded randomised placebo-controlled trial protocol.

INTRODUCTION: Ketorolac has been shown to provide quality postoperative pain control and decrease opioid requirement with minimal side effects following spinal surgery. However, the literature addressing its use in spinal fusions is highly variable in both its effectiveness and complications, such as pseudarthrosis. Recent literature postulates that ketorolac may not affect fusion rates and large randomised controlled trials are needed to demonstrate ketorolac as a safe and effective adjuvant treatment to opioids for postoperative pain control. METHODS AND ANALYSIS: This is a multihospital, prospective, double-blinded, randomised placebo-controlled trial. Data concerning fusion rates, postoperative opioid use, pain scores, length of stay will be recorded with the aim of demonstrating that the use of ketorolac does not decrease thoracolumbar spinal fusion rates while identifying possible adverse events related to short-term minimal effective dose compared with placebo. Additionally, this investigation aims to demonstrate a decrease in postoperative opioid use demonstrated by a decrease in morphine equivalence while showing equivalent postoperative pain control and decrease the average length of stay. ETHICS AND DISSEMINATION: Ethical approval was obtained at all participating hospitals by the institutional review board. The results of this study will be submitted for publication in peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT03278691.