Per-protocol Group Research Articles

Safety of a Novel Continuous Glucose Monitoring–Informed Insulin Bolus Calculator Mobile Application for People With Type 1 or Type 2 Diabetes

BACKGROUND Managing bolus insulin dosing can be a significant burden for people with diabetes, many of whom have limited numeracy skills. Insulin bolus calculators (IBCs) may improve glycemia as well as treatment satisfaction. OBJECTIVE The purpose of this study was to demonstrate the safety of a novel, continuous glucose monitoring (CGM)-informed IBC mobile device app that applies trend arrow adjustments to bolus insulin dose recommendations. RESEARCH DESIGN AND METHODS This clinical trial was an open-label, industry-sponsored single-arm study conducted at two sites. Fifty-four participants with type 1 or type 2 diabetes were enrolled and used the IBC app on their mobile device for 30 days. Study participants were adults who were already using CGM and dosing bolus insulin. The analysis examined both noninferiority and superiority of time in range (TIR) during the study period compared with baseline. Other important end points included hypoglycemia, glucose variability, nocturnal and diurnal TIR, and diabetes distress. The per-protocol (PP) group was defined as participants who used the IBC >30 times during the study. RESULTS Mean TIR improved by 3.8% (95% CI 0.7–6.9%) from 69.2 to 73.0% (P = 0.017) in the PP group. This TIR corresponds to a mean of 0.9 more hours per day spent in range, and the improvement was driven by those with type 2 diabetes. There was no increase in measures of hypoglycemia or diabetes distress. Exploratory analysis revealed a reduction in measures of glucose variability. In addition, individuals with type 1 diabetes had greater improvements in diurnal TIR than in nocturnal TIR. CONCLUSION A CGM-informed IBC app that applies trend arrow adjustments to bolus insulin dose recommendations improved TIR without increasing hypoglycemia or diabetes distress in individuals with type 1 or type 2 diabetes.

Efficacy of Bismuth Quadruple Therapy in the Treatment of Helicobacter pylori-Infected Peptic Ulcer Children in Vietnam.

The continuous increase in drug-resistant strains, the lack of novel antibiotics, and the fewer options available to combat antibiotic-resistant infections in pediatrics pose significant challenges to the eradication of Helicobacter pylori (H. pylori) in children. This study evaluated the efficacy of first-line therapy with bismuth quadruple therapy in H. pylori-positive pediatric patients with peptic ulcers. 136 patients (aged between 8 and 17 years) diagnosed with active peptic ulcers with H. pylori infection were enrolled in this study. Patients with H. pylori strain sensitive to tetracycline and metronidazole were assigned to bismuth quadruple therapy, including a proton pump inhibitor (PPI), bismuth, tetracycline, and metronidazole. Antibiotic resistance of H. pylori was analyzed by the Epsilometer test. Treatment efficacy was evaluated at 12 weeks based on H. pylori eradication and peptic ulcer healing rates. H. pylori infection status was evaluated by a 13C-urea breath test. Most isolates showed extremely high rates of resistance to commonly prescribed antibiotics used for children, including clarithromycin (97.0%) and amoxicillin (84.6%), while the low rate of resistance to levofloxacin (16.2%). The overall success rate of eradication therapy in the intention-to-treat and the per-protocol group were 86.0% and 89.3%, respectively. Peptic ulcer healing rates for total patients at 6 weeks and 12 weeks were 75.0% and 97.7%, respectively. There were no entail unpleasant adverse events, and peptic ulcer symptoms decreased steadily over time in all cases. The bismuth quadruple therapy with a 2-week PPI pretreatment and followed by prolonged PPI was highly successful in eradicating H. pylori infection and healing ulcers in pediatric patients with active peptic ulcer. This might be preferable as a first-line empiric treatment regimen for H. pylori-positive pediatric patients with peptic ulcers, especially in populations with high rates of resistance to amoxicillin and clarithromycin.

Response to atezolizumab plus bevacizumab specific for lung and lymph node metastases affects survival of patients with HCC.

Tumour microenvironment heterogeneity among different organs can influence immunotherapy responses. Here, we evaluated the impact of differential organ-specific responses on survival in patients with advanced-stage hepatocellular carcinoma (HCC) treated with atezolizumab plus bevacizumab (Atezo/Bev). We retrospectively analysed 366 consecutive patients with advanced-stage HCC treated with Atezo/Bev as first-line systemic treatment. Therapeutic response was assessed using RECIST v1.1. Patients were divided into an intention-to-treat (ITT) group (patients treated with ≥1 dose of Atezo/Bev) and a per-protocol (PP) analysis group (patients with at least one measurable lesion irrespective of location treated with ≥3 doses of Atezo/Bev). Overall response and organ-specific response at initial and best response were evaluated in the PP group. Responders were defined as patients achieving complete remission or partial response. Initial progressors were defined as patients with progressive disease after three doses of Atezo/Bev. The ITT and PP groups comprised 324 and 236 patients, respectively. In the PP group, the organ-specific response rate of lung and lymph node (LN) metastases at both initial and best responses were higher than those of intrahepatic lesions and macrovascular tumour thrombosis. Lung and LN-specific response rates were 21.1% and 23.5%, respectively, at initial response, and 24.7% and 31.4%, respectively, at best response. Both initial pulmonary and lymphatic progressors (adjusted hazard ratios [95% confidence intervals], 6.37 [2.10-19.3], and 8.36 [2.16-32.4], respectively) were independently associated with survival regardless of intrahepatic response. The response of metastatic HCC to the Atezo/Bev regimen may be used to determine whether to continue treatment or switch to second-line treatment at an early phase of therapy.

Efficacy and safety of losartan in childhood immunoglobulin A nephropathy: a prospective multicenter study

Purpose: Angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers (ARBs) are frequently employed to counteract the detrimental effects of proteinuria on glomerular diseases. However, the effects of ARBs remain poorly examined in pediatric patients with immunoglobulin A (IgA) nephropathy. Herein, we evaluated the efficacy and safety of losartan, an ARB, in pediatric IgA nephropathy with proteinuria.Methods: This prospective, single-arm, multicenter study included children with IgA nephropathy exhibiting proteinuria. Changes in proteinuria, blood pressure, and kidney function were prospectively evaluated before and 4 and 24 weeks after losartan administration. The primary endpoint was the difference in proteinuria between baseline and 24 weeks.Results: In total, 29 patients were enrolled and received losartan treatment. The full analysis set included 28 patients who received losartan at least once and had pre- and post-urinary protein to creatinine ratio measurements (n=28). The per-protocol analysis group included 22 patients who completed all scheduled visits without any serious violations during the study period. In both groups, the mean log (urine protein to creatinine ratio) value decreased significantly at 6 months. After 24 weeks, the urinary protein to creatinine ratio decreased by more than 50% in approximately 40% of the patients. The glomerular filtration rate was not significantly altered during the observation period.Conclusions: Losartan decreased proteinuria without decreasing kidney function in patients with IgA nephropathy over 24 weeks. Losartan could be safely employed to reduce proteinuria in this patient population. <i>ClinicalTrials.gov trial registration (NCT0223277)</i>

Community-Based Point-of-Diagnosis Hepatitis C Treatment for Marginalized Populations

Disparities persist in testing and treatment for hepatitis C virus (HCV), leaving socially marginalized populations less likely to benefit from curative treatment. Linkage services are often insufficient to overcome barriers to navigating the medical system and contextual factors. To determine the feasibility, acceptability, and safety of HCV treatment at the point of HCV infection diagnosis disclosure in a nonclinical community setting. In this single-arm nonrandomized controlled trial conducted between July 1, 2020, and October 31, 2021, street-outreach recruitment targeted people experiencing homelessness and injecting drugs in an urban US community who were eligible for simplified HCV treatment. Study procedures were designed to reflect the community environment and services needed to provide HCV testing, disclosure, and treatment in a nonclinical site. The test-and-treat No One Waits (NOW) model of care provided a 2-week starter pack of 400 mg of sofosbuvir and 100 mg of velpatasvir at time of HCV RNA results disclosure. Participants were transitioned to insurance-provided sofosbuvir-velpatasvir when feasible to complete a 12-week treatment course. The primary end point was sustained virologic response at posttreatment week 12 or later (SVR12). Acceptability end points were treatment initiation and completion. Safety end points were treatment discontinuation because of a late exclusion criterion and adverse events. Of the 492 people (median [IQR] age, 48 [37-58] years; 62 [71%] male) who underwent anti-HCV testing, 246 (50%) tested anti-HCV positive, and 111 (23%) tested HCV RNA positive and were eligible for simplified HCV treatment. Eighty-nine of the 111 eligible participants (80%) returned for confirmatory RNA results, and 87 (98%) accepted and initiated HCV treatment. Seventy (80%) were currently injecting drugs, 83 (97%) had an income below the poverty line, and 53 (61%) were currently unsheltered. Most had HCV genotype 1a (45 [52%]) or 3 (20 [23%]). Sixty-nine (79%) completed 12 weeks of sofosbuvir-velpatasvir treatment, 2 stopped treatment because of low adherence, and 16 were lost to follow-up. Of the 66 participants who completed treatment and had a successful blood draw, 61 (92%) had undetectable HCV RNA at treatment completion. Of the 87 treated patients, 58 achieved SVR12, leading to a treatment response of 67% (95% CI, 56%-76%) among the intention-to-treat group and 84% (95% CI, 73%-92%) among the per-protocol group. There were no adverse events, late exclusions, or deaths. In this nonrandomized controlled trial of HCV treatment at the point of diagnosis, the NOW model of care reduced steps between HCV testing and treatment initiation and resulted in high levels of treatment initiation, completion, and cure. The NOW model of care can expand the current HCV test-and-treat toolkit by reaching a broader population of marginalized communities and expediting curative therapy. ClinicalTrials.gov Identifier: NCT03987503.

Fluorescence-guided Two-port Robotic Gastrectomy Versus Conventional Laparoscopic Gastrectomy: A Nonrandomized Controlled Trial.

To compare the number of retrieved lymph nodes between conventional laparoscopic gastrectomy (CLG) and robotic gastrectomy integrated with fluorescence guidance and a two-port system (integrated robotic gastrectomy, IRG). The benefits of robotic surgery over laparoscopic surgery for gastric cancer have not yet been established. Using built-in features of robotic system, further benefit can be provided to the patients with effective lymphadenectomy and enhanced recovery. A nonrandomized controlled trial was performed by a single surgeon at single-center, tertiary referral hospital between January 2018 and October 2021. Overall, 140 patients scheduled to undergo minimally invasive subtotal gastrectomy for early gastric cancer were enrolled. The primary endpoint was the number of retrieved lymph nodes. Secondary endpoints were complications, hospital stay, pain score, body image, and operative cost. This study analyzed 124 patients in the per-protocol group (IRG, 64; CLG, 60). The number of retrieved lymph nodes was higher in the IRG group than those in the CLG group (IRG vs CLG; 42.1 ± 17.9 vs 35.1 ± 14.6, P = 0.019). Moreover, other surgical parameters, such as hospital stay (4.1 ± 1.0 vs 5.2 ± 1.8, P < 0.001) and body image scale (better in 4 of the 10 questions), were significantly better in the IRG than in the CLG. Robotic surgical procedures integrated with fluorescence guidance and a reduced-port system yielded more retrieved lymph nodes. In addition, the IRG group showed better perioperative surgical outcomes, particularly regarding the length of hospital stay and postoperative body image. NCT03396354.

928-P: The Use of a Novel CGM-Informed Insulin Bolus Calculator Mobile Application by People with Type 1 and Type 2 Diabetes Improves Time in Range

Background and Aims: People with diabetes on basal-bolus insulin regimens face challenges calculating bolus doses. Continuous glucose monitoring (CGM) systems can assist users with bolus dosing optimization through trend arrows. The purpose of this study was to demonstrate the safety and effectiveness of a CGM-informed insulin bolus calculator (IBC, Welldoc, Inc., Columbia, MD, U.S.A.) integrated into a mobile application that applies trend arrow and exercise adjustments to the bolus insulin dose recommendation. This investigational software also provided real-time coaching on CGM data to assist users in improving their time in range (TIR). Methods: Fifty-four participants with diabetes using CGM (Dexcom G6, San Diego, CA, U.S.A.) were enrolled in a 30-day prospective study conducted at two research sites. Participants were asked to use the mobile application to monitor their CGM data and calculate their insulin doses. TIR during the prospective 30-day period was compared to that from 30 days of baseline data. Three populations were defined: 1) the intention-to-treat (ITT) group consisted of all enrolled subjects; 2) the complete cases (CC) group had ≥90% sensor wear time; and 3) the per-protocol (PP) group used the IBC at least 30 times during the study period. Results: In the ITT group, the TIR improved from 68.4% to 71.8% (N=54, P=0.013). In the CC group, the TIR improved from 69.1% to 73.0% (N=49, P=0.005). In the PP group, the TIR improved from 69.2% to 73.0% (N=39, P=0.017). There was no increase in time with low glucose (&amp;lt;70 mg/dL) in all three populations. In a subgroup analysis, TIR increased from 74.7% to 81.4% in those with type 2 diabetes and from 64.4% to 65.2% in those with type 1 diabetes. Conclusions: Use of a novel CGM-informed insulin bolus calculator with trend arrow and exercise dose adjustment by individuals with type 1 and type 2 diabetes was associated with significant improvement in TIR. Disclosure M.Shomali: Employee; WellDoc. C.Kelly: Consultant; WellDoc, Caladrius Biosciences, Inc., Epigenomics AG, Luna, Nevro Corp., Presidio Medical, Hitachi, Ltd., Resmed, Inc., Seaspine Hldgs, Inc., ViaCyte, Inc. A.K.Iyer: Employee; WellDoc. J.Y.Park: None. G.Aleppo: Advisory Panel; Medscape, Consultant; Bayer Inc., Insulet Corporation, Research Support; Dexcom, Inc., Eli Lilly and Company, Emmes, Insulet Corporation, Fractyl Health, Inc., WellDoc, Speaker's Bureau; Dexcom, Inc. Funding Welldoc Inc.

When Characteristics of Clinical Trials Require Per-Protocol as Well as Intention-to-Treat Outcomes to Draw Reliable Conclusions: Three Examples.

Under exceptional circumstances, including high rates of protocol non-compliance, per-protocol (PP) analysis can better indicate the real-world benefits of a medical intervention than intention-to-treat (ITT) analysis. Exemplifying this, the first randomized clinical trial (RCT) considered found that colonoscopy screenings were marginally beneficial, based upon ITT analysis, with only 42% of the intervention group actually undergoing the procedure. However, the study authors themselves concluded that the medical efficacy of that screening was a 50% reduction in colorectal cancer deaths among that 42% PP group. The second RCT found a ten-fold reduction in mortality for a COVID-19 treatment drug vs. placebo by PP analysis, but only a minor benefit by ITT analysis. The third RCT, conducted as an arm of the same platform trial as the second RCT, tested another COVID-19 treatment drug and reported no significant benefit by ITT analysis. Inconsistencies and irregularities in the reporting of protocol compliance for this study required consideration of PP outcomes for deaths and hospitalizations, yet the study coauthors refused to disclose them, instead directing inquiring scientists to a data repository which never held the study's data. These three RCTs illustrate conditions under which PP outcomes may differ significantly from ITT outcomes and the need for data transparency when these reported or indicated discrepancies arise.

Neurocognitive and radiological follow-up of children under 5 years of age treated for medulloblastoma according to the HIT-SKK protocol.

The HIT-SKK protocol is used for low/standard-risk medulloblastomas in young children with the aim to eliminate cranial irradiation and its neuropsychological (NP) sequelae. This therapy includes IV and intraventricular (ITV) methotrexate (MTX) potentially responsible for leukoencephalopathy (LE) and neurocognitive disorders. This study describes the risk factors and course of LE, and investigates its correlation with neurocognitive impact. A retrospective, multicenter study was conducted in 35 children under 5 years old, with a median follow-up of 72 months (range 14 to 130). The main analysis was performed in 30 patients who received cumulative doses of MTX as per-protocol (group 1). Five patients who received higher cumulative doses of MTX were analyzed separately. All follow-up MRIs and NP assessments were centrally reviewed by experts. Twenty patients in group 1 developed LE, grade 2 and 3 abnormalities did not correlate with higher cumulative doses of ITV-MTX (p = 0.698). Considering the most recent NP evaluation, the Full-Scale IQ (FSIQ) and Wechsler indices were in the average to lower average range. The FSIQ was deficient in 6/17 evaluable patients. Cumulative dose of ITV-MTX was almost associated with decreased processing speed competence (p = 0.055) which was the most frequently impaired neurocognitive domain. Neuropsychological assessment scores were not statistically lower in patients with persistent grade 2 LE at the end of follow-up. This study described that the use of cumulative dose of MTX (IV and ITV) according to the HIT-SKK protocol resulted in LE that tented to decrease over time, without significant correlation with a decline in neuro-intellectual skills.

Indobufen versus aspirin in patients with acute ischaemic stroke in China (INSURE): a randomised, double-blind, double-dummy, active control, non-inferiority trial

Aspirin is recommended for secondary stroke prevention in patients with moderate-to-severe ischaemic stroke but can lead to gastrointestinal intolerance and bleeding. Indobufen is used as an alternative antiplatelet agent in some countries, despite an absence of large-scale clinical trials for this indication. We tested the hypothesis that indobufen is non-inferior to aspirin in reducing the risk of new stroke at 90 days in patients with moderate-to-severe ischaemic stroke. We conducted a randomised, double-blind, double-dummy, active control, non-inferiority trial at 163 tertiary and district general hospitals in China. Eligible participants were aged 18-80 years with acute moderate-to-severe ischaemic stroke (National Institutes of Health Stroke Scale score 4-18). We randomly assigned (1:1) participants within 72 h of the onset of symptoms to receive either indobufen (100 mg tablet twice per day) or aspirin (100 mg tablet once per day) for 90 days. The randomisation sequence was computer generated centrally and stratified by local participating centres. Masked local investigators assigned the random code to patients in ascending order and provided a treatment kit corresponding to the random code. The primary efficacy outcome was new stroke and the primary safety outcome was severe or moderate bleeding, both within 90 days. This primary efficacy outcome was assessed in all randomly assigned and consenting patients and in a per-protocol group (ie, all patients finishing the treatment without major violation of the trial protocol). Safety analyses were done in the safety-analysis population (ie, all patients who received at least one dose of the study drug and had a safety assessment available). We assessed the non-inferiority of indobufen versus aspirin using the one-sided upper limit of the 95% CI of the hazard ratio (HR) with a prespecified non-inferiority margin of 1·25. This trial is registered with ClinicalTrials.gov (NCT03871517). This trial took place between June 2, 2019, and Nov 28, 2021. Of 84 093 patients screened, 5438 patients were randomly assigned to receive either indobufen (n=2715) or aspirin (n=2723), all of whom were included in the primary analyses. Median age was 64·2 years (IQR 56·1-70·6); 1921 (35·3%) were women and 3517 (64·7%) were men. Stroke occurred within 90 days in 213 (7·9%) patients in the indobufen group versus 175 (6·4%) in the aspirin group (HR 1·23, 95% CI 1·01-1·50; pnon-inferiority=0·44). Moderate or severe bleeding occurred in 18 (0·7%) patients in the indobufen group and in 28 (1·0%) in the aspirin group (0·63, 95% CI 0·35 to 1·15; p=0·13). Adverse events within 90 days occurred in 666 (24·5%) patients in the indobufen group and 679 (24·9%) patients in the aspirin group (p=0·73). In patients with acute moderate-to-severe ischaemic stroke, indobufen was not non-inferior to aspirin because the upper limit of the 95% CI was greater than 1·25. Furthermore, indobufen seemed to be inferior to aspirin in reducing the risk of recurrent stroke at 90 days because the lower limit of the 95% CI was greater than 1·00. Although moderate or severe bleeding did not differ between groups, these findings do not support the use of indobufen for secondary stroke prevention in patients with moderate-to-severe ischaemic stroke. Hangzhou Zhongmei Huadong Pharmaceutical and Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences. For the Chinese translation of the abstract see Supplementary Materials section.

Treadmill training with virtual reality to enhance gait and cognitive function among people with multiple sclerosis: a randomized controlled trial.

Motor and cognitive impairments impact the everyday functioning of people with MS (pwMS). The present randomized controlled trial (RCT) evaluated the benefits of a combined motor-cognitive virtual reality training program on key motor and cognitive symptoms and related outcomes in pwMS. In a single-blinded, two-arm RCT, 124 pwMS were randomized into a treadmill training with virtual reality (TT + VR) group or a treadmill training alone (TT) (active-control) group. Both groups received three training sessions per week for 6weeks. Dual-tasking gait speed and cognitive processing speed (Symbol Digit Modalities Test, SDMT, score) were the primary outcomes. Secondary outcomes included additional tests of cognitive function, mobility, and patient-reported questionnaires. These were measured before, after, and 3months after training. Gait speed improved (p < 0.005) in both groups, similarly, by about 10cm/s. The TT + VR group (n = 53 analyzed per-protocol) showed a clinically meaningful improvement of 4.4 points (95% CI 1.9-6.8, p = 0.001) in SDMT, compared to an improvement of only 0.8 points in the TT (n = 51 analyzed per-protocol) group (95% CI 0.9-2.5 points, p = 0.358) (group X time interaction effect p = 0.027). Furthermore, TT + VR group-specific improvements were seen in depressive symptoms (lowered by 31%, p = 0.003), attention (17%, p < 0.001), and verbal fluency (11.6% increase, p = 0.002). These findings suggest that both TT and TT + VR improve usual and dual-task gait in pwMS. Nonetheless, a multi-modal approach based on VR positively impacts multiple aspects of cognitive function and mental health, more than seen after treadmill-treading alone. Trial registered at ClinicalTrials.Gov NCT02427997.

Efficacy, Immunogenicity, and Safety of the Two-Dose Schedules of TURKOVAC versus CoronaVac in Healthy Subjects: A Randomized, Observer-Blinded, Non-Inferiority Phase III Trial.

We present the interim results of the efficacy, immunogenicity, and safety of the two-dose schedules of TURKOVAC versus CoronaVac. This was a randomized, observer-blinded, non-inferiority trial (NCT04942405). Volunteers were 18-55 years old and randomized at a 1:1 ratio to receive either TURKOVAC or CoronaVac at Day 0 and Day 28, both of which are 3 μg/0.5 mL of inactivated severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) adsorbed to aluminum hydroxide. The primary efficacy outcome was the prevention of polymerase chain reaction (PCR)-confirmed symptomatic coronavirus disease 2019 (COVID-19) at least 14 days after the second dose in the modified per-protocol (mPP) group. Safety analyses were performed in the modified intention-to-treat (mITT) group. Between 22 June 2021 and 7 January 2022, 1290 participants were randomized. The mITT group consisted of 915 participants, and the mPP group consisted of 732 participants. During a median follow-up of 90 (IQR 86-90) days, the relative risk reduction with TURKOVAC compared to CoronaVac was 41.03% (95% CI 12.95-60.06) for preventing PCR-confirmed symptomatic COVID-19. The incidences of adverse events (AEs) overall were 58.8% in TURKOVAC and 49.7% in CoronaVac arms (p = 0.006), with no fatalities or grade four AEs. TURKOVAC was non-inferior to CoronaVac in terms of efficacy and demonstrated a good safety and tolerability profile.

Comparison of the Effects of Regular Periods of Immobilization and Prolonged Immobilization on Hand Function Post Distal Radial Fracture.

Introduction Distal radius fracture (DRF) is one of the most common orthopedic cases managed in the emergency room. DRF treatment is either non-operative or operative. Regardless of the treatment methodology, a period of immobilization of 4-6 weeks is required. Purpose The study aims to evaluate hand function for patients who sustained DRF with different immobilization periods in King Abdul-Aziz Medical City, National Guard Hospital - Jeddah (NGHA) from December 2016 until December 2019. Materials and methods This is a retrospective cohort study where we collected data of DRF patients managed in NGHA. Data was collected directly from NGHA medical records (December 2016-December 2019). A total of 44 patients met the inclusion criteria. Patients were divided into two groups; a group that was immobilized as per protocol (six weeks) and a group that deviated from protocol and immobilization exceeded six weeks. A data collection sheet included the patient's demographics, history, fracture description, management method, and hand function measurements. Results Of the 44 participants, 24 (54%) deviated from protocol; the remaining 20 (46%)were immobilized as per protocol. The prolonged immobilization group had limitations in hand function,restriction in extension (P-value=0.641), and a decrease in grip strength (P-value =0.291) compared to the per-protocol group. Flexion and radial deviation were affected similarly in both groups. Conclusion Although the results were not significant,immobilization for more than six weeks is associated with decreased hand function, range of motion (ROM), grip strength, and higher pain scores based on occupational therapy (OT) measurements.

Early, continuing exposure to cow's milk formula and cow's milk allergy: The COMEET study, a single center, prospective interventional study

BackgroundCow's milk allergy (CMA) is a common food allergy among infants. Information regarding the best timing for first exposure to cow's milk formula (CMF) is controversial and more evidence is required. Few randomized control trials have tried to accurately assess the timing and preventive effect of exposure to CMF on small cohorts. ObjectiveThis study assessed the association between early, continuing exposure to CMF on the basis of the parents’ preferences and the development of immunoglobulin E (IgE)–mediated CMA in a large birth cohort. MethodsNewborns were prospectively recruited shortly before birth and divided into 2 groups according to parental feeding preference for the first 2 months of life: (1) exclusive breastfeeding (EBF); or (2) at least 1 meal of CMF (with or without breastfeeding) daily. Infants were followed up monthly until the age of 12 months. ResultsAmong 1992 infants participating in the study, 1073 (53.86%) were in the EBF group until 2 months of age. IgE-mediated CMA was confirmed in 0.85% (n = 17); all were in the EBF group. Within this group, the prevalence of IgE-mediated CMA was 1.58% compared with 0 in the other groups (relative risk, 29.98; P < .001). Post hoc analysis revealed IgE-mediated CMA prevalence of 0.7% in the per-protocol EBF group vs 3.27% among breastfed infants who were exposed to a small amount of CMF during the first 2 months of life. A family atopic background did not affect the results. ConclusionEarly, continuing exposure to CMF from birth has the potential to prevent the development of IgE-mediated CMA and should be encouraged. However, the exposure needs to be consistent because occasional exposure increases the risk of developing IgE-mediated CMA and should be avoided.

Effectiveness and Safety of High-Dose Thromboprophylaxis in Morbidly Obese Major Trauma Patients.

Trauma increases risk for venous thromboembolism (VTE) and obesity is a known independent risk factor for VTE development. Currently, no consensus on an optimal prophylactic dosing strategy for morbidly obese trauma patients exists. The objective of this study is to evaluate the effectiveness and safety of a BMI-stratified dosing strategy for VTE prophylaxis in morbidly obese trauma patients. This was a single center, retrospective cohort study of adult major trauma patients with a body mass index (BMI) of ≥40 kg/m2 admitted to the surgical-trauma intensive care unit from April 2014 to July 2020. Patients included were those who received enoxaparin 40 mg subcutaneously (SQ) every 12 hours (Q12H) for BMI of 40 to 49.9 kg/m2 or 60 mg SQ Q12H BMI ≥ 50 kg/m2 (per protocol), or enoxaparin 40 mg SQ Q12H for BMI of 40 to 49.9 kg/m2 (non-protocol). The primary endpoint was confirmed incidence of VTE. Secondary endpoints included occurrence of deep vein thrombosis (DVT) or pulmonary embolism (PE) during hospitalization, bleeding events, intensive care unit (ICU) and hospital length of stay (LOS) and hospital mortality. One hundred forty-five morbidly obese major trauma patients were included, with 123 patients (84.8%) in the per-protocol group. The primary outcome of in-hospital VTE did not occur in any patients in this group. Bleeding events occurred in 3 patients (2.7%) with a BMI of 40 to 49.9 kg/m2 and in 2 patients (16.7%) with a BMI of ≥50 kg/m2 (P = .064). Twenty-two patients in the non-protocol group were reviewed. One VTE event (4.5%) and no bleeding events occurred in this group. Median ICU LOS was 5 days, and hospital LOS was 11 days for the entire study group. Administration of enoxaparin 40 mg SQ Q12H to morbidly obese major trauma patients with a BMI of 40 to 49.9 kg/m2 and enoxaparin 60 mg SQ Q12H in those with a BMI of ≥50 kg/m2 resulted in low rates of VTE and bleeding events in the current study. However, future larger studies using this BMI-stratified dosing strategy are necessary to confirm these findings.

A Novel Mobile App-Based Neuromuscular Electrical Stimulation Therapy for Improvement of Knee Pain, Stiffness, and Function in Knee Osteoarthritis: A Randomized Trial.

BackgroundKnee osteoarthritis (OA) is a widespread and debilitating disease that continues to plague patients. Over the past decade, neuromuscular electrical stimulation (NMES) therapy has shown promise in alleviating knee OA-related symptoms. This study sought to evaluate the efficacy and safety of a home-based NMES therapy for reduction of pain, stiffness, and function associated with knee OA.Material and methodsA randomized, sham-controlled, double-blind, multicenter trial was conducted with 12-week follow-up in 156 knee OA patients receiving either home-based NMES therapy or a modified low-voltage NMES therapy. Outcome measures including knee pain, stiffness, and functionality were collected at baseline through week 12 after the therapy. The primary endpoint was the percentage change from baseline (PCFB) in the Visual Analog Scale (VAS) pain for a patient-nominated physical activity. Secondary endpoints included VAS for general knee pain, Western Ontario and McMaster Universities Osteoarthritis Index, Knee Injury and Osteoarthritis Outcome Score Joint Replacement, and isometric quadriceps strength test.ResultsA clinically meaningful reduction for VAS Nominated Activity was higher in the per-protocol treatment-compliant NMES group than that in the sham low-voltage NMES group at week 12 (PCFB of 42.8% vs 38.6%, P = .562). This was similarly true for the Western Ontario and McMaster Universities Osteoarthritis Index pain subscale (PCFBs of 36.8% vs 26.6%, P = .038). Similar trends and reductions of pain were observed for VAS General, Knee Injury and Osteoarthritis Outcome Score Joint Replacement Pain subscale, and isometric quadriceps strength.ConclusionHome-based NMES treatment resulted in a clinically meaningful reduction of knee pain, stiffness, and knee functional improvements at week 12 compared with sham NMES treatment.

The Safety and Effectiveness of the Contour Neurovascular System (Contour) for the Treatment of Bifurcation Aneurysms: The CERUS Study.

The Contour is a novel intra-aneurysmal flow disrupting device to treat intracranial aneurysms. To evaluate the safety and effectiveness of the Contour device for treatment of nonruptured intracranial bifurcation aneurysms through a prospective, multicenter, single-arm study. Thirty-four patients were enrolled. Primary end points were successful occlusion at 6 mo for efficacy and any major stroke or nonaccidental death up to 30 d or major disabling stroke within 6 mo for safety. Secondary end points were occlusion at 12 mo, retreatment rate, procedure time, and procedure-related/device-related adverse events. Procedural and follow-up imaging was reviewed by an independent core laboratory. Adverse events were reviewed and adjudicated by a clinical events committee. In total, 32 of 34 aneurysms were successfully implanted and, 2 of 34 in the intention-to-treat (ITT) group did not receive the Contour and were excluded from follow-up after 30 d. In addition, 2 of 32 were lost to angiographic follow-up and regarded as treatment failure. The primary safety end point was met in 2 patients in the ITT group. In the perprotocol (PP) group, complete occlusion was seen in 14 of 32 (44%) at 6 mo and 22 of 32 (69%) at 12 mo. Adequate occlusion (Raymond-Roy [RR] 1 and 2) was reached in 84% at a last available follow-up. One patient from the ITT group and 1 from the PP group received additional treatment during follow-up. The Contour seems to be both safe and effective in the treatment of intracranial bifurcation aneurysms.

Intervention fidelity and process outcomes of the IMMENSE study, a pharmacist-led interdisciplinary intervention to improve medication safety in older hospitalized patients.

The majority of hospitalized older patients experience medication-related problems (MRPs), and there is a call for interventions to solve MRPs and improve clinical outcomes like medical visits. The IMMENSE study is a randomized controlled trial investigating the impact of a pharmacist-led interdisciplinary intervention on emergency medical visits. Its multistep intervention is based on the integrated medicines management methodology and includes a follow-up step with primary care. This study aims to describe how the intervention in the IMMENSE study was delivered and its process outcomes. The study includes the 221 intervention patients in the per-protocol group of the IMMENSE study. Both intervention delivery, reasons for not performing interventions and process outcomes were registered daily by the study pharmacists in a Microsoft Access® database. Process outcomes were medication discrepancies, MRPs and how the team solved these. A total of 121 (54.8%) patients received all intervention steps if appropriate. All patients received medication reconciliation (MedRec) and medication Review (MedRev) (step 1 and 2), while between 10% and 20% of patients were missed for medication list in discharge summary (step 3), patient counselling (step 4), or communication with general practitioner and nurse (step 5). A total of 437 discrepancies were identified in 159 (71.9%) patients during MedRec, and 1042MRPs were identified in 209 (94.6%) patients during MedRev. Of these, 292 (66.8%) and 700 (67.2%), respectively, were communicated to and solved by the interdisciplinary team during the hospital stay. The fidelity of the single steps of the intervention was high even though only about half of the patients received all intervention steps. The impact of the intervention may be influenced by not implementing all steps in all patients, but the many discrepancies and MRPs identified and solved for the patients could explain a potential effect of the IMMENSE study.

Efficacy and cost-effectiveness of task-shared care for people with severe mental disorders in Ethiopia (TaSCS): a single-blind, randomised, controlled, phase 3 non-inferiority trial

BackgroundThere have been no trials of task-shared care (TSC) using WHO's mental health Gap Action Programme for people with severe mental disorders (psychosis or affective disorder) in low-income or middle-income countries. We aimed to evaluate the efficacy and cost-effectiveness of TSC compared with enhanced specialist mental health care in rural Ethiopia. MethodsIn this single-blind, phase 3, randomised, controlled, non-inferiority trial, participants had a confirmed diagnosis of a severe mental disorder, recruited from either the community or a local outpatient psychiatric clinic. The intervention was TSC, delivered by supervised, non-physician primary health care workers trained in the mental health Gap Action Programme and working with community health workers. The active comparison group was outpatient psychiatric nurse care augmented with community lay workers (PSY). Our primary endpoint was whether TSC would be non-inferior to PSY at 12 months for the primary outcome of clinical symptom severity using the Brief Psychiatric Rating Scale, Expanded version (BPRS-E; non-inferiority margin of 6 points). Randomisation was stratified by health facility using random permuted blocks. Independent clinicians allocated groups using sealed envelopes with concealment and outcome assessors and investigators were masked. We analysed the primary outcome in the modified intention-to-treat group and safety in the per-protocol group. This trial is registered with ClinicalTrials.gov, number NCT02308956. FindingsWe recruited participants between March 13, 2015 and May 21, 2016. We randomly assigned 329 participants (111 female and 218 male) who were aged 25–72 years and were predominantly of Gurage (198 [60%]), Silte (58 [18%]), and Mareko (53 [16%]) ethnicity. Five participants were found to be ineligible after randomisation, giving a modified intention-to-treat sample of 324. Of these, 12-month assessments were completed in 155 (98%) of 158 in the TSC group and in 158 (95%) of 166 in the PSY group. For the primary outcome, there was no evidence of inferiority of TSC compared with PSY. The mean BPRS-E score was 27·7 (SD 4·7) for TSC and 27·8 (SD 4·6) for PSY, with an adjusted mean difference of 0·06 (90% CI –0·80 to 0·89). Per-protocol analyses (n=291) were similar. There were 47 serious adverse events (18 in the TSC group, 29 in the PSY group), affecting 28 participants. These included 17 episodes of perpetrated violence and seven episodes of violent victimisation leading to injury, ten suicide attempts, six hospital admissions for physical health conditions, four psychiatric admissions, and three deaths (one in the TSC group, two in the PSY group). The incremental cost-effectiveness ratio for TSC indicated lower cost of –US$299·82 (95% CI –454·95 to –144·69) per unit increase in BPRS-E scores from a health care sector perspective at 12 months. InterpretationWHO's mental health Gap Action Programme for people with severe mental disorders is as cost-effective as existing specialist models of care and can be implemented effectively and safely by supervised non-specialists in resource-poor settings. FundingUS National Institute of Mental Health.

Evaluation of a patient specific, targeted-intensity pharmacologic thromboprophylaxis protocol in hospitalized patients with COVID-19.

Patients with COVID-19 are at higher risk of thrombosis due to the inflammatory nature of their disease. A higher-intensity approach to pharmacologic thromboprophylaxis may be warranted. The objective of this retrospective cohort study was to determine if a patient specific, targeted-intensity pharmacologic thromboprophylaxis protocol incorporating severity of illness, weight, and biomarkers decreased incidence of thrombosis in hospitalized patients with COVID-19. Included patients were hospitalized with COVID-19 and received thromboprophylaxis within 48 h of admission. Exclusion criteria included receipt of therapeutic anticoagulation prior to or within 24 h of admission, history of heparin-induced thrombocytopenia, extracorporeal membrane oxygenation, pregnancy, or incarceration. Per-protocol patients received thromboprophylaxis according to institutional protocol involving escalated doses of anticoagulants based upon severity of illness, total body weight, and biomarker thresholds. The primary outcome was thrombosis. Secondary outcomes included major bleeding, mortality, and identification of risk factors for thrombosis. Of 1189 patients screened, 803 were included in the final analysis. The median age was 54 (42–65) and 446 (55.5%) were male. Patients in the per-protocol group experienced significantly fewer thrombotic events (4.4% vs. 10.7%, p = 0.002), less major bleeding (3.1% vs. 9.6%, p < 0.001), and lower mortality (6.3% vs. 11.8%, p = 0.02) when compared to patients treated off-protocol. Significant predictors of thrombosis included mechanical ventilation and male sex. Post-hoc regression analysis identified mechanical ventilation, major bleeding, and D-dimer ≥ 1500 ng/mL FEU as significant predictors of mortality. A targeted pharmacologic thromboprophylaxis protocol incorporating severity of illness, body weight, and biomarkers appears effective and safe for preventing thrombosis in patients with COVID-19.Supplementary InformationThe online version contains supplementary material available at 10.1007/s11239-021-02552-x.