Multicenter Pilot Study Research Articles

Feasibility of sentinel node navigated surgery in high-risk T1b esophageal adenocarcinoma patients using a hybrid tracer of technetium-99\xa0m and indocyanine green

BackgroundMinimally invasive esophagectomy with two-field lymphadenectomy is standard of care for T1b esophageal adenocarcinoma (EAC) with a high risk of lymph node metastasis. Sentinel node navigation surgery (SNNS) is a well-known concept to tailor the extent of lymphadenectomy. The aim of this study was to evaluate the feasibility and safety of SNNS with a hybrid tracer (technetium-99 m/indocyanine green/nanocolloid) for patients with high-risk T1b EAC.MethodsIn this prospective, multicenter pilot study, 5 patients with high-risk T1b EAC were included. The tracer was injected endoscopically around the endoscopic resection scar the day before surgery, followed by preoperative imaging (lymphoscintigraphy/SPECT-CT). During surgery, first the SNs were localized and resected based on preoperative imaging and intraoperative gammaprobe- and fluorescence-based detection, followed by esophagectomy. Primary endpoints were the percentage of patients with detectable SNs, concordance between preoperative and intraoperative SN detection, and the additive value of indocyanine green.ResultsSNs could be identified and resected in all patients (median 3 SNs per patient, range 2–7). There was a high concordance between preoperative and intraoperative SN detection. In 2 patients additional peritumoral SNs were identified with fluorescence-based detection. None of the resected lymph nodes showed signs of (micro)metastases and no nodal metastases were detected in the surgical resection specimen.ConclusionsSNNS using technetium-99 m/indocyanine green/nanocolloid seems feasible and safe in patients with high-risk T1b EAC. Indocyanine green fluorescence seems to be of additive value for detection of peritumoral SNs. Whether this approach can optimize selection for esophagectomy needs to be studied in future research.

Safety and Efficacy of the Noncessation Method of Antithrombotic Agents after Emergency Endoscopic Hemostasis in Patients with Nonvariceal Upper Gastrointestinal Bleeding: A Multicenter Pilot Study.

Background and Aims The present study aimed to clarify the safety and efficacy of the noncessation method of antithrombotic agents after emergency endoscopic hemostasis in patients with nonvariceal upper gastrointestinal bleeding (UGIB). Methods In this multicenter, prospective, pilot study, we performed emergency endoscopic hemostasis for nonvariceal UGIB in patients taking antithrombotic agents and resumed the medications without a cessation period (group A). The clinical characteristics, types of antithrombotic agents, UGIB etiology, treatment outcome, and adverse events were evaluated. We used propensity score matching to compare treatment outcomes and adverse events with our previous cohort (group B) in whom antithrombotic agents were transiently discontinued after emergency endoscopic hemostasis. Results Forty-three consecutive patients were prospectively enrolled. The main antithrombotic agents were low-dose aspirin and direct oral anticoagulants; 11 patients (25.6%) were taking multiple antithrombotics. Peptic ulcers were the main cause of bleeding (95.4%). Endoscopic hemostasis was successful in all patients and the incidence of rebleeding within a month was 7.0%. Propensity score matching created 40 matched pairs. Endoscopic hemostasis was performed by soft coagulation significantly more frequently in group A than in group B (97.5% versus 60.0%, P < 0.001). Neither the rebleeding rate within a month nor thromboembolic event rate was different between the two groups. However, the mean duration of hospitalization was significantly shorter in group A than in group B (8.6 ± 5.2 d versus 14.4 ± 7.1 d, P < 0.001). Conclusions Antithrombotic agents possibly can be continued after successful emergency endoscopic hemostasis for nonvariceal UGIB.

Pilot study of nivolumab in pediatric patients with hypermutant cancers.

10011 Background: Responses to immune checkpoint inhibitors (ICI) in unselected pediatric solid tumors have been disappointing. We hypothesized that pediatric cancers with an increased tumor mutation burden (TMB) and/or replication repair deficiency (RRD) may be uniquely susceptible to ICI therapy. Methods: OZM-075 (NCT2992964) is a multicenter pilot study in patients (pts) aged 1-25 yrs with relapsed/refractory cancers (including CNS tumors). Pts were eligible only if tumor showed evidence of RRD (based on immunohistochemistry showing loss of expression of relevant RR protein) or elevated TMB &gt; 5mut/Mb determined by gene panel DNA sequencing. Pts with measurable or evaluable disease were eligible. Enrolment began in May 2017 and was completed in Nov 2020. Pts received programmed death-1 (PD-1) inhibitor nivolumab (NIVO) at a fixed dose of 3mg/kg every 2 weeks. Primary objective was objective response rate (ORR) by iRECIST or iRANO for those with measurable disease. Tumor tissue and serial blood samples were collected for analysis of biomarkers of response and survival. Results: As of 26Jan2021, 6 male and 5 female patients aged 9-18 yrs received treatment with NIVO (5 glioblastoma (GBM), 2 anaplastic astrocytoma (AA), 2 neuroblastoma, 1 colorectal adenocarcinoma (CRC), 1 adrenocortical carcinoma). 3pts had TMB 5-10mut/Mb, 5pts had TMB &gt; 10mut/Mb (range 14-837, median 64), 3 pts enrolled on basis of RRD. Time on treatment ranged from 0-21 months and 2 pts remain on therapy. Best OR was partial response (PR) in 2 pts (both GBM), with an additional patient with CRC achieving pathological CR. Remarkably one of the pts with PR showed early evidence of progression on imaging and elected to discontinue NIVO. Without further therapy, subsequent imaging 7 months later showed PR. Best response of stable disease was demonstrated in 5 further pts, lasting ≥5 months in 3 pts. Median overall survival (OS) not reached. Of 7 patients with relapsed GBM/AA, 5 were alive for ≥12 months following start of NIVO including 4 pts with confirmed TMB &gt; 10mut/Mb. Conclusions: This pilot study showed evidence of impressive clinical benefit particularly for relapsed GBM/AA patients for whom median survival is typically ̃6 months (JCO 1995 13(1):112-). These data contrast previous pediatric data and suggest that in the context of RRD and hypermutation ICI therapy may provide profound long-term response and survival for these children. Analysis of other correlative biomarkers is ongoing. Clinical trial information: 2992964.

Primary care oncology model (PCOM): Implementation of a model integrating primary and oncology care for patients taking oral anticancer agents.

TPS1587 Background: Non-adherence to oral anticancer agents (OAA) has been reported among 30% of individuals. Often, individuals with cancer are not just managing their new OAA but also medications to treat multiple chronic conditions (MCC). Multiple factors contribute to the extent patients on OAAs and MCC medications adhere to therapy. The objective of this study is to improve medication, symptom, and disease management of patients with hematological malignancies and MCC through care coordination between pharmacists. Methods: Design. This is a multi-center prospective single arm pilot study at two academic medical centers in Michigan and Tennessee. Subjects. Ninety participants will be recruited, 60 from site 1 and 30 from site 2. Inclusion criteria are: adults &gt; 18 years, diagnosed with and initiating oral treatment for chronic myeloid leukemia, chronic lymphocytic leukemia, or multiple myeloma, diagnoses of at least 2 chronic conditions, where one is type 2 diabetes, hypertension, congestive heart failure, depression/anxiety, gastroesophageal reflux disease, hyperlipidemia, or chronic obstructive pulmonary disease, taking at least two chronic medications, and able to provide electronic consent. Exclusion criteria are: inability to speak English, and diagnosis of type 1 diabetes or HIV. Intervention. Participants will complete two Patient Reported Outcome Measures (PROMs) for their OAA that will be reviewed by the oncology pharmacist, with follow-up to the care team if needed. Participants will be scheduled for a Comprehensive Medication Review with a primary care pharmacist for up to two visits for their chronic medications. The intervention over 2 months, and the oncology and primary care pharmacists communicate via electronic health record about medications, symptoms, and disease control. Outcomes. The primary endpoints are (a) dose-adjusted adherence by proportion days covered (PDC) for the OAA and (b) PDC for chronic condition medications, assessed using 6 months of prescription claims. Data will be collected from patients using REDCap surveys and abstracted data will be entered into REDCap. Implementation by pharmacists and patient acceptability will be examined. Analysis. The association of OAA and chronic medication adherence (PDC) will be examined via correlation. Participant demographics,clinical characteristics, and the symptom experience from the PROM will be described. Using CMR results, medication problems, recommendations, and changes will be provided. Program implementation will be assessed and patient perceptions obtained from post-CMR interviews. A joint display for the quantitative and qualitative data for feasibility, appropriateness, and acceptability from pharmacists will be completed. Results: Screening and recruitment has begun. Clinical trial information: NCT04595851 and NCT04663100.

Surgical Management of Urinary Tract Endometriosis: A 1-year Longitudinal Multicenter Pilot Study at 31 French Hospitals (by the FRIENDS Group)

To describe the surgical management and risks of postoperative complications of patients with urinary tract endometriosis in France in 2017. Multicenter retrospective cohort pilot study. Departments of gynecology at 31 expert endometriosis centers. All women managed surgically for urinary tract endometriosis from January 1, 2017, to December 31, 2017. We distinguished patients with isolated bladder endometriosis or isolated ureteral endometriosis (IUE) from those with endometriosis in both locations (mixed locations [ML]). Surgeons belonging to the French Colorectal Infiltrating Endometriosis Study (FRIENDS) group enrolled patients who filled a 24-item questionnaire on the day of the inclusion and 3 months later. Data were collected on operative routes, surgical management, and postoperative complications according to the Clavien-Dindo classification in a single anonymized database. A total of 232 patients from 31 centers were included. Isolated bladder endometriosis was found in 82 patients (35.3%), IUE in 126 patients (54.4%), and ML in 24 patients (10.3%). Surgery was performed by laparoscopy, laparotomy, or robot-assisted laparoscopy in 74.1%, 11.2%, and 14.7% of the cases, respectively. Among the 150 ureteral lesions (IUE and ML), 114 were managed with ureterolysis (76%), 28 with ureteral resection (18.7%), 4 with nephrectomy (2.7%), and 23 with cystectomy (15.3%). Concerning bladder endometriosis, a partial cystectomy was performed in 94.3% of the cases. We reported 61 postoperative complications (26.3%): 44 low-grade complications according to the Clavien-Dindo classification (18%), 16 grade III complications (7%), and 1 grade IV complication (peritonitis). The surgical management of ureteral and bladder endometriosis is usually feasible and safe through laparoscopic surgery. Ureteral resection, when necessary, is more strongly associated with laparotomy and with more complications than other procedures. Prospective controlled studies are still mandatory to assess the best surgical management for patients.

Close relationships in Parkinson´s disease patients with device-aided therapy.

ObjectivesDeep brain stimulation, continuous subcutaneous apomorphine infusion, and levodopa–carbidopa intestinal gel infusion, together called device‐aided therapies (DAT), are introduced when oral and transdermal pharmacotherapy are not enough for a satisfactory control of Parkinson's disease (PD) symptoms. Solid relationships are central to an individual's well‐being, but the impact of close relationships in advanced PD remains underexplored. The aim of this study was to investigate the development of close relationships between PD patients and their partners following the initiation of DAT and to examine the relationship structures in these relationships.Materials and MethodsThis was a retrospective quantitative multicenter pilot study wherein 41 couples, patients with advanced PD and their partners, retrospectively rated their relationship satisfaction before the start of DAT, after one year of DAT and at the time of the interview. The couples also answered the Experiences in Close Relationships—Questionnaire of Relational Structures (ECR‐RS).ResultsPartners more often report changes in relationship satisfaction than patients between baseline and both 1 year after start of DAT (p = .049) and last evaluation (p = .041). The ECR‐RS data reported significantly higher avoidance score for partners (p = .005) and significantly higher anxiety score for patients (p = .024).ConclusionsThe close relationship wherein one part has PD and receives DAT has a high risk of being unequal. Prospective studies are needed for further clarification of the interplay between advanced PD, DAT, and close relationships, this in order to improve pre‐ and postinterventional support for PD patients receiving DAT, as well as their partners.

Resuscitation in Paediatric Sepsis Using Metabolic Resuscitation-A Randomized Controlled Pilot Study in the Paediatric Intensive Care Unit (RESPOND PICU): Study Protocol and Analysis Plan.

Introduction: Septic shock remains amongst the leading causes of childhood mortality. Therapeutic options to support children with septic shock refractory to initial resuscitation with fluids and inotropes are limited. Recently, the combination of intravenous hydrocortisone with high dose ascorbic acid and thiamine (HAT therapy), postulated to reduce sepsis-related organ dysfunction, has been proposed as a safe approach with potential for mortality benefit, but randomized trials in paediatric patients are lacking. We hypothesize that protocolised early use of HAT therapy (“metabolic resuscitation”) in children with septic shock is feasible and will lead to earlier resolution of organ dysfunction. Here, we describe the protocol of the Resuscitation in Paediatric Sepsis Using Metabolic Resuscitation–A Randomized Controlled Pilot Study in the Paediatric Intensive Care Unit (RESPOND PICU).Methods and Analysis: The RESPOND PICU study is an open label randomized-controlled, two-sided multicentre pilot study conducted in paediatric intensive care units (PICUs) in Australia and New Zealand. Sixty children aged between 28 days and 18 years treated with inotropes for presumed septic shock will be randomized in a 1:1 ratio to either metabolic resuscitation (1 mg/kg hydrocortisone q6h, 30 mg/kg ascorbic acid q6h, 4 mg/kg thiamine q12h) or standard septic shock management. Main outcomes include feasibility of the study protocol and survival free of organ dysfunction censored at 28 days. The study cohort will be followed up at 28-days and 6-months post enrolment to assess neurodevelopment, quality of life and functional status. Biobanking will allow ancillary studies on sepsis biomarkers.Ethics and Dissemination: The study received ethical clearance from Children's Health Queensland Human Research Ethics Committee (HREC/18/QCHQ/49168) and commenced enrolment on June 12th, 2019. The primary study findings will be submitted for publication in a peer-reviewed journal.Trial Registration: Australian and New Zealand Clinical Trials Registry (ACTRN12619000829112). Protocol Version: V1.8 22/7/20.

Midregional proadrenomedullin safely reduces hospitalization in a low severity cohort with infections in the ED: a randomized controlled multi-centre interventional pilot study

IntroductionThe midregional fragment of proadrenomedullin (MR-proADM) is known to provide accurate short-, mid- and long term prognostic information in the triage and multi-dimensional risk assessment of patients in the emergency department (ED). In two independent observational cohorts MR-proADM values identified low disease severity patients without risk of disease progression in the ED with no 28 days mortality that wouldn´t require hospitalization. In this interventional study we want to show that the combination of an MR-proADM algorithm with clinical assessment is able to identify low risk patients not requiring hospitalization to safely reduce the number of hospital admissions. MethodsA randomized-controlled interventional multicenter study in 4 EDs in Spain. The study protocol was approved by Ethics Committees. Control arm patients received Standard Care. MR-proADM guided arm patients with low MR-proADM value (≤0.87 nmol/L) were treated as out-patients, with high MR-proADM value (>0.87 nmol/L) were hospitalized. The hospitalization rate was compared between the study arms. ResultsTwo hundred patients with suspicion of infection were enrolled. In the MR-proADM guided arm the hospital admission rate in the intention-to-treat (ITT) population was 17% lower than in the control arm (40.6% vs. 57.6%, p=0.024) and 20% lower in the per protocol (PP) population (37.2% vs. 57.6%, p=0.009). No deaths of out-patients and no significant difference for the safety endpoints readmission and representation rates were observed. The readmission rate was only slightly higher in the MR-proADM guided arm compared to the control arm (PP population: at 14 days 9.3% vs. 7.1%, difference 2.1% (95% CI: -11.0% to 15.2%); and at 28 days 11.1% vs. 9.5%, difference 1.6% (95% CI: -12.2% to 15.4%)). The rate of 28 days representation was slightly lower in the MR-proADM guided arm compared to the control arm (20.4% vs. 26.2%, difference -5.8% (95% CI: -25.0% to 13.4%); PP population). ConclusionsImplementing a MR-proADM algorithm optimizes ED workflows efficiently and sustainably. Hospitals can highly benefit from a reduced rate of hospitalizations by 20% using MR-proADM. The safety in the MR-proADM guided study arm was similar to the Standard Care arm. Trial registrationClinicalTrials.gov Identifier NCT03770533

An evaluation of the differences in paediatric skeletal trauma between fatal simple short falls and physical abuse blunt impact loads: An international multicentre pilot study

In cases where a deceased child exhibits trauma as a result of a physical abuse blunt impact load, a parent/caregiver may provide a simple short fall (SSF) as the justification for that trauma. The skeletal fractures remain difficult to differentiate between a SSF and physical abuse however, as both are the result of a blunt impact load, and are therefore biomechanically alike, and the rare nature of these fatalities means only anecdotal research has been available to validate such claims. The aim of this pilot study was to investigate if there may be differences in the skeletal fracture patterns and types resulting from SSFs compared with those resulting from physical abuse blunt impacts. Paediatric (<10 years) cases of fatal SSFs (≤1.5 m) and physical abuse were collected from the Victorian Institute of Forensic Medicine (Australia), Institut Médico-Légal de Paris (France), University of Pretoria (South Africa) and Great Ormond Street Hospital (England). For each case the intrinsic and extrinsic variables were recorded from medico-legal reports and skeletal trauma was documented using post-mortem computed tomography scans and/or skeletal surveys. Three SSFs and 18 physical abuse cases were identified. Of the SSF cases, two exhibited fractures; both of which were simple linear neurocranial fractures. Comparatively, 12 of the physical abuse cases exhibited fractures and these were distributed across the skeleton; 58% located only in the skull, 17% only in the post-cranial and 25% located in both. Skull fracture types were single linear, multiple linear and comminuted. This pilot study suggests, anecdotally, there may be differences in the fracture patterns and types between blunt impact loads resulting from a SSF and physical abuse. This data will form the foundation of the Registry of Paediatric Fatal Fractures (RPFF) which, with further multicentre contributions, would allow this finding to be validated.

Virtual Reality for Motor and Cognitive Rehabilitation From Clinic to Home: A Pilot Feasibility and Efficacy Study for Persons With Chronic Stroke.

Aims: Continuity of care is an important issue in healthcare for persons after stroke. The present multi-center pilot study investigates the feasibility and efficiency of an innovative approach, the Human Empowerment Aging and Disability (HEAD), for digital-health motor and cognitive rehabilitation. The approach is explored within an in-clinic context (ClinicHEAD) and in continuity of care (HomeHEAD) for persons after chronic stroke.Methods: Thirty-four outpatients with chronic stroke (mean age 55 years, SD 13.7) participated. The HEAD VR protocol was administered in two consecutive phases: Phase I in clinic (ClinicHEAD) consisting of 4 weeks of 12 supervised HEAD rehabilitation sessions (45-min), including motor, cognitive and dual task for all participants; Phase II at home (HomeHEAD) consisted of 60 sessions of the same VR activities, 5 times/week for 3 months. All participants in the ClinicHEAD were allocated (ratio 1:2) to continue with tele-monitored home rehabilitation (HH, N = 11) or to follow usual care (UC, N = 23). Blind evaluation was carried out at baseline, after ClinicHEAD, after 3 months of HomeHEAD and at 3 months Follow-up. Primary outcomes were functional mobility [2-min Walking Test (2MWT)] and cognition [Montreal Cognitive Assessment (MoCA)]. Feasibility and acceptance were assessed with adherence to treatment and the System Usability Satisfaction. Within group analyses were done with dependent samples t-tests, and between groups HomeHEAD comparisons were carried out on change scores with independent samples t-test (p = 0.05, two tailed).Results: The HEAD protocol was feasible with good adherence both in the ClinicHEAD phase (92%) and HomeHEAD (89%) phase, along with good perceived system satisfaction. ClinicHEAD resulted in a significant increase in functional mobility (2MWT, p = 0.02) and cognition (MoCA, p = 0.003) and most secondary outcome variables. At 3 months follow up of HomeHEAD the HH_group showed a further significantly greater maintenance of functional mobility with respect to UC_group (p = 0.04).Conclusion: The HEAD VR protocol was feasible in clinical and at home tele-rehabilitation for persons in the chronic phase after stroke. In clinic the approach was effective in augmenting motor and cognitive abilities and at home it was effective in longterm maintenance of functional mobility, indicating its usefulness in continuity of care.Clinical Trial Registration: ClinicalTrials.gov, NCT03025126.

High-dose pyridoxine treatment for inherited glycosylphosphatidylinositol deficiency

ObjectiveWe aimed to assess the efficacy and safety of high-dose pyridoxine treatment for seizures and its effects on development in patients with inherited glycosylphosphatidylinositol deficiencies (IGDs). MethodsIn this prospective open-label multicenter pilot study, we enrolled patients diagnosed with IGDs using flow cytometry and/or genetic tests. The patients received oral pyridoxine (20–30 mg/kg/day) for 1 year, in addition to previous treatment. ResultsAll nine enrolled patients (mean age: 66.3 ± 44.3 months) exhibited marked decreases in levels of CD16, a glycosylphosphatidylinositol-anchored protein, on blood granulocytes. The underlying genetic causes of IGDs were PIGO, PIGL, and unknown gene mutations in two, two, and five patients, respectively. Six patients experienced seizures, while all patients presented with developmental delay (mean developmental age: 11.1 ± 8.1 months). Seizure frequencies were markedly (>50%) and drastically (>90%) reduced in three and one patients who experienced seizures, respectively. None of the patients presented with seizure exacerbation. Eight of nine patients exhibited modest improvements in development (P = 0.14). No adverse events were observed except for mild transient diarrhea in one patient. ConclusionOne year of daily high-dose pyridoxine treatment was effective in the treatment of seizures in more than half of our patients with IGDs and modestly improved development in the majority of them. Moreover, such treatment was reasonably safe. These findings indicate that high-dose pyridoxine treatment may be effective against seizures in patients with IGDs, although further studies are required to confirm our findings. (University Hospital Medical Information Network Clinical Trials Registry [UMIN-CTR] number: UMIN000024185.)

Digital therapeutic improves visual acuity and encourages high adherence in amblyopic children in open-label pilot study

The effectiveness of amblyopia therapy can be limited by poor adherence. Dichoptic therapies are a new approach, but recent trials have demonstrated difficulty maintaining high adherence over extended periods of at-home treatment. We evaluated the efficacy and adherence of Luminopia One-a dichoptic treatment that applies therapeutic modifications to streaming content chosen by the patient. This single-arm, multicenter prospective pilot study enrolled children aged 4-12 with anisometropic, strabismic, or mixed amblyopia at 10 pediatric ophthalmic and optometric practices across the United States. The therapeutic was prescribed for 1hour/day, 6days/week for 12weeks of at-home use. The primary endpoint was best-corrected visual acuity (BCVA) at the 12-week follow-up visit. In total, 90 participants (mean age, 6.7±2.0years) were enrolled, and 73/90 participants (81%) had prior treatment beyond refractive correction. For those who completed the 12-week visit, mean amblyopic eye BCVA improved from 0.50 logMAR to 0.35 logMAR (1.5 logMAR lines; 95% CI, 1.2-1.8 lines; P<0.0001). Mean stereoacuity improved by 0.28 log arcsec (95% CI, 0.14-0.42 log arcsec; P<0.0001). Median adherence was 86% (interquartile range, 70%-97%). In our study cohort, adherence over the 12-week study period was high, and participants demonstrated clinically and statistically significant improvements in visual acuity and stereoacuity.

Subchondral and intra-articular injections of bone marrow concentrate are a safe and effective treatment for knee osteoarthritis: a prospective, multi-center pilot study.

Subchondral bone is becoming a treatment target for knee OA patients, with promising early findings on the use of bone marrow aspirate concentrate (BMAC). The aim of this prospective, multi-centric pilot study was to evaluate safety as well as clinical and MRI outcomes of a combined approach of intra-articular and subchondral BMAC injections. Thirty patients (19 men, 11 women, 56.4 ± 8.1years) with symptomatic knee OA were treated with a combination of an intra-articular and two subchondral BMAC injections (femoral condyle and tibial plateau). Patients were evaluated at baseline and at 1-3-6-12months of follow-up with the IKDC subjective, VAS, KOOS, and EQ-VAS scores. The MRI evaluation was performed with the WORMS score. No major complications were reported and only two patients were considered treatment failures, requiring a new injective or surgical treatment. The IKDC subjective score improved significantly from 40.5 ± 12.5 to 59.9 ± 16.1 at 3months, 59.1 ± 12.2 at 6months, and 62.6 ± 19.4 at 12months (p < 0.0005). A similar improvement was reported for VAS pain and all KOOS subscales at all follow-ups, while EQ-VAS did not show any significant improvement. The MRI analysis showed a significant bone marrow edema reduction (p = 0.003), while the remaining WORMS parameters did not show any significant changes. The pilot evaluation of this combined BMAC injective treatment showed safety and positive outcome up to 12months of follow-up in patients with symptomatic knee OA associated with subchondral bone alterations. These findings suggest that targeting both subchondral bone and joint environment can provide promising results, and that BMAC can be a valid option for this combined approach to treatknee OA.

Newborn infant parasympathetic evaluation for the assessment of analgosedation adequacy in infants treated by mechanical ventilation - a multicenter pilot study.

IntroductionAdequate analgosedation is important in infants treated in pediatric/neonatal intensive care units (P/NICUs), because both too deep and insufficient analgosedation is disadvantageous. To assess the severity of pain, several behavioral and behavioral-physiological scales are used, but their usefulness is limited. It is therefore justified to search for additional methods to assess the adequacy of analgosedation in these patients. The aim of the present study is to evaluate the usefulness of Newborn Infant Parasympathetic Evaluation (NIPE) in the assessment of analgosedation quality in infants requiring mechanical ventilation, who are treated in P/NICUs.Material and methodsWe performed simultaneously 180 COMFORT-B assessments and heart rate variability measurements using a NIPE monitor in 30 mechanically ventilated infants receiving analgosedation. A generalized linear mixed model with the logit link function was used in order to perform logistic regression analysis to assess the relationship between NIPEi/NIPEm and deep sedation.ResultsThe multivariable logistic regression model showed that NIPEi and NIPEm values were higher when analgosedation was deep as compared to when it was moderate or insufficient (OR (95% CI): NIPEm – 1.065 (1.007–1.126), p = 0.03; NIPEi – 1.068 (1.016–1.123), p = 0.01).ConclusionsThe NIPE indexes are significantly higher in patients whose assessment on the behavioral scale indicates deep analgosedation as compared to those in whom it indicates moderate or insufficient analgosedation. Allowing continuous monitoring, the NIPE device may be a valuable assisting tool in the assessment of analgosedation quality in mechanically ventilated newborns and infants.

Effect of timing of acupuncture on limb dysfunction in patients with cerebral infarction: a multicenter prospective cohort pilot study

To evaluate the clinical efficacy of acupuncture at different timings in acute stage for limb dysfunction in patients with cerebral infarction. A total of 101 patients with cerebral infarction limb dysfunction were divided into an early exposure group (n=51) and a late exposure group (n=50) according to the time of first acupuncture treatment during the acute phase. SPSS 25.0 software was used to balance the baseline between the two groups, and 31 pairs of matched patients were included, including 31 cases in the early exposure group and 31 cases in the late exposure group. The two groups were treated with Xingnao Kaiqiao acupuncture at Shuigou (GV 26), Neiguan (PC 6), Sanyinjiao (SP 6), Jiquan (HT 1), Chize (LU 5), Weizhong (BL 40), etc., once a day, and the course of treatment was not limited. In the early exposure group, acupuncture was started after 1 to 3 days of onset; in the late exposure group, acupuncture was started after 11 to 14 days of onset. The modified Rankin scale (mRS) grade was recorded before treatment, 30 and 60 days after onset; Fugl-Meyer assessment (FMA) grade was observed before treatment and 30 days after onset; the effect of acupuncture timing on the patients was analyzed by logistic analysis. Compared before treatment, the mRS grade at 30 and 60 days after onset in the early exposure group was improved (P<0.05), which was superior to the late exposure group (P<0.05); compared before treatment, the FMA grade at 30 days after onset in the early exposure group was improved (P<0.05), which was superior to the late exposure group (P<0.05). The timing of acupuncture was independently correlated with the disability status and the severity of motor dysfunction at 30 days after onset, and the disability status at 60 days after onset (P<0.05). Compared with the late exposure group, the possibility of becoming non-disabled at 30 days after onset (OR=22.882, 95%CI: 4.034-129.778), normal limb motor dysfunction (OR=22.320, 95%CI: 3.454-144.213) and non-disabled at 60 days after onset (OR=8.650, 95%CI: 2.437-30.696) in the early exposure group was increased. The timing of acupuncture is an independent factor affecting the disability status and limb motor dysfunction in patients with cerebral infarction, and the effect of early intervention may be better than late intervention.

Cross-Sectional Study on Vitamin D, Zinc Oxide and Fatty Acid Status in a Population with a Moderate to High Risk of AMD Identified by the STARS® Questionnaire.

IntroductionA prospective study was carried out in Belgium to determine the proportion of subjects with a moderate to high risk of developing age-related macular degeneration (AMD), identified using the STARS® (Simplified Théa AMD Risk-Assessment Scale) questionnaire, who were in need of nutritional supplementation, by assessing the vitamin D, zinc oxide and fatty acid profile status.MethodsThis multicentre cross-sectional pilot study involved 50 Belgian subjects with no or early AMD, aged > 55 years who were at moderate to high risk for AMD. Subjects were assessed using the STARS® questionnaire, visual acuity assessment, an optical coherence tomography scan of the macula and fundus photography. Blood samples were collected, and serum analyses were performed to determine the the omega-6:omega-3 (Ω6:Ω3) ratio and the levels of eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), zinc and cupric oxides and vitamin D.ResultsAbnormal serum levels for at least one of the micronutrients was detected in 94% of the subjects. Lower than optimal vitamin D levels were found in 76% of the participants, and 68% of the subjects demonstrated at least one abnormal fatty acid profile. The Ω6:Ω3 ratio was above the reference range for normal values in 54% of the subjects; DHA and EPA levels were below the reference range in 60 and 46% of the subjects, respectively; and zinc oxide concentration was below the reference range in 50% of the subjects. Only 12% of the subjects exhibited cupric oxide deficiency.ConclusionIn this study, the STARS® questionnaire was used for early identification of patients at moderate to high risk of AMD in real life. These patients presented a suboptimal nutritional status. Further research is needed to determine if specific diet modification or micronutrient supplement intake delays the onset or slows down the progression of AMD in these subjects.Trial RegistrationTrial registration: ClinicalTrials.Gov, identifier: NCT04482465.Supplementary InformationThe online version of this article (10.1007/s40123-021-00335-4) contains supplementary material, which is available to authorized users.

Digital therapeutics for essential hypertension using a smartphone application: A randomized, open-label, multicenter pilot study.

Hypertension is the most considerable but treatable risk factor for cardiovascular disease. Although physicians prescribe multiple antihypertensive drugs and promote lifestyle modifications, the real‐world blood pressure (BP) control rate remains poor. To improve BP target achievement, we developed a novel digital therapeutic—the HERB software system —to manage hypertension. Here, we performed a randomized pilot study to assess the safety and efficacy of the HERB system for hypertension. We recruited 146 patients with essential hypertension from March 2018 to March 2019. We allocated eligible patients to the intervention group (HERB system + standard lifestyle modification) or control group (standard lifestyle modification alone). The primary outcome was the mean change from baseline to 24 weeks in 24‐hour systolic BP (SBP) measured by ambulatory blood pressure monitoring (ABPM). The baseline characteristics in each group were well balanced; the mean age was approx. 57 years, and 67% were male. In the primary end point at 24 weeks, HERB intervention did not lower the mean change of 24‐hour SBP by ABPM compared with the controls (adjusted difference: −0.66 mmHg; p = .78). In an exploratory analysis focusing on antihypertensive drug‐naïve patients aged <65, the effects of the HERB intervention were significantly greater than the control for reducing 24‐hour SBP by ABPM at 16 weeks (adjusted difference: −7.6 mmHg; p = .013; and morning home SBP at 24 weeks (adjusted difference − 6.0 mmHg; p = .012). Thus, the HERB intervention did not achieve a primary efficacy end point. However, we observed that antihypertensive drug‐naïve adult hypertensive patients aged <65 years could be a potential HERB system‐effective target for further investigations of the efficacy of the system.

A pilot study on the use of prednisolone-encapsulated liposomes for the treatment of moderate-to-severe Graves' orbitopathy with reduced systemic steroid exposure.

To demonstrate that long-circulating PEGylated liposomal prednisolone is a safe and effective therapy in patients with active moderate-to-severe Graves' orbitopathy. Open-label, proof-of-concept, multicentre pilot study. Ten patients with moderate-to-severe Graves's orbitopathy, who were euthyroid for at least three months. Long-circulating PEGylated liposomal prednisolone 150mg was administered intravenously twice, with 2-week interval. Total follow-up was 12months, with visits at baseline, week 2, 6, 13, 26 and 52. Physical, laboratory and ophthalmological examinations were performed. Response to treatment was defined as a reduction in Clinical Activity Score by ≥2 points; palpebral aperture by ≥3mm; soft tissue signs by ≥2 grades; exophthalmos by ≥2mm; and motility by >8 degrees or improvement in diplopia score. A response was sustained when equally observed at weeks 6 and 13. One patient achieved a sustained response according to the predetermined definition. All patients showed a decrease in Clinical Activity Score after one infusion, with a mean decrease of two points. The Clinical Activity Score was ≤1 at week 52 for all patients. Improvement was also observed in the soft tissue signs. Most of the adverse events were mild and of a transient nature. Two patients required further treatment with intravenous methylprednisolone. This pilot study showed a positive effect of long-circulating PEGylated liposomal prednisolone on the Clinical Activity Score in patients with moderate-to-severe Graves's orbitopathy, resulting in fewer hospital visits and possibly less glucocorticoid-related side-effects.

Influence of Post Annealing Rates on Porosity, Dispersion Energy and Associated Dielectric Energy Losses of TiO&amp;lt;sub&amp;gt;2&amp;lt;/sub&amp;gt; Thin Films

A chiropractic multicenter observational pilot study to compile statistics on the examination procedures, diagnosis, types of treatments rendered, results of treatment, number of days of care, and number of treatments required to arrive at a 50% and a maximum clinical improvement was collected on 576 patients with low back and/or leg pain. The purpose was to determine the congenital and developmental changes in patients with low back and/or leg pain, the combinations of such anomalies, the accuracy of orthodox diagnostic tests in assessing low back pain, ergonomic factors affecting onset and, ultimately, the specific difficulty factors encountered in treating the various conditions seen in the average chiropractor's office. For all conditions treated, the average number of days to attain maximum improvement was 43 and the number of visits 19. It was concluded that this study provided useful data for assessment of routine chiropractic office based diagnosis and treatment of related conditions; however, further controlled studies are necessary for validation of specific parameters.

Value of preoperative HE4 as predictor of advanced disease in endometrioid endometrial cancer.

To explore the predictive value of serum human epididymis protein 4 (HE4) marker in the preoperative prediction of the risk of advanced disease in the endometrioid subtype of endometrial cancer, and its association with poor prognostic factors. In addition, a cut-off value of HE4 was defined to classify patients according to these results. Prospective and multicenter cohort analytical pilot study of patients operated for endometrial cancer at the Miguel Servet University Hospital of Zaragoza (Spain) and the Complejo Universitario of León (Spain) from January 2017 to May 2019. Preoperative serum levels of HE4 were analyzed by clinical and pathologic characteristics. In all, 126 patients were included. A statistically significant association was found between the preoperative HE4 value and node involvement (P=0.008), late-stage disease (P=0.003), high histologic grade (P=0.007), deep myometrial invasion (P=0.001), lymphovascular space invasion (P=0.001), and other pathologic factors. In addition, an HE4 cut-off value (156.4pmol/L) has been determined to predict, preoperatively, which patients will present with early stage disease. The preoperative marker HE4 is a useful tool in the preoperative study of patients with endometrial cancer as it relates to late-stage disease as well as other prognostic factors in the endometrioid subtype of endometrial cancer.