Prospective Open-label Study Research Articles

CYP2C19 gene polymorphism and its impact on the long-term prognosis after myocardial infarction

Background: Despite advanced in interventional and medical treatment, mortality after myocardial infarction (MI) remains high, which necessitates the search for predictors of poor outcome. An association between the gene CYP2C19 alleles with lower functional activity and the rates of cardiovascular events has been found. In a number of studies, negative impact of the *2 and *3 alleles of this polymorphic gene on the post-infarction course was shown. However, in most of these studies the patients were followed up from 3 months to 1 year.
 Aim: To evaluate the effect of CYP2C19 gene polymorphism (*2, *3) on the long-term prognosis in patients with a history of ST-segment elevation myocardial infarction (STEMI).
 Materials and methods: This open-label prospective two-center study included 145 patients aged 45 to 75 years with a history of STEMI. For 1 year from STEMI on, all the patients were taking medications recommended for outcome improvement, such as statins, clopidogrel as a component of dual antiplatelet therapy, beta-blockers, angiotensin converting enzyme inhibitors. The outcomes were assessed at 12 months by the endpoints of cardiovascular death and recurrent non-fatal MI, and at 5 years by the endpoints of overall mortality and recurrent non-fatal MI.
 Results: During one year of the follow up, 7 of 145 patients (4.8%) died from cardiovascular causes. Recurrent MI occurred in 8.3% (n = 12) of the patients. The carriers of *1*2 and *1*3 genotypes of the polymorphic CYP2C19 gene were 3.27-fold more likely to experience recurrent MI within 1 year, compared to the carriers of other genotypes (relative risk = 3.27 [95% confidence interval 1.03; 10.36], p = 0.03). After 5 years of the follow up, this association has disappeared. No influence of the assessed polymorphisms on overall and cardiovascular mortality was found (p 0.05). One hundred and seven (107) patients were followed up for 5 years; 14 (13.0%) of them died, other 15 patients (14.0%) had recurrent MIs.
 Conclusion: *2 and *3 alleles of the polymorphic CYP2C19 gene responsible for the metabolism of clopidogrel, are risk factors of an unfavorable 12-month outcome after STEMI. Subsequently, the influence of the CYP2C19 gene polymorphism on the outcomes evades and is not associated with a 5-year prognosis. To improve post-STEMI outcomes at 1 year, it is necessary to implement the earliest personalized approached to antiplatelet treatment based on the results of the CYP2C19 gene polymorphism analysis.

Development and Validation of a Deep Learning System for Sound-based Prediction of Urinary Flow

BackgroundUroflowmetry remains an important tool for the assessment of patients with lower urinary tract symptoms (LUTS), but accuracy can be limited by within-subject variation of urinary flow rates. Voiding acoustics appear to correlate well with conventional uroflowmetry and show promise as a convenient home-based alternative for the monitoring of urinary flows. ObjectiveTo evaluate the ability of a sound-based deep learning algorithm (Audioflow) to predict uroflowmetry parameters and identify abnormal urinary flow patterns. Design, setting, and participantsIn this prospective open-label study, 534 male participants recruited at Singapore General Hospital between December 1, 2017 and July 1, 2019 voided into a uroflowmetry machine, and voiding acoustics were recorded using a smartphone in close proximity. The Audioflow algorithm consisted of two models—the first model for the prediction of flow parameters including maximum flow rate (Qmax), average flow rate (Qave), and voided volume (VV) was trained and validated using leave-one-out cross-validation procedures; the second model for discrimination of normal and abnormal urinary flows was trained based on a reference standard created by three senior urologists. Outcome measurements and statistical analysisLin’s correlation coefficient was used to evaluate the agreement between Audioflow predictions and conventional uroflowmetry for Qmax, Qave, and VV. Accuracy of the Audioflow algorithm in the identification of abnormal urinary flows was assessed with sensitivity analyses and the area under the receiver operating curve (AUC); this algorithm was compared with an external panel of graders comprising six urology residents/general practitioners who separately graded flow patterns in the validation dataset. Results and limitationsA total of 331 patients were included for analysis. Agreement between Audioflow and conventional uroflowmetry for Qmax, Qave, and VV was 0.77 (95% confidence interval [CI], 0.72–0.80), 0.85 (95% CI, 0.82–0.88) and 0.84 (95% CI, 0.80–0.87), respectively. For the identification of abnormal flows, Audioflow achieved a high rate of agreement of 83.8% (95% CI, 77.5–90.1%) with the reference standard, and was comparable with an external panel of six residents/general practitioners. AUC was 0.892 (95% CI, 0.834–0.951), with high sensitivity of 87.3% (95% CI, 76.8–93.7%) and specificity of 77.5% (95% CI, 61.1–88.6%). ConclusionsThe results of this study suggest that a deep learning algorithm can predict uroflowmetry parameters and identify abnormal urinary voids based on voiding sounds, and shows promise as a simple home-based alternative to uroflowmetry in the management of patients with LUTS. Patient summaryIn this study, we trained a deep learning–based algorithm to measure urinary flow rates and identify abnormal flow patterns based on voiding sounds. This may provide a convenient, home-based alternative to conventional uroflowmetry for the assessment and monitoring of patients with lower urinary tract symptoms.

The effects of drinking bicarbonate-rich mineral water in calcium oxalate stone formers: an open label prospective randomized controlled study in an Asian cohort.

To examine the effects of drinking bicarbonate-rich mineral water in patients with calcium oxalate stones. This was an open label prospective randomized controlled study comparing the effects of a bicarbonate-rich mineral water versus plain water on urine biochemistry in patients with calcium oxalate stones. The mineral water group were instructed to consume 1.25L of mineral water per day at meal times, and supplemented by plain water. Their total intake was up to 3L/day. Control group consumed only plain water up to 3L/day. 24h urine analyses were performed at baseline, 1, 4, 8 and 12weeks after starting protocol. 58 patients were recruited for the study. 51 patients were included in the final analysis. Baseline data were comparable between the two groups. Over the course of 12weeks, compared to patients drinking plain water, those drinking mineral water had higher overall urinary volume (difference = 644.0ml/24h, 95% CI = (206.7, 1081.3)), higher overall urinary magnesium (difference = 1.894mmol/24h, 95% CI = (1.006, 2.782)), and pH (difference = 0.477, 95% CI = (0.149, 0.804)). However, there was no difference in urinary oxalate and Tiselius index. Mineral water group had net increase of urinary citrate (at each study point compared to baseline) which was sustained until week 12, whereas plain water group showed no significant change. Drinking bicarbonate-rich mineral water in calcium oxalate stone formers increased stone inhibitors such as magnesium, citrate and moderate degree of urinary alkalinization compared to patients drinking plain water, but it did not alter Tiselius index or urinary oxalate after 12weeks.

Post-transplant Diabetes Mellitus: What Physicians Need to Know.

Post-transplant diabetes mellitus (PTDM) is a common problem among solid organ transplant recipients contributing to morbidity and affecting patient as well as graft survival adversely. It can occur at any period following transplantation, but maximum incidence is observed in the first few months, with a second peak after a few years after transplantation. The pathogenesis is complex and poorly understood, however, it is associated with both dysfunctional beta-cells and insulin resistance. Both nonpharmacologic and antidiabetic therapies are important for adequate glycemic control. This point of view article provides a short review on PTDM in solid organ transplantation (SOT) recipients from a general physician's perspective.

Nocturnal acid breakthrough and esophageal acidification during treatment with dexlansoprazole as compared to omeprazole in patients with gastroesophageal reflux disease.

Nocturnal acid breakthrough (NAB) may differ based on duration of proton pump inhibitor (PPI) action and Helicobacter pylori (H. pylori) infection; NAB may influence esophageal acidification (EA) and mucosal damage. Dexlansoprazole, a long-acting PPI, was not compared with omeprazole for NAB, gastric acid suppression, and EA in relation to H. pylori infection. In this prospective open-label comparative observational study, gastroesophageal reflux disease (GERD) patients were evaluated using 24-h dual-channel pH-impedance monitoring while on dexlansoprazole (60 mg, n = 39) and omeprazole (20 mg, n = 41) to study the degree of gastric acid suppression, esophageal acid exposure, and NAB (primary outcome measures). H. pylori was detected by rapid urease test and histology. NAB tended to be frequent with omeprazole than dexlansoprazole (33/41 [80.5%] vs. 23/39 [59%]; p = 0.06). Though nocturnal mean esophageal pH was comparable between the dexlansoprazole and omeprazole groups, its duration was less with the former (181.5 [15.2-334.2] vs. 283 [158-366] min, p = 0.03). NAB was as frequent in the H. pylori-infected than the non-infected group (11/19 [57.9%] vs. 45/61 [73.8%]; p = 0.1). The nocturnal gastric and esophageal pH in the H. pylori-infected group was higher than in the non-infected group (4.6 ± 1.7 vs. 4 ± 1.6, p = 0.157; 6.1 ± 0.6 vs. 5.8 ± 0.6, p = 0.128). Dexlansoprazole tended to increase 24-h and nocturnal mean gastric pH among H. pylori-infected more than omeprazole (5.9 ± 1.1 vs. 4.2 ± 1.7, p = 0.023; 5.7 ± 1.2 vs. 3.8 ± 1.5, p = 0.006). Dexlansoprazole is more effective than omeprazole in suppressing gastric acid secretion, resulting in lesser EA and NAB, particularly in the presence of H. pylori.

Non-invasive fetal monitoring: Fetal Heart Rate multimodal estimation from abdominal electrocardiography and phonocardiography

BackgroundFetal cardiac well-being is essential during labor as the delivery is at risk for fetal distress. Continuous monitoring by cardiotocography (CTG) is daily used to record the fetal heart rate (FHR) but this technique has important drawbacks in clinical use. ObjectivesWe propose to monitor FHR with a non-invasive technique, using multimodal recordings of the fetus cardiac activity, associating electrocardiographic (ECG) and phonocardiographic (PCG) sensors. The aim of this study is to evaluate the quality of these multimodal FHR estimations by comparison with CTG, based on clinical criteria. MethodsA clinical protocol was established and a prospective open label study was carried out in the University Hospital of Grenoble. The objective was to record thoracic and abdominal PCG and ECG signals on pregnant women over 37 WG (weeks of gestation), simultaneously with CTG recordings. Adapted signal processing algorithms were then applied on abdominal PCG and ECG signals to extract FHR. Quantitative evaluation was carried out on FHR estimations compared with FHR extracted from CTG. ResultsA total of 40 recordings were performed. Due to technical mistakes the analysis was made possible for 38. 35 recordings allowed a FHR follow-up by ECG or PCG, 30 recordings allowed a FHR follow-up by PCG only, 25 recordings allowed a FHR follow-up by ECG only and 20 recordings allowed a FHR follow-up by both ECG and PCG. ConclusionReliable multimodal recording of FHR associating ECG and PCG sensors is possible during the last month of pregnancy. These positive results encourage the study of multimodal FHR recording during labor and delivery.

Electroconvulsive Therapy for Neuropsychiatric Symptoms due to Major Neurocognitive Disorder: A Prospective, Observational Study.

Neuropsychiatric symptoms (NPSs) in those with major neurocognitive disorder (MNCD) include the responsive behaviors of agitation and aggression. Electroconvulsive therapy (ECT) has shown some effectiveness based on retrospective studies and one open label prospective study. We hypothesized that ECT will reduce NPSs between baseline and after treatment in those with medication-refractory behaviors. This Canadian prospective multicenter study included MNCD patients admitted to geriatric psychiatry units for the management of refractory NPSs. All treatment-refractory participants suffered from advanced MNCD. We conducted the Neuropsychiatric Inventory-Clinician version and the Pittsburgh Agitation Scale at baseline, and during and after the ECT course. A bitemporal or bifrontal ECT series based on dose titration to 1.5 to 2.5 times seizure threshold was administered. Data were collected for 33 patients with a mean age of 73 and categorized with severe MNCD using the Functional Assessment Staging of Alzheimer's Disease scale (stages 6 and 7). The data showed a drop in mean Neuropsychiatric Inventory-Clinician version from 58.36 to 24.58 (P < 0.0001). Mean Neuropsychiatric Inventory agitation subscale dropped from 7.12 to 3.09 (P = 0.007). Mean Neuropsychiatric Inventory aggression subscale dropped from 6.94 to 0.97 (P < 0.0001). There was a concomitant significant decline in Pittsburgh Agitation Scale scores. No participants dropped out because of intolerance of ECT. One participant died from pneumonia, which did not appear related to ECT. In this naturalistic study, ECT was found to be a safe and effective treatment for certain NPSs in people with MNCD. This can translate into improving quality of life.

Levetiracetam in the prophylactic treatment of episodic migraine: A prospective open label study.

The prophylactic treatment of migraine includes anticonvulsant drugs such as valproic acid and topiramate. However, these substances are often poorly tolerated by migraine patients. So far levetiracetam has hardly been studied as an episodic migraine prophylactic agent in adults. To perform a prospective pilot study for the evaluation of the efficacy and tolerability of levetiracetam in the prophylactic treatment of episodic migraine. Fifty patients with episodic migraine were enrolled in this prospective, open label study. After a baseline period of four weeks, patients received 1,000 mg (starting dose 500 mg) bid levetiracetam for 12 weeks. Migraine frequency and accompanying symptoms were recorded in a headache diary. The primary endpoint was the comparison of attack frequency during the baseline with attack frequency during the last four weeks of treatment (treatment period 3). In the Intent-To-Treat analysis, 46% of the patients had a migraine reduction of more than 50% in the third period as compared to the baseline period. The mean number of migraine attacks decreased from 5.2 +/- 2.1 (baseline) to 3.4 +/- 2.7 (period 3). The most frequently reported side effects were somnolence, nausea, and weight gain; all were mild and transient. In a post-hoc comparison, responders to levetiracetam had significantly less migraine attacks at baseline and had significantly more often migraine with aura. The data suggest that levetiracetam has some potential in the prophylactic treatment of episodic migraine which seems, however, to be not superior to that of other anticonvulsant drugs. Levetiracetam was well tolerated and showed better efficacy in patients with migraine with aura and in less affected migraine patients. A larger placebo-controlled, double-blind study in adults seems justified on the basis of these data.

Effect of Erythropoietin-stimulating agent on uremic neuropathy in hemodialysis patients: a single-center open-label prospective study

BackgroundUremic neuropathy is a distal sensorimotor polyneuropathy caused by uremic toxins; its severity is correlated with the degree of renal insufficiency. Erythropoietin (EPO) and erythropoietin receptors (EpoR) are produced in the peripheral nervous system. This is a single-center open-label prospective study was designed to investigate the possible effect of erythropoietin-stimulating agents (ESAs) on uremic neuropathy. Twenty-four newly diagnosed end-stage kidney disease (ESKD) patients were selected, clinical assessment, laboratory, and neurophysiological study were done at 1 and follow-up after 3 months. Patients were divided into two groups (group A received ESA and group B did not receive ESA).ResultsEighteen patients completed the study, eight patients (44.4%) did not have symptoms but had electrophysiological findings of neuropathy (subclinical neuropathy). After 3 months of hemodialysis, patients in group A showed improvement of some electrophysiological features (ulnar MNCV; P = 0.016).ConclusionsThe use of ESA may improve uremic neuropathy in patients with newly diagnosed ESKD who have been started on hemodialysis.

Clinical Impact of Intraoperative Margin Assessment in Breast-Conserving Surgery With a Novel Pegulicianine Fluorescence–Guided System

Positive margins following breast-conserving surgery (BCS) are often identified on standard pathology evaluation. Intraoperative assessment of the lumpectomy cavity has the potential to reduce residual disease or reexcision rate following standard of care BCS in real time. To collect safety and initial efficacy data on the novel pegulicianine fluorescence-guided system (pFGS) when used to identify residual cancer in the tumor bed of female patients undergoing BCS. This prospective single-arm open-label study was conducted as a nonrandomized multicenter controlled trial at 16 academic or community breast centers across the US. Female patients 18 years and older with newly diagnosed primary invasive breast cancer or ductal carcinoma in situ DCIS undergoing BCS were included, excluding those with previous breast cancer surgery and a history of dye allergies. Of 283 consecutive eligible patients recruited, 234 received a pegulicianine injection and were included in the safety analysis; of these, 230 were included in the efficacy analysis. Patients were enrolled between February 6, 2018, and April 10, 2020, and monitored for a 30-day follow-up period. Data were analyzed from April 10, 2020, to August 5, 2021. Participants received an injection of a novel imaging agent (pegulicianine) a mean (SD) of 3.2 (0.9) hours prior to surgery at a dose of 1 mg/kg. After completing standard of care (SOC) excision, pFGS was used to scan the lumpectomy cavity to guide the removal of additional shave margins. Adverse events and sensitivity, specificity, and reexcision rate. Of 234 female patients enrolled (median [IQR] age, 62.0 [55.0-69.0] years), 230 completed the trial and 1 patient with a history of allergy to contrast agents had an anaphylactic reaction and recovered without sequelae. Correlation of pFGS with final margin status on a per-margin analysis showed a marked improvement in sensitivity over standard pathology assessment of the main lumpectomy specimen (69.4% vs 38.2%, respectively). On a per-patient level, the false-negative rate of pFGS was 23.7% (9 of 38), and sensitivity was 76.3% (29 of 38). Among 32 patients who underwent excision of pFGS-guided shaves, pFGS averted the need for reexcision in 6 (19%). In this pilot feasibility study, the safety profile of pegulicianine was consistent with other imaging agents used in BCS, and was associated with a reduced need for second surgery in patients who underwent intraoperative additional excision of pFGS-guided shaves. These findings support further development and clinical performance assessment of pFGS in a prospective randomized trial. ClinicalTrials.gov Identifier: NCT03321929.

Impact of low-intensity extracorporeal shock wave therapy on sexual function after non-nerve-sparing robot-assisted laparoscopic radical prostatectomy

ABSTRACT Objective Considering the natural course of cavernous nerve recovery following robot-assisted laparoscopic radical prostatectomy (RARP), early intervention of low-intensity extracorporeal shockwave therapy (LIESWT) would be more effective for enhancing overall recovery of potency. We analyzed longitudinally alterations in sexual function in patients after RARP, with focus on the effect of early and delayed intervention with LIESWT. Method This study was open-label prospective study. Four patients after RARP were enrolled into this study's protocol over a period between January and June 2017. This early intervention was performed three times a week for two weeks in admission and one time per week in our out patient clinic for six weeks. For the purpose of setting a control group, the same surgeon performed RARP on 4 patients over a period between June 2012 and December 2014. These patients received LIESWT and this delayed protocol was same as that by Vardi et al. The same surgeon performed RARP on 100 patients over a period between April 2012 and February 2015. These patients were assigned to the non-LIESWT group for setting another control group. Sexual function (SF) was assessed with the Expanded Prostate Cancer Index Composite (EPIC). A validated form of self-reported questionnaire was administered to the inpatients before RARP, and mailed to all patients receiving RARP at 3, 6, 9, and 12 months after RARP. Results There was no significant inter-group difference in the baseline patient characteristics and surgical outcomes. The mean duration from RARP to the start of penile rehabilitation was 6 months for patients of the delayed LIESWT group. The SF score was significantly higher at preoperative, postoperative 6 and 9 months (p=0.0024, 0.0001, and 0.0004) in the early-LIESWT group. The SF score of early-LIESWT was significantly higher than that of delayed-LIESWT at postoperative 6 and 9 months (19.7 vs. 7.4; p = 0.0153, 26.2 vs. 6.1; p = 0.0154). On the other hand, there was no significant difference in the SF score between delayed and non-LIESWT groups at all time points. Conclusions Our findings show that penile rehabilitation with LIESWT immediately before urethral catheter removal improved sexual function scores. Our preliminary results suggest that LIESWT could be used as a treatment option in penile rehabilitation. Disclosure Work supported by industry: no.

One-year clinical efficacy and safety of indigo naturalis for active ulcerative colitis: a real-world prospective study.

Background/Aims Recent studies suggested a favorable effect of indigo naturalis (IN) in inducing remission for refractory ulcerative colitis (UC), however, the maintenance effect of IN for patients with UC remains unknown. Therefore, we conducted a prospective uncontrolled open-label study to analyze the efficacy and safety of IN for patients with UC.Methods Patients with moderate to severe active UC (clinical activity index [CAI] ≥ 8) took 2 g/day of IN for 52 weeks. CAI at weeks 0, 4, 8, and 52 and Mayo endoscopic subscore (MES) and Geboes score (GS) at weeks 0, 4, and 52 were assessed. Clinical remission (CAI ≤ 4), mucosal healing (MES ≤ 1), and histological healing (GS ≤ 1) rates at each assessment were evaluated. Overall adverse events (AEs) during study period were also evaluated. The impact of IN on mucosal microbial composition was assessed using 16S ribosomal RNA gene sequences.Results Thirty-three patients were enrolled. The rates of clinical remission at weeks 4, 8, and 52 were 67%, 76%, and 73%, respectively. The rates of mucosal healing at weeks 4 and 52 were 48% and 70%, respectively. AEs occurred in 17 patients (51.5%) during follow-up. Four patients (12.1%) showed severe AEs, among whom 3 manifested acute colitis. No significant alteration in the mucosal microbial composition was observed with IN treatment.Conclusions One-year treatment of moderate to severe UC with IN was effective. IN might be a promising therapeutic option for maintaining remission in UC, although the relatively high rate of AEs should be considered.

Predictors for patient satisfaction of a single intra-articular injection of crosslinked hyaluronic acid combined with mannitol (HANOX-M-XL) in patients with temporomandibular joint osteoarthritis. Results of a prospective open-label pilot study (HAPPYMINI-ARTEMIS trial)

BackgroundChronic pain and functional impairment interfere with the quality of life of subjects suffering from temporomandibular joint (TMJ) disorders. Intra-articular (IA) hyaluronic acid (HA) injections have been shown to alleviate pain and improve mandibular mobility in patients with TMJ osteoarthritis (OA).ObjectivesThe primary aim of the study was to identify the prognostic factors of patient satisfaction for a single IA injection of a mannitol-modified crosslinked HA (HANOX-M-XL) in patients with TMJ-OA. The second goal was to obtain clinical data on effectiveness, safety and mandibular mobility throughout a six-month follow-up period.Patients and methodsThis was an observational single-arm prospective trial with a six-month follow-up. Inclusion criteria: patients with TMJ-OA which is not relieved by analgesics and/or non-steroidal-anti-inflammatory drugs and/or orthotics, with radiological evidence of TMJ-OA. All patients received a single IA injection of 1 ml HANOX-M-XL in the target TMJ. The primary endpoint was patient satisfaction on day 180. The main secondary outcome measures were pain variation on a 11-point numeric scale (0–11) between the date of injection and month six, the variation over time of the Maximum Inter-Incisal Opening Distance (MIIOD) and the patient’s assessment of effectiveness. Predictive factors of success or failure were also studied. All adverse events were recorded.Results36 subjects (mean age 55.3 years, mean disease duration 98 months), covering a total of 52 injected TMJs, were included. Between baseline and endpoint, the average pain while chewing decreased dramatically from 6.9 ± 1.2 to 2.9 ± 1.3 (p < 0.0001) and the MIIOD increased from 29 ± 7 to 35 ± 5 mm (p < 0.01). On day 180, all patients were satisfied with the treatment, with 34 patients (94%) rating it as highly effective or effective. Tolerability was good in all but one patient. In the multivariate analysis, patient satisfaction on day 180 was highly correlated with the pain while chewing score, pain on palpation score and the decrease of pain over time (all p < 0.0001) but not with MIIOD, gender, age, bruxism, articular noise and symptom duration. Previous viscosupplementation was also related to higher satisfaction (p = 0.01).ConclusionDespite a long history of pain, most of the patients with symptomatic TMJ-OA benefited from a single injection of HANOX-M-XL, as shown by the sustained (up to 6 months) decrease in pain and improvement in mandibular mobility, with no safety concerns.

Deep Brain Stimulation of the Nucleus Accumbens in Severe Enduring Anorexia Nervosa: A Pilot Study.

IntroductionAnorexia nervosa (AN) is one of the most debilitating psychiatric disorders, becoming severe and enduring in a third of cases; with few effective treatments. Deep brain stimulation is a reversible, adjustable neurosurgical procedure that has been gaining ground in psychiatry as a treatment for depression and obsessive–compulsive disorder, yet few studies have investigated AN. Abnormal eating behavior and the compulsive pursuit of thinness in AN is, in part, a consequence of dysfunction in reward circuitry and the nucleus accumbens (NAcc) is central to reward processing.MethodsPhase 1 prospective open-label pilot study of seven individuals with severe enduring AN. Electrodes were implanted bilaterally into the NAcc with stimulation at the anterior limb of the internal capsule using rechargeable implantable pulse generators. The protocol of 15 months included 12 months of deep brain stimulation incorporating two consecutive, randomized blind on-off fortnights 9 months after stimulation onset. The primary objectives were to investigate safety and feasibility, together with changes in eating disorder psychopathology.ResultsFeasibility and safety was demonstrated with no serious adverse events due to deep brain stimulation. Three patients responded to treatment [defined as > 35% reduction in Eating Disorders Examination (EDE) score at 12 months] and four patients were non-responders. Responders had a statistically significant mean reduction in EDE scores (50.3% reduction; 95% CI 2.6–98.2%), Clinical Impairment Assessment (45.6% reduction; 95% CI 7.4–83.7%). Responders also had a statistically significant mean reduction in Hamilton Depression Scale, Hamilton Anxiety Scale and Snaith-Hamilton pleasure scale. There were no statistically significant changes in Body Mass Index, Yale-Brown-Cornell Eating Disorder Scale, Yale-Brown Obsessive–Compulsive Scale and World Health Organization Quality of Life Psychological subscale.ConclusionThis study provides some preliminary indication that deep brain stimulation to the NAcc. Might potentially improve some key features of enduring AN. In this small study, the three responders had comorbid obsessive-compulsive disorder which predated AN diagnosis. Future studies should aim to further elucidate predictors of outcome.Clinical Trial Registration[www.ClinicalTrials.gov], identifier [Project ID 128658].

Personalized management of hypertensive patients: focus on prognostic biomarkers

Aim. To analyze level of circulating biomarkers of plasma vascular endothelial growth factor (VEGF) and tumor necrosis factor-α (TNF-α) during 3-month therapy with a fixed-dose combination of ramipril/indapamide (Konsilar-D24, AO Vertex, Russia), as well as to evaluate the antihypertensive efficacy of a fixed-dose combination of ramipril/indapamide (Konsilar-D24, JSC “Vertex”, Russia) in hypertensive (HTN) patients with type 2 diabetes (T2D).Material and methods. This prospective open-label study included 44 patients (aged 35 to 60 years) of both sexes with essential grade 1-2 HTN and concomitant compensated T2D, who did not reach the target blood pressure (BP) level using single or dual antihypertensive therapy, as well as patients who did not take antihypertensives. All patients included in the study initially underwent a set of standard clinical, laboratory and functional examinations in accordance with the clinical guidelines for the management of patients with HTN and T2D, as well as an assessment of the level of C-reactive protein, VEGF and TNF-α. Patients were monitored and treated with Konsilar-D24 for 3 months.Results. In 93,2% of patients, individual target BP values were achieved during the first 2-4 weeks of therapy with a fixed combination of ramipril/indapamide (Konsilar-D24). In the subsequent 3-month follow-up, the average daily BP level in all patients ranged from 129/79 mm Hg to 110/70 mm Hg. Three-month Konsilar-D24 therapy showed a decrease in microalbuminuria: the median values of microalbuminuria decreased by 2 times, and the decrease in the maximum recorded values reached 40% of the baseline. Decrease in mean TNF-α values after 3-month therapy with Konsilar-D24 was 33% of the baseline values, while the maximum recorded values during the specified period decreased by 17%. Decrease in median VEGF values after 3-month Konsilar-D24 therapy was 28%, while the maximum value decreased by 7%, the minimum — by 8%.Conclusion. Konsilar-D24 improves the prognosis in hypertensive patients not only by reducing BP to target values, but also by reducing the level of VEGF and TNF-α biomarkers that determine the progression of endothelial dysfunction, diabetic retinopathy, and microalbuminuria.

Personalized management of hypertensive patients: focus on prognostic biomarkers

Aim. To analyze level of circulating biomarkers of plasma vascular endothelial growth factor (VEGF) and tumor necrosis factor-α (TNF-α) during 3-month therapy with a fixed-dose combination of ramipril/indapamide (Konsilar-D24, AO Vertex, Russia), as well as to evaluate the antihypertensive efficacy of a fixed-dose combination of ramipril/indapamide (Konsilar-D24, JSC “Vertex”, Russia) in hypertensive (HTN) patients with type 2 diabetes (T2D).Material and methods. This prospective open-label study included 44 patients (aged 35 to 60 years) of both sexes with essential grade 1-2 HTN and concomitant compensated T2D, who did not reach the target blood pressure (BP) level using single or dual antihypertensive therapy, as well as patients who did not take antihypertensives. All patients included in the study initially underwent a set of standard clinical, laboratory and functional examinations in accordance with the clinical guidelines for the management of patients with HTN and T2D, as well as an assessment of the level of C-reactive protein, VEGF and TNF-α. Patients were monitored and treated with Konsilar-D24 for 3 months.Results. In 93,2% of patients, individual target BP values were achieved during the first 2-4 weeks of therapy with a fixed combination of ramipril/indapamide (Konsilar-D24). In the subsequent 3-month follow-up, the average daily BP level in all patients ranged from 129/79 mm Hg to 110/70 mm Hg. Three-month Konsilar-D24 therapy showed a decrease in microalbuminuria: the median values of microalbuminuria decreased by 2 times, and the decrease in the maximum recorded values reached 40% of the baseline. Decrease in mean TNF-α values after 3-month therapy with Konsilar-D24 was 33% of the baseline values, while the maximum recorded values during the specified period decreased by 17%. Decrease in median VEGF values after 3-month Konsilar-D24 therapy was 28%, while the maximum value decreased by 7%, the minimum — by 8%.Conclusion. Konsilar-D24 improves the prognosis in hypertensive patients not only by reducing BP to target values, but also by reducing the level of VEGF and TNF-α biomarkers that determine the progression of endothelial dysfunction, diabetic retinopathy, and microalbuminuria.

Clinical and Microbiological Performances and Effects on Lipid and Cytokine Production of a Ceruminolytic Ear Cleaner in Canine Erythemato-Ceruminous Otitis Externa.

Erythemato-ceruminous otitis externa (ECOE) is the most common type of otitis in dogs and is generally associated with bacterial and/or yeast infections. The performance of an ear cleaner was assessed over two weeks in canine ECOE, associated with a mild or moderate secondary infection, in a prospective open-label study. Forty ear canals with ECOE that did not receive any type of aural treatment and were not cleaned for 7 days were included. Pruritus (PS), 0–3 Otitis Index Score (OTIS-3) and 0–4 scale cytology (CYTO) scores were assessed on Day (D) 0, D7 and D14. Concentrations of a panel of 13 cytokines on the ear canal surface and the lipid profile of the exudate were measured on D0 and D14. From D0 to D12 or D13, the dogs’ ears were cleaned daily if the secretion score (SEC) was 3/3, every second day if the score was 2/3 and every third day if the score was 1/3. PS, OTIS-3, SEC and CYTO were significantly lower on D7 compared to baseline (−40%, −31%, −36%, −34%, respectively; p < 0.0001). The same parameters decreased further on D14 (−60%, −53%, −61%, −73%, respectively; p < 0.0001) and amounts of interleukin 8 and chemokine KC-like were also reduced compared to baseline (−45%, p < 0.01; −36%, p = 0.3, respectively). The lipid profile was also modified, with a decrease in free lipids and an increase in bound lipids.

Pain sensitivities predict prophylactic treatment outcomes of flunarizine in chronic migraine patients: A prospective study.

We aimed to assess the differences in quantitative sensory testing between chronic migraine and healthy controls and to explore the association between pain sensitivities and outcomes in chronic migraine following preventive treatment. In this prospective open-label study, preventive-naïve chronic migraine and healthy controls were recruited, and cold, heat, mechanical punctate, and pressure pain thresholds over the dermatomes of first branch of trigeminal nerve and first thoracic nerve were measured by quantitative sensory testing at baseline. Chronic migraines were treated with flunarizine and treatment response was defined as ≥50% reduction in the number of monthly headache days over the 12-week treatment period. Eighty-four chronic migraines and fifty age-and-sex-matched healthy controls were included in the analysis. The chronic migraine had higher cold pain thresholds over the dermatomes of the first branch of trigeminal nerve and the first thoracic nerve (p < 0.001 and < 0.001), lower pressure pain thresholds over the dermatomes of the first thoracic nerve (p = 0.003), heat pain thresholds over the dermatomes of the first branch of the trigeminal nerve and the first thoracic nerve (p < 0.001 and p = 0.015) than healthy controls. After treatment, 24/84 chronic migraine had treatment response. The responders with relatively normal pain sensitivity had higher heat pain thresholds over the dermatome of the first branch of the trigeminal nerve (p = 0.002), mechanical punctate pain thresholds over the dermatomes of the first branch of the trigeminal nerve (p = 0.023), and pressure pain thresholds over the dermatomes of the first branch of the trigeminal nerve (p = 0.026) than the hypersensitive non-responders. Decision tree analysis showed that patients with mechanical punctate pain threshold over the dermatomes of the first branch of the trigeminal nerve > 158 g (p = 0.020) or heat pain threshold over the dermatome of the first branch of the trigeminal nerve > 44.9°C (p = 0.002) were more likely to be responders. Chronic migraine were generally more sensitive compared to healthy controls. Preventive treatment with flunarizine should be recommended particularly for chronic migraine who have relatively normal sensitivity to mechanical punctate or heat pain.Trial registration: This study was registered on ClinicalTrials.gov (Identifier: NCT02747940).

The Effect of Antihypertensive Drugs on NADH in Newly Diagnosed Primary Hypertension.

Background Some antihypertensive medications alter cellular energy production, presumably by modification of the mitochondrial function. In vivo studies of such effects are challenging in humans. We applied a noninvasive forearm skin measurement of the 460-nm fluorescence specific for the reduced form of nicotinamide adenine dinucleotide (NADH) to study the 6-week effects of four different antihypertensive medications on mitochondrial function using the Flow-Mediated Skin Fluorescence (FMSF). Methods In a prospective open-label study, we compared the long-term effects of a 6-week treatment with either amlodipine (5 mg), perindopril (5 mg), nebivolol (5 mg), or metoprolol (50 mg) on the dynamic flow-mediated changes in the skin NADH content in 76 patients (29 women) with untreated primary arterial hypertension (HA). Patients underwent 24-hour ambulatory blood pressure monitoring. To study mitochondrial function, the FMSF was measured at rest, during 100-second ischemia and postischemic reperfusion. The control group consisted of 18 healthy people (7 women). Results There were no significant differences in the FMSF parameters between the control and the study group before medication. After the 6-week treatment, all drugs similarly reduced blood pressure. Neither amlodipine, perindopril, nor nebivolol changed the flow-mediated 460-nm skin fluorescence significantly. However, metoprolol raised this fluorescence at rest, during ischemia and reperfusion (P at most <0.05), indicating an increase in the total NADH skin content. Conclusion Amlodipine, perindopril, and nebivolol appear neutral for the skin NADH content during the 6-week antihypertensive treatment. Similar treatment with metoprolol increased skin NADH at rest, during ischemia and reperfusion, probably due to an effect on microcirculation and altered mitochondrial function. Explanation of the potential mechanisms behind metoprolol influence on the skin NADH metabolism requires further investigation.

Early Improvement as a Predictor of Treatment Response in Patients With Obsessive-Compulsive Disorder: A 12-Week Randomized Trial of Sertraline and Fluvoxamine.

Objective: Early response to selective serotonin reuptake inhibitors (SSRIs) at 4 weeks may predict response at 12 weeks. The objective of this study was to examine if early response to SSRIs can reliably indicate future response to the same drug, while simultaneously comparing 2 medications frequently used to treat obsessive-compulsive disorder (OCD): sertraline and fluvoxamine.Methods: This was a randomized, open-label prospective study of 50 drug-naive patients with OCD (per DSM-5 criteria) conducted from January 2019 to November 2020 in the outpatient department of a tertiary care teaching hospital in North India. Patients were randomly assigned to receive either sertraline or fluvoxamine after assessing the severity of illness with the Yale-Brown Obsessive-Compulsive Scale (YBOCS). Following the induction phase of treatment for 2 weeks, patients were assessed for early response, defined as ≥ 20% reduction in YBOCS score after 4 weeks of reaching the minimum therapeutic dose of each drug. The final YBOCS assessment to evaluate response was conducted at 12 weeks.Results: A total of 60% (n = 30) of patients with OCD showed early response at week 4 with a mean dose of sertraline 95 mg and fluvoxamine 102 mg/d. Both drugs showed significant reduction in YBOCS score at week 12. However, fluvoxamine fared significantly better than sertraline (P = .012).Conclusions: The study results show that early response can predict future response to the drug with a good sensitivity and specificity.Trial Registration: Clinical Trial Registry of India: CTRI/2020/01/022890.