Nevin Manimala

Hum Brain Mapp. 2021 Apr 2. doi: 10.1002/hbm.25427. Online ahead of print.

ABSTRACT

Humans are capable of acquiring multiple types of information presented in the same information stream. It has been suggested that at least two parallel learning processes are important during learning of sequential patterns-statistical learning and rule-based learning. Yet, the neurophysiological underpinnings of these parallel learning processes are not fully understood. To differentiate between the simultaneous mechanisms at the single trial level, we apply a temporal EEG signal decomposition approach together with sLORETA source localization method to delineate whether distinct statistical and rule-based learning codes can be distinguished in EEG data and can be related to distinct functional neuroanatomical structures. We demonstrate that concomitant but distinct aspects of information coded in the N2 time window play a role in these mechanisms: mismatch detection and response control underlie statistical learning and rule-based learning, respectively, albeit with different levels of time-sensitivity. Moreover, the effects of the two learning mechanisms in the different temporally decomposed clusters of neural activity also differed from each other in neural sources. Importantly, the right inferior frontal cortex (BA44) was specifically implicated in visuomotor statistical learning, confirming its role in the acquisition of transitional probabilities. In contrast, visuomotor rule-based learning was associated with the prefrontal gyrus (BA6). The results show how simultaneous learning mechanisms operate at the neurophysiological level and are orchestrated by distinct prefrontal cortical areas. The current findings deepen our understanding on the mechanisms of how humans are capable of learning multiple types of information from the same stimulus stream in a parallel fashion.

PMID:33797825 | DOI:10.1002/hbm.25427

Pharmacoepidemiol Drug Saf. 2021 Apr 2. doi: 10.1002/pds.5239. Online ahead of print.

ABSTRACT

PURPOSE: Opioid use after surgical repair for pelvic organ prolapse (POP) is intended for short-term post-operative pain. This study compared the incidence of opioid prescribing in women undergoing POP transabdominal repair with mesh and transvaginal native tissue repair.

METHODS: A retrospective cohort of women undergoing POP transabdominal repair with mesh or transvaginal native tissue repair, was derived from a 10% random sample of enrollees from 2007-2015 within the IQVIA PharMetrics® Plus Database. Primary outcomes were any prescription of opioids and cumulative days of opioids prescribed in the 14 to 180 days following surgical intervention. Inverse probability of treatment weights controlled for observed baseline confounders. Any opioid prescription was estimated using logistic regression and generalized linear regression for cumulative days of opioids prescribed.

RESULTS: The cohort of 49 052 women who underwent POP surgical repair included 46 813 women with transvaginal native tissue repair and 2239 women with transabdominal repair with mesh. Women with a transabdominal repair with mesh had a 1.19(95%CI:1.09-1.31) significantly higher odds of receiving an opioid prescription than women with transvaginal native tissue repair. Post-operatively, over 29% of women received opioid prescriptions. Mean cumulative days of post-surgical opioid prescribing was 32.2(SD = 43.1), and was not statistically different between groups. Thirteen percent of women were prescribed opioids for 90 days or more.

CONCLUSIONS: Women undergoing POP with transabdominal mesh are more likely to receive prescriptions for opioids after surgery compared to transvaginal native tissue repair. Treatment plans that address pain while mitigating the risks associated with prolonged opioid prescribing should be employed. This article is protected by copyright. All rights reserved.

PMID:33797822 | DOI:10.1002/pds.5239

J Card Surg. 2021 Apr 2. doi: 10.1111/jocs.15547. Online ahead of print.

ABSTRACT

BACKGROUND: Limited data exist regarding the coronary revascularization procedures needed during the repair of several congenital and pediatric cardiac malformations. We aimed to determine risk factors for in-hospital mortality and long-term outcomes of various pediatric coronary revascularization procedures.

METHODS: We retrospectively reviewed the records of 32 consecutive pediatric patients who underwent coronary revascularization procedures at our institution between May 1995 and June 2020. In-hospital mortality, risk factors, surgical indications, revascularization patency, and mid- and long-term follow-up data were investigated. Patients were categorized into the coronary artery bypass grafting (n = 11) and other coronary artery procedure (n = 21) groups.

RESULTS: The median age and weight of patients at the time of surgery were 9 months and 4.8 kg, respectively. There were five in-hospital deaths (5/32, 15.6%). The mortality rates were 27.2% (3/11) in the coronary artery bypass grafting group and 9.5% (2/21) in the other coronary artery procedure group (p = .206; 95% confidence interval: 0.496-25.563). The mortality rates for planned and rescue procedures were 8.3% (2/24) and 37.5% (3/8) (p = .06), respectively. The median follow-up time was 12.5 years. Control imaging studies for coronary patency were performed in 70.3% (19/27) of surviving patients. The overall coronary patency rate was 94.7% (18/19).

CONCLUSIONS: Pediatric coronary revascularization procedures with elective-planned indications can be performed with good outcomes. Young age and rescue and emergency procedures may carry an increased risk of in-hospital mortality, although not found to be statistically significant. Surviving patients require lifelong follow-up regarding the patency of reperfused coronary arteries.

PMID:33797801 | DOI:10.1111/jocs.15547

Acta Paediatr. 2021 Apr 2. doi: 10.1111/apa.15868. Online ahead of print.

ABSTRACT

Retinopathy of prematurity (ROP) is the leading cause of vision loss in children. A well-known risk factor for the development of ROP is duration of oxygen supplementation. Other postnatal factors have also been associated with ROP risk, including poor post-natal weight gain. The weight, insulin-like growth factor, neonatal retinopathy of prematurity (WINROP) algorithm predicts severe ROP based on postnatal weight gain and has been validated in several studies,^1,2 including a high sensitivity for prediction of severe ROP in our local NICU populations. However, target oxygen saturation levels were subsequently increased in many NICUs based on results from the Neonatal Oxygen Prospective Meta-analysis (NeOProM) Collaboration, which showed statistically higher death and disability rates among preterm infants randomized to a lower oxygen-saturation target range (85 – 89%) versus a higher target range (91 – 95%),³ which may affect the incidence and severity of ROP⁴ as well as the validity of the WINROP algorithm. In 2018, Lundgren et al reported that the WINROP algorithm was no longer able to predict ROP requiring treatment at their institution after the implementation of higher target oxygen saturation levels, with a sensitivity of only 50%.⁵ The objective of this review was to evaluate WINROP’s ability to identify infants at risk for severe ROP at our institution after target oxygen saturation levels were increased in 2014.

PMID:33797784 | DOI:10.1111/apa.15868

J Oral Rehabil. 2021 Apr 2. doi: 10.1111/joor.13174. Online ahead of print.

ABSTRACT

Backround Orofacial dysfunctions (OFD; orofacial myofunctional disorders) in children and childhood apraxia of speech (CAS) often cause severe problems in articulation, chewing, swallowing and oral posture.

OBJECTIVES: Pathognomonic symptoms could yet not be identified, but central problems in planning, programming, timing and automating orofacial, as well as other fine motor skills, are assumed to be affected.

METHODS: To investigate the nature of motor and coordinative deficits in OFD and CAS, digitomotography was applied. The testing focused on recording frequency, force, rhythm and regularity of the index finger including speeded and metronome tapping tasks. 25 children with OFD (7 girls and 18 boys, age 7.9 ± 2.3) and 5 children with CAS (0 girls and 5 boys, age 7.6 ± 2.3) as well as 31 healthy controls were tested (12 girls and 19 boys, age 9.3 ± 2.2). Statistical significance was accepted at α = 0.05. Anova test, nonparametric Mann-Whitney U test, Kruskal Wallis test and Spearman’s rank correlation coefficient were used.

RESULTS: Cross-sectional data revealed consistent significant differences between children with OFD and healthy controls concerning frequency, force, rhythm and regularity of index finger tapping. Individuals with CAS showed particularly low results. Tapping results correlated with disease burden.

CONCLUSION: These findings support that underlying superordinated sensorimotor deficits exist. This may help phenotyping and influence diagnostical and therapeutical approaches.

PMID:33797781 | DOI:10.1111/joor.13174

Pharmacotherapy. 2021 Apr 2. doi: 10.1002/phar.2523. Online ahead of print.

ABSTRACT

STUDY OBJECTIVE: Lefamulin is a novel IV and oral pleuromutilin recently approved for the treatment of community-acquired bacterial pneumonia (CABP). Given that renal comorbidities are common in patients admitted for CABP, understanding the pharmacokinetics of lefamulin in the face of severe renal impairment, including those requiring hemodialysis, is needed.

DESIGN: Open-label, Phase-1 pharmacokinetic study SETTING: Research Study Center PATIENTS: Twenty-three matched subjects were included, seven with “Normal” renal function (creatinine clearance >90 mL/min), eight with “Severe” renal impairment (glomerular filtration rate <30 mL/min/1.73 m2), and eight subjects requiring hemodialysis.

MEASUREMENTS AND MAIN RESULTS: Subjects were administered a single dose of lefamulin IV 150 mg as a 1-h infusion. Subjects in the hemodialysis group started hemodialysis within 1 h after lefamulin infusion (On-dialysis), as well as, on a non-dialysis day (Off-dialysis). Plasma, urine, and dialysate fluid was collected for 36 h and analyzed for lefamulin and its major metabolite, BC-8041. Lefamulin was primarily excreted non-renally across groups. Statistical analyses revealed lefamulin and BC-8041 pharmacokinetics were similar between Normal and Severe groups, except for renal clearance, which decreased in Severe subjects (mean 1.3 L/h Normal vs. 0.4 L/h Severe). Likewise, lefamulin pharmacokinetics during On- and Off-dialysis were unchanged, with lefamulin not measurably filtered in dialysate fluid. Two, three, and three subjects reported drug-related treatment emergent adverse events (TEAE) in Normal, Severe, and Hemodialysis groups, respectively. All TEAEs were mild, except one (infusion-site reaction) that was classified as moderate.

CONCLUSION: No dosage adjustment is required for patients with renal impairment, and lefamulin can be administered without regard to hemodialysis timing.

PMID:33797776 | DOI:10.1002/phar.2523

J Echocardiogr. 2021 Apr 2. doi: 10.1007/s12574-021-00523-y. Online ahead of print.

ABSTRACT

BACKGROUND: The use of enhancing agents in echocardiography has been shown to facilitate improved study quality. Despite the known benefits, its use remains limited by institutional policies.

METHODS: We aimed to retrospectively evaluate if allowing sonographers to place a peripheral intravenous catheter and administer enhancing agent led to a decrease in time to complete outpatient transthoracic echocardiograms in comparison to using nursing personnel. Three separate protocols were employed. The ‘nurse driven protocol’ utilized nurses to place a peripheral intravenous catheter and inject enhancing agent. In a ‘mixed protocol,’ a nurse placed a peripheral intravenous catheter and the sonographer gave the enhancing agent. The ‘sonographer driven protocol’ involved the sonographer placing the peripheral intravenous catheter and delivering enhancing agent.

RESULTS: A total of 232 echocardiograms were included for analysis. Patient characteristics across the three protocols were not statistically significant. The ‘mixed protocol’ had an average study time that was significantly less than the ‘nurse driven protocol’ (49.4 min ± 11.4 vs 54.6 min ± 12.9; p = 0.024). The ‘sonographer driven protocol’ also showed a significant reduction in study time (50.3 min ± 12.6) when compared to the ‘nurse driven protocol’ (p = 0.017). The additional task for the sonographer to place the peripheral intravenous catheter did not significantly increase the time to complete the study.

CONCLUSION: Allowing sonographers to administer enhancing agent reduced individual echocardiogram study times by approximately 5 min, supporting that a ‘sonographer driven protocol’ is more efficient with potential downstream economic benefits.

PMID:33797745 | DOI:10.1007/s12574-021-00523-y

Int Urol Nephrol. 2021 Apr 2. doi: 10.1007/s11255-021-02840-8. Online ahead of print.

ABSTRACT

OBJECTIVE: To evaluate the effect of myofascial manipulation by observing the changes in pelvic floor myofascial scores and electromyography (EMG) data before and after treatment.

METHODS: A total of 106 patients with myofascial pelvic pain (MFPP) were enrolled in a treatment group, and 50 healthy women were enrolled in a control group. The changes in the pelvic floor EMG data in the two groups were monitored by using Myo Trac before and after treatment. Pelvic trigger points and their distribution in the MFPP patients were examined using a finger pressure test. The visual analogue scale was used to assess the severity of pain in both groups. After one course of manipulation (twice per week for a total of 10 times), the effectiveness of the manipulation was analyzed by comparing the changes in pain scores before and after treatment.

RESULTS: The main symptoms of MFPP in the study sample consisted of lower abdominal pain, lumbosacral pain, or mixed pain, which together accounted for 67% of all symptoms. Patients often had multiple trigger points, covering 47.17% of the body. The differences between the treatment group and control group in the changes in pelvic floor muscle strength, number of pain points, pain scores, resting EMG of pelvic floor muscles, and relaxation time after muscle contraction were all statistically significant (P < 0.05). The differences between the pre-treatment and post-treatment groups in the changes in pelvic floor muscle strength, number of pain points, pain scores, resting EMG of pelvic floor muscles, and relaxation time after muscle contraction were all statistically significant (P < 0.05) CONCLUSION: Manipulation is an effective treatment for MFPP and is worthy of further clinical promotion.

PMID:33797710 | DOI:10.1007/s11255-021-02840-8

CNS Drugs. 2021 Apr 2. doi: 10.1007/s40263-021-00798-w. Online ahead of print.

ABSTRACT

Fingolimod (Gilenya) received regulatory approval from the US FDA in 2010 as the first-in-class sphingosine 1-phosphate (S1P) receptor (S1PR) modulator and was the first oral disease-modifying therapy (DMT) used for the treatment of the relapsing forms of multiple sclerosis (MS). Development of this new class of therapeutic compounds has continued to be a pharmacological goal of high interest in clinical trials for treatment of various autoimmune disorders, including MS. S1P is a physiologic signaling molecule that acts as a ligand for a group of cell surface receptors. S1PRs are expressed on various body tissues and regulate diverse physiological and pathological cellular responses involved in innate and adaptive immune, cardiovascular, and neurological functions. Subtype 1 of the S1PR (S1PR₁) is expressed on the cell surface of lymphocytes, which are well known for their major role in MS pathogenesis and play an important regulatory role in the egress of lymphocytes from lymphoid organs to the lymphatic circulation. Thus, S1PR₁-directed pharmacological interventions aim to modulate its role in immune cell trafficking through sequestration of autoreactive lymphocytes in the lymphoid organs to reduce their recirculation and subsequent infiltration into the central nervous system. Indeed, receptor subtype selectivity for S1PR₁ is theoretically favored to minimize safety concerns related to interaction with other S1PR subtypes. Improved understanding of fingolimod’s mechanism of action has provided strategies for the development of the more selective second-generation S1PR modulators. This selectivity serves to reduce the most important safety concern regarding cardiac-related side effects, such as bradycardia, which requires prolonged first-dose monitoring. It has led to the generation of smaller molecules with shorter half-lives, improved onset of action with no requirement for phosphorylation for activation, and preserved efficacy. The shorter half-lives of the second-generation agents allow for more rapid reversal of their pharmacological effects following treatment discontinuation. This may be beneficial in addressing further treatment-related complications in case of adverse events, managing serious or opportunistic infections such as progressive multifocal leukoencephalopathy, and eliminating the drug in pregnancies. In March 2019, a breakthrough in MS treatment was achieved with the FDA approval for the second S1PR modulator, siponimod (Mayzent), for both active secondary progressive MS and relapsing-remitting MS. This was the first oral DMT specifically approved for active forms of secondary progressive MS. Furthermore, ozanimod received FDA approval in March 2020 for treatment of relapsing forms of MS, followed by subsequent approvals from Health Canada and the European Commission. Other second-generation selective S1PR modulators that have been tested for MS, with statistically significant data from phase II and phase III clinical studies, include ponesimod (ACT-128800), ceralifimod (ONO-4641), and amiselimod (MT-1303). This review covers the available data about the mechanisms of action, pharmacodynamics and kinetics, efficacy, safety, and tolerability of the various S1PR modulators for patients with relapsing-remitting, secondary progressive, and, for fingolimod, primary progressive MS.

PMID:33797705 | DOI:10.1007/s40263-021-00798-w

Endocrine. 2021 Apr 2. doi: 10.1007/s12020-021-02702-4. Online ahead of print.

ABSTRACT

PURPOSE: Radioactive-iodine (RAI)-resistant differentiated thyroid cancer (DTC) patients benefit from multi-kinase inhibitors (MKIs), such as lenvatinib. Incidence of treatment-related (TR) late toxicities has been not yet described.

METHODS: From January 2015 to June 2019 we retrospectively reviewed clinical records of patients with RAI-resistant DTC treated with lenvatinib at Istituto Nazionale dei Tumori (Milan, Italy). New side effect of any grade, appeared after 12 months of lenvatinib, was defined as late adverse event (AE). Descriptive analyses were performed. Survival curves were estimated with Kaplan-Meier method and compared with log-rank test.

RESULTS: Thirty-seven patients were included, 65% had ≥65 years and 68% were female. Thirty patients received lenvatinib for >12 months. Lenvatinib was started at ≤20 mg/daily in 59% of patients, 64% were ≥65 years. The frequency of late AEs was 80% and cardiovascular toxicity was the most common (57%). There was no difference in the incidence of late AEs between younger/older population (77% and 82%, respectively). Median lenvatinib treatment duration (TD) was 39.96 months (95% CI 21.64-NR): 39.96 months for patients <65 years (95% CI: 13.25-NR) and 37.53 months for those ≥65 years, respectively (95% CI: 15.85-NR). Median overall survival (OS) was 39.96 months (95% CI: 21.84-NR), no statistically differences in OS was observed between younger (<65 years) and older patients (≥65 years) (HR 1.013; 95% CI 0.963-1.065; p = 0.62).

CONCLUSION: Late toxicity burden of lenvatinib is not negligible. Cardiovascular toxicity remains the principal side effect even after a prolonged lenvatinib exposition.

PMID:33797698 | DOI:10.1007/s12020-021-02702-4