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Emotional blunting is theorized to be an adverse effect of antidepressants, particularly serotonin reuptake inhibitors, but this has not been firmly established. Another possibility is that emotional blunting represents a residual depressive symptom.We analyzed data from adult outpatients with acute major depressive disorder who participated in three 8-week randomized controlled trials. Trials 1 and 2 were pooled (venlafaxine, n = 378; bupropion, n = 389; placebo, n = 383) and Trial 3 (escitalopram, n = 254; bupropion, n = 260) was analyzed separately. Emotional blunting was measured with the "inability to feel" item from the Montgomery-Åsberg Depression Rating Scale.Emotional responsiveness improved, on average, in all treatment groups. Only a minority of participants (≤6 %) experienced more emotional blunting post-treatment, compared to baseline, with no significant differences between treatment groups, although roughly 20-25 % continued to report an inability to feel normal emotions at the final assessment. In Trials 1 and 2, emotional blunting was associated with poorer outcomes in terms of depressive symptoms, suicidal ideation, and sexual function, but these correlations were nearly identical in the placebo group.The trials were short and cannot speak to the possibility of emotional blunting from long-term treatment. Emotional blunting was measured with a single item.The study medications did not significantly decrease emotional responsiveness, and there was no evidence that emotional blunting mediated treatment response. In acute treatment, emotional blunting may be better conceptualized as a residual symptom than as an adverse drug effect.

To compare rates of catheter-related bloodstream infections (CR-BSI) in pediatric patients who received parenteral nutrition (PN) with either soybean oil-based intravenous fat emulsion (SO-IFE) or mixed oil-IFE (MO-IFE). We hypothesized that the use of MO-IFE would be independently associated with reduced infection rates compared with SO-IFE.Retrospective cohort study.Tertiary referral children's hospital and its associated gastrointestinal rehabilitation clinic (01 January, 2015-31 July, 2019).Days of IFE exposure were counted for patients aged18 years on IFE initiated during the review period, who had a central venous catheter (CVC) placed for PN administration, received IFE at least three times weekly, and for at least 7 days.The primary outcome included total and categorical CR-BSI rates expressed as the average with standard error (SE) number of infections per 1000 fat emulsion days. The following categories were specified: Candida albicans, non-albicans Candida spp., coagulase-negative Staphylococcus (CoNS), Enterobacterales, methicillin-resistant S. aureus, methicillin-susceptible S. aureus, and Pseudomonadales. Average infection rate comparisons were quantified as incidence rate ratios (IRR) using generalized linear mixed modeling with a Poisson distribution.Seven hundred and forty-three SO-IFE and 450 MO-IFE exposures were reviewed from 1131 patients, totaling 37,599 and 19,796 days of therapy, respectively. From those found significantly different, the average rate of infections with CoNS was 3.58 (SE 0.5)/1000 days of SO-IFE and 1.39 (SE 0.45)/1000 days of MO-IFE (IRR [95% confidence interval, CI]: 0.27 [0.16-0.46]; p 0.01). Total average rates of infection were 7.33 (SE 0.76)/1000 days of SO-IFE and 4.52 (SE 0.75)/1000 days of MO-IFE (IRR [95% CI]: 0.60 [0.44-0.81]; p 0.01). Other factors associated with higher infection rates include female gender, neonatal age, and inpatient-only IFE exposure.Receipt of MO-IFE was associated with lower rates of CoNS and total CR-BSIs compared with SO-IFE in pediatric patients. These findings could have major implications on IFE selection for pediatric patients receiving PN.

Intermittent rescue therapy may be used for seizure clusters, which are clinical emergencies that may persist ≥24 h and increase risk of status epilepticus, emergency room visits, and reduced quality of life for patients with epilepsy. Beyond effectiveness for aborting seizure clusters, no data exist on how intermittent rescue therapy may impact the long-term natural course of seizure clusters. This novel analysis explores SEIzure interVAL (SEIVAL; time between seizure clusters) in patients from a long-term safety study of diazepam nasal spray (Valtoco) to assess SEIVAL changes with intermittent rescue therapy across time.Patients were aged 6-65 years. Age- and weight-based doses of diazepam nasal spray were administered during a 12-month treatment period with an optional follow-up period. SEIVAL was evaluated in patients receiving two or more doses of diazepam nasal spray using 90-day periods.Of 163 treated patients, 151 had one or more SEIVALs. One hundred twenty had SEIVALs in Period 1 and one or more other periods. An increase in SEIVAL was noted from Period 1 compared with all subsequent periods (p ≤ .001). A consistent cohort (n = 76) had one or more SEIVALs in each of Periods 1-4 (360 days); mean SEIVALs increased significantly (p .01) from 12.2 days (Period 1) to 25.7 days (Period 4). Similar SEIVAL patterns occurred when repeat doses within a seizure cluster were eliminated and irrespective of age group, treatment duration, and change to concomitant medications. In adults, Quality of Life in Epilepsy scores were maintained with increased SEIVALs.Across 12 months, increases in SEIVAL were demonstrated in patients using diazepam nasal spray for seizure cluster treatment in a phase 3 safety study. Increased time between seizure clusters may reflect a previously unrecognized beneficial effect of intermittent rescue therapy. These results generate a range of biological and behavioral hypotheses and warrant exploration of the impact of intermittent rescue therapy.

Transcatheter cardiovascular interventions have the advantage of patient safety, reduced surgery time and minimal trauma to the patient's body. Transcathether interventions, which are performed percutaneously, are limited by the lack of direct line of sight with the procedural tools and the patient anatomy. Therefore, such interventional procedures rely heavily on image guidance for navigating toward and delivering therapy at the target site. Vascular navigation via the inferior vena cava, from the groin to the heart, is an imperative part of most transcatheter cardiovascular interventions including heart valve repair surgeries and ablation therapy. Traditionally, the inferior vena cava is navigated using fluoroscopic techniques such as venography and computed tomography venography. These X-ray-based techniques can have detrimental effects on the patient as well as the surgical team, causing increased radiation exposure, leading to risk of cancer, fetal defects and eye cataracts. The use of a heavy lead apron has also been reported to cause back pain and spine issues, thus leading to interventionalist's disc disease. We propose the use of a catheter-based ultrasound augmented with electromagnetic tracking technology to generate a vascular roadmap in real time and perform navigation without harmful radiation. In this pilot study, we used spatially tracked intracardiac echocardiography to reconstruct a vessel from a phantom in a 3-D virtual environment. We illustrate how the proposed ultrasound-based navigation will appear in a virtual environment, by navigating a tracked guidewire within the vessels in the phantom without any radiation-based imaging. The geometric accuracy is assessed using a computed tomography scan of the phantom, with a Dice coefficient of 0.79. The average distance between the surfaces of the two models comes out to be 1.7 ± 1.12 mm.

Delineation of the seizure onset zone (SOZ) is required in children with drug resistant epilepsy (DRE) undergoing neurosurgery. Intracranial EEG (icEEG) serves as gold standard but has limitations. Here, we examine the utility of virtual implantation with electrical source imaging (ESI) on ictal scalp EEG for mapping the SOZ and predict surgical outcome.We retrospectively analyzed EEG data from 35 children with DRE who underwent surgery and dichotomized into seizure-free (SF) and non-seizure-free (NSF). We estimated virtual sensors (VSs) at brain locations that matched icEEG implantation and compared ictal patterns at VSs vs icEEG. We calculated the agreement between VSs SOZ and clinically defined SOZ and built receiver operating characteristic (ROC) curves to test whether it predicted outcome.Twenty-one patients were SF after surgery. Moderate agreement between virtual and icEEG patterns was observed (kappa = 0.45, p 0.001). Virtual SOZ agreement with clinically defined SOZ was higher in SF vs NSF patients (66.6% vs 41.6%, p = 0.01). Anatomical concordance of virtual SOZ with clinically defined SOZ predicted outcome (AUC = 0.73; 95% CI: 0.57-0.89; sensitivity = 66.7%; specificity = 78.6%; accuracy = 71.4%).Virtual implantation on ictal scalp EEG can approximate the SOZ and predict outcome.SOZ mapping with VSs may contribute to tailoring icEEG implantation and predict outcome.

The success of epilepsy surgery in children with tuberous sclerosis complex (TSC) hinges on identification of the epileptogenic zone (EZ). We studied structural MRI markers of epileptogenic lesions in young children with TSC.We included 26 children with TSC who underwent epilepsy surgery before the age of 3 years at five sites, with 12 months or more follow-up. Two neuroradiologists, blinded to surgical outcome data, reviewed 10 candidate lesions on preoperative MRI for characteristics of the tuber (large affected area, calcification, cyst-like properties) and of focal cortical dysplasia (FCD) features (cortical malformation, gray-white matter junction blurring, transmantle sign). They selected lesions suspect for the EZ based on structural MRI, and reselected after unblinding to seizure onset location on electroencephalography (EEG).None of the tuber characteristics and FCD features were distinctive for the EZ, indicated by resected lesions in seizure-free children. With structural MRI alone, the EZ was identified out of 10 lesions in 31%, and with addition of EEG data, this increased to 48%. However, rates of identification of resected lesions in non-seizure-free children were similar. Across 251 lesions, interrater agreement was moderate for large size (κ = .60), and fair (κ = .24) for all other features.In young children with TSC, the utility of structural MRI features is limited in the identification of the epileptogenic tuber, but improves when combined with EEG data.

The rare genetic neurodevelopmental disease Angelman syndrome (AS) is caused by the loss of function of UBE3A, a ubiquitin ligase. The disease results in a lifetime of severe symptoms, including intellectual disability and motor impairments for which there are no effective treatments. One avenue of treatment for AS is the use of gene therapy to reintroduce a functional copy of the UBE3A gene. Our group had previously shown that recombinant adeno-associated virus (rAAV) expressing mouse Ube3a could rescue deficits in a mouse model of AS. Here, we expand on this work and show that this approach could be successfully replicated in a second AS model using the human UBE3A gene. Furthermore, we address the challenge of limited vector distribution in the brain by developing a novel modified form of UBE3A. This modified protein, termed STUB, was designed with a secretion signal and a cell-penetrating peptide. This allowed transduced cells to act as factories for the production of UBE3A protein that could be taken up by neighboring non-transduced cells, thus increasing the number of neurons receiving the therapeutic protein. Combining this construct with intracerebroventricular injections to maximize rAAV distribution within the brain, we demonstrate that this novel approach improves the recovery of behavioral and electrophysiological deficits in the AS rat model. More importantly, a comparison of rAAV-STUB to a rAAV expressing the normal human UBE3A gene showed that STUB was a more effective therapeutic. These data suggest that rAAV-STUB is a new potential approach for the treatment of AS. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13311-022-01239-2.

It is unclear whether the frequency and mechanisms of expiratory flow limitation (EFL) during exercise differ between males and females.This study aimed to determine which factors predispose individuals to EFL during exercise and whether these factors differ based on sex. We hypothesized that i) EFL frequency would be similar in males and females and ii) in females, EFL would be associated with indices of low ventilatory capacity, whereas in males, EFL would be associated with indices of high ventilatory demand.Data from n = 126 healthy adults (20-45 y, n = 60 males, n = 66 females) with a wide range of cardiorespiratory fitness (81%-182% predicted maximal oxygen uptake) were included in the study. Participants performed spirometry and an incremental cycle exercise test to exhaustion. Standard cardiorespiratory variables were assessed throughout exercise. The tidal flow-volume overlap method was used to assess EFL based on a minimum threshold of 5% overlap between the tidal and the maximum expiratory flow-volume curves. Predictors of EFL during exercise were determined via multiple logistical regression using anthropometric, pulmonary function, and peak exercise data.During exercise, EFL occurred in 49% of participants and was similar between the sexes (females = 45%, males = 53%; P = 0.48). In males, low forced expired flow between 25% and 75% of forced vital capacity and high slope ratio as well as low end-expiratory lung volume, high breathing frequency, and high relative tidal volume at peak exercise were associated with EFL ( P0.001; Nagelkerke R2 = 0.73). In females, high slope ratio, high breathing frequency, and tidal volume at peak exercise were associated with EFL ( P0.001; Nagelkerke R2 = 0.61).Despite sex differences in respiratory system morphology, the frequency and the predictors of EFL during exercise do not substantially differ between the sexes.

Ventilation plays an important role in mitigating the risk of airborne virus transmission in university classrooms. During the early phase of the COVID-19 pandemic, methods to assess classrooms for ventilation adequacy were needed. The aim of this paper was to compare the adequacy of classroom ventilation determined through an easily accessible, simple, quantitative measure of air changes per hour (ACH) to that determined through qualitative "expert judgment" and recommendations from the American Society of Heating, Refrigerating and Air-Conditioning Engineers (ASHRAE), and the American Conference of Governmental Industrial Hygienists (ACGIH)

Worker exposure to occupational hazards is traditionally measured by equipping workers with wearable exposure monitors. An emerging alternative measurement first generates time-varying hazard maps from permanent monitors within the facility, then estimating worker exposure by integrating hazard levels traversed in map, following the tracked movement of workers. Complex environments may require many monitors to produce a hazard map with the necessary accuracy, but effective interpolation functions can reduce the required number of monitors needed. This work assesses the effectiveness of three models for accurately interpolating hazard levels among monitors: a traditional Kriging model, a physics-based model, and a hybrid model that combines the Kriging and physics-based models. The effectiveness of each interpolation function was tested with sound levels collected in four environmental settings. These detailed experimental data were used to generate over 10,000 simulation trials, where each trial configured the experimental data into a unique arrangement of simulated monitoring and sampling positions. For each simulation trial, the effectiveness of the three models was assessed with the root mean square error of the sound levels at the simulated sampling positions, using the simulated monitoring positions as input. The interpolated values between the monitored positions were analyzed separately from the extrapolated values beyond the monitored positions. The hybrid model consistently reported among the lowest errors in each trial. The Kriging model performed best for the densest networks (those with the most monitors). Even in these cases, the hybrid model performed within 10% of the Kriging model with less than a third of the monitors. The experiment demonstrates that the hybrid model is highly effective at estimating hazardous sound levels; future work may demonstrate similar advantages for gas and aerosol hazards.

Dynamic position errors were examined in an eccentric and a passive elbow extension proprioceptive-targeting task, before and after eccentric exercise, with and without muscle vibration. Participants actively undershot the target more when fatigued while fatigue did not exacerbate task accuracy during passive movement. Vibration caused undershoots regardless of fatigue state during active and passive movements. We propose that the CNS continues to rely on muscle spindles for kinesthesia, even when they reside in a fatigued muscle.

Background: Research has shown a strong relationship between psychosis and sexual assault. Theories on developmental trauma as a causal factor for psychosis suggest that exposure to sexual trauma in childhood would have a stronger association with psychosis than sexual trauma in adulthood. We hypothesized that exposure to sexual trauma earlier in childhood and adolescence would be more strongly associated with hallucinations, delusional beliefs and psychotic disorder than sexual trauma that occurred later in life. Methods: Using the 2007 and 2014 Adult Psychiatric Morbidity Surveys (N = 14,949) we calculated the prevalence of sexual assault, hallucinations, delusional beliefs, and psychotic disorder. We used logistic regression to examine the relationship between age of exposure to sexual assault (first exposure 16. Our findings do not support the idea that childhood and adolescence are uniquely sensitive periods for the emergence of psychotic experiences or psychotic disorder in relation to sexual trauma.

ObjectiveRadiofrequency ablation (RFA)±endoscopic resection (ER) is the preferred treatment for early neoplasia in Barrett’s oesophagus (BE). We aimed to report short-term and long-term outcomes for all 1384 patients treated in the Netherlands (NL) from 2008 to 2018, with uniform treatment and follow-up (FU) in a centralised setting.DesignEndoscopic therapy for early BE neoplasia in NL is centralised in nine expert centres with specifically trained endoscopists and pathologists that adhere to a joint protocol. Prospectively collected data are registered in a uniform database. Patients with low/high-grade dysplasia or low-risk cancer, were treated by ER of visible lesions followed by trimonthly RFA sessions of any residual BE until complete eradication of BE (CE-BE). Patients with ER alone were not included.ResultsAfter ER (62% of cases; 43% low-risk cancers) and median 1 circumferential and 2 focal RFA (p25-p75 0–1; 1–2) per patient, CE-BE was achieved in 94% (1270/1348). Adverse events occurred in 21% (268/1386), most commonly oesophageal stenosis (15%), all were managed endoscopically. A total of 1154 patients with CE-BE were analysed for long-term outcomes. During median 43 months (22–69) and 4 endoscopies (1–5), 38 patients developed dysplastic recurrence (3%, annual recurrence risk 1%), all were detected as endoscopically visible abnormalities. Random biopsies from a normal appearing cardia showed intestinal metaplasia (IM) in 14% and neoplasia in 0%. A finding of IM in the cardia was reproduced during further FU in only 33%, none progressed to neoplasia. Frequent FU visits in the first year of FU were not associated with recurrence risk.ConclusionIn a setting of centralised care, RFA±ER is effective for eradication of Barrett’s related neoplasia and has remarkably low rates of dysplastic recurrence. Our data support more lenient FU intervals, with emphasis on careful endoscopic inspection. Random biopsies from neosquamous epithelium and cardia are of questionable value.Netherlands trial register numberNL7039.

Purpose Secretory carcinoma (SC) of the salivary gland, formerly known as mammary analogue secretory carcinoma, is an uncommon and fairly newly described, low grade malignant neoplasm of the salivary gland. Given the small number of cases reported in the literature to date, treatment guidelines are scarce. This study aimed to describe the clinical characteristics of SC, discuss prior management strategies, and provide recommendations for future treatment. Methods We performed a systematic review of all the cases of SC reported in the literature since it was first recognized in 2010. Using Pubmed, Crossref, and Google Scholar, we identified all articles reporting cases of SC. Results We identified 657 cases of SC in 109 articles. In addition, we provided 2 new cases, for a total of 659 cases in 110 articles. To our knowledge, this is the largest review of cases of SC in the literature to date. We summarized the clinical characteristics of SC, as well as the nodal status, clinical management, recurrence rate, and death rate. Conclusions SC occurs on average in middle age (with a large age range), presents most often initially as localized disease without metastasis, and has a low but not insignificant recurrence rate. Deaths have been reported. The generalized recommendations for treatment of SC are in line with those of other low-grade salivary gland malignancies.

Objectives Given the strong association between systemic inflammation and cognitive decline, we aimed to determine whether nonneurologic infections are associated with accelerated cognitive decline and structural changes in the brain using pre- and post-infection neuropsychologic assessments and repeated brain MR images. Design Additional analysis of the prospective observational Radboud University Nijmegen Diffusion Tensor and Magnetic Resonance Cohort study. Setting Single-center study at the Radboud university medical center, Nijmegen, The Netherlands, between January 2006 and September 2015. Patients Five-hundred three participants (50-85 yr old) with cerebral small vessel disease were included and followed for 9 years. Measurements and main results Participants underwent repeated cognitive measurements and brain MRI. Infectious events were collected. Sepsis episodes were analyzed, and additionally, patients were stratified in three groups: having had a severe infectious episode (e.g., sepsis or hospitalization for infection), a mild, or no infectious episode. Development of dementia, trajectories of cognition, and structural brain changes on MRI in the subsequent follow-up periods were compared between the groups. Complete infectious data were available from 331 patients (mean age 64 ± 8 yr, 57% males). Twenty-nine participants (9%) suffered from a sepsis episode, 69 (21%) from a severe, 201 (61%) from a mild, and 61 (18%) had no infectious episode during follow-up. After correction for age, baseline cognition, and brain volume, each sepsis episode remained associated with an 82% increased risk to develop dementia within the follow-up period (hazard ratio, 1.82; 95% CI, 1.07-3.10; p = 0.027). Infections had no effect on the trajectory of structural changes to the brain after correction for baseline differences. Conclusions In this 9-year observational follow-up study, sepsis episodes were associated with subsequent development of dementia. Nonneurologic infections had no effect on the trajectory of structural cerebral changes.

Ion-ion reactions are valuable tools in mass-spectrometry-based peptide and protein sequencing. To boost the generation of sequence-informative fragment ions from low charge-density precursors, supplemental activation methods, via vibrational and photoactivation have become widely adopted. However, long-lived radical peptide cations undergo intramolecular hydrogen atom transfer from c-type ions to z•-type ions. Here we investigate the degree of hydrogen transfer for thousands of unique peptide cations where electron transfer dissociation (ETD) was performed and was followed by beam-type collisional activation (EThcD), resonant collisional activation (ETcaD), or concurrent infrared photoirradiation (AI-ETD). We report on precursor charge density and local amino acid environment surrounding bond cleavage to illustrate the effects of intramolecular hydrogen atom transfer for various precursor ions. Over 30% of fragments from EThcD spectra comprise distorted isotopic distributions, whereas over 20% of fragments from ETcaD have distorted distributions and less than 15% of fragments derived from ETD and AI-ETD reveal distorted isotopic distributions. Both ETcaD and EThcD give a relatively high degree of hydrogen migration, especially when D, G, N, S, and T residues were directly C-terminal to the cleavage site. Whereas all post-activation methods boost the number of c- and z•-type fragment ions detected, the collision-based approaches produce higher rates of hydrogen migration, yielding fewer spectral identifications when only c- and z•-type ions are considered. Understanding hydrogen rearrangement between c- and z•-type ions will facilitate better spectral interpretation.

Occupational exposure assessments are dominated by small sample sizes and low spatial and temporal resolution with a focus on conducting Occupational Safety and Health Administration regulatory compliance sampling. However, this style of exposure assessment is likely to underestimate true exposures and their variability in sampled areas, and entirely fail to characterize exposures in unsampled areas. The American Industrial Hygiene Association (AIHA) has developed a more realistic system of exposure ratings based on estimating the 95th percentiles of the exposures that can be used to better represent exposure uncertainty and exposure variability for decision-making; however, the ratings can still fail to capture realistic exposure with small sample sizes. Therefore, low-cost sensor networks consisting of numerous lower-quality sensors have been used to measure occupational exposures at a high spatiotemporal scale. However, the sensors must be calibrated in the laboratory or field to a reference standard. Using data from carbon monoxide (CO) sensors deployed in a heavy equipment manufacturing facility for eight months from August 2017 to March 2018, we demonstrate that machine learning with probabilistic gradient boosted decision trees (GBDT) can model raw sensor readings to reference data highly accurately, entirely removing the need for laboratory calibration. Further, we indicate how the machine learning models can produce probabilistic hazard maps of the manufacturing floor, creating a visual tool for assessing facility-wide exposures. Additionally, the ability to have a fully modeled prediction distribution for each measurement enables the use of the AIHA exposure ratings, which provide an enhanced industrial decision-making framework as opposed to simply determining if a small number of measurements were above or below a pertinent occupational exposure limit. Lastly, we show how a probabilistic modeling exposure assessment with high spatiotemporal resolution data can prevent exposure misclassifications associated with traditional models that rely exclusively on mean or point predictions.

Background. Structural integrity of the ipsilesional corticospinal tract (CST) is important for upper limb motor recovery after stroke. However, additional neuromechanisms associated with motor function poststroke are less well understood, especially regarding the lower limb. Objective. To investigate the neural basis of upper/lower limb motor deficits poststroke by correlating measures of motor function with diffusion tensor imaging-derived indices of white matter integrity (fractional anisotropy (FA), mean diffusivity (MD)) in primary and secondary motor tracts/structures. Methods. Forty-three individuals with chronic stroke (time poststroke, 64.4 ± 58.8 months) underwent a comprehensive motor assessment and MRI scanning. Correlation and multiple regression analyses were performed to examine relationships between FA/MD in a priori motor tracts/structures and motor function. Results. FA in the ipsilesional CST and red nucleus (RN) was positively correlated with motor function of both the affected upper and lower limb ( r = 0.36 ‐ 0.55 , p ≤ 0.01 ), while only ipsilesional RN FA was associated with gait speed ( r = 0.50 ). Ipsilesional CST FA explained 37.3% of the variance in grip strength ( p < 0.001 ) and 31.5% of the variance in Arm Motricity Index ( p = 0.004 ). Measures of MD were not predictors of motor performance. Conclusions. Microstructural integrity of the ipsilesional CST is associated with both upper and lower limb motor function poststroke, but appears less important for gait speed. Integrity of the ipsilesional RN was also associated with motor performance, suggesting increased contributions from secondary motor areas may play a role in supporting chronic motor function and could become a target for interventions.

Excessive, chronic alcohol consumption can lead to alcoholic liver disease. The etiology of alcoholic liver disease is multifactorial and is influenced by alterations in gene expression and changes in fatty acid metabolism, oxidative stress, and insulin resistance. These events can lead to steatosis, fibrosis, and eventually to cirrhosis and liver cancer. Many of these functions are regulated by peroxisome proliferator-activated receptors (PPARs). Thus, it is not surprising that PPARs can modulate the mechanisms that cause alcoholic liver disease. While the roles of PPARα and PPARγ are clearer, the role of PPARβ/δ in alcoholic liver disease requires further clarification. This review summarizes the current understanding based on recent studies that indicate that PPARβ/δ can likely be targeted for the treatment and/or the prevention of alcoholic liver disease.

Contains fulltext : 293588.pdf (Publisher’s version ) (Open Access) BACKGROUND AND PURPOSE: Periprosthetic femoral fracture (PPF) after total hip arthroplasty (THA) is a serious complication, as it often is followed by functional deficits and morbidity. There is no consensus regarding the optimal stem fixation method and whether additional cup replacement is beneficial. The aim of our study was to perform a direct comparison of reasons and risk of re-revision between cemented and uncemented revision THAs following PPF using registry data. PATIENTS AND METHODS: 1,879 patients registered in the Dutch Arthroplasty Registry (LROI) who underwent a first-time revision for PPF between 2007 and 2021 (cemented stem: n = 555; uncemented stem: n = 1,324) were included. Competing risk survival analysis and multivariable Cox proportional hazard analyses were performed. RESULTS: 5- and 10-year crude cumulative incidence of re-revision following revision for PPF was similar between cemented (resp. 13%, 95% CI 10-16 and 18%, CI 13-24) and uncemented (resp. 11%, CI 10-13 and 13%, CI 11-16) revisions. Multivariable Cox regression analysis, adjusting for potential confounders, showed a similar risk of revision for uncemented and cemented revision stems. Finally, we found no difference in risk of re-revision between a total revision (HR 1.2, 0.6-2.1) compared with a stem revision. CONCLUSION: We found no difference in the risk of re-revision between cemented and uncemented revision stems after revision for PPF.

This article describes a 23-year-old woman with bruising, hair loss, and stretch marks, which was found to be due to Cushing syndrome. Because of its nonspecific symptoms, this disease of hypercortisolism can be mistaken for other conditions.

Establishing spatial correspondence between subject and template images is necessary in neuroimaging research and clinical applications such as brain mapping and stereotactic neurosurgery. Our anatomical fiducial (AFID) framework has recently been validated to serve as a quantitative measure of image registration based on salient anatomical features. In this study, we sought to apply the AFIDs protocol to the clinic, focusing on structural magnetic resonance images obtained from patients with Parkinson’s disease (PD). We confirmed AFIDs could be placed to millimetric accuracy in the PD dataset with results comparable to those in normal control subjects. We evaluated subject-to-template registration using this framework by aligning the clinical scans to standard template space using a robust open preprocessing workflow. We found that registration errors measured using AFIDs were higher than previously reported, suggesting the need for optimization of image processing pipelines for clinical grade datasets. Finally, we examined the utility of using point-to-point distances between AFIDs as a morphometric biomarker of PD, finding evidence of reduced distances between AFIDs that circumscribe regions known to be affected in PD including the substantia nigra. Overall, we provide evidence that AFIDs can be successfully applied in a clinical setting and utilized to provide localized and quantitative measures of registration error. AFIDs provide clinicians and researchers with a common, open framework for quality control and validation of spatial correspondence and the location of anatomical structures, facilitating aggregation of imaging datasets and comparisons between various neurological conditions. Supplementary Information The online version contains supplementary material available at 10.1007/s00429-021-02408-3.

Walking dysfunction such as slow walking speed and reduced independent mobility are common impairments following stroke. Neural mechanisms of upper limb impairment and motor recovery have been highly studied, while less is known about the neural correlates of walking dysfunction and rehabilitation after stroke. Our objective was to review the literature on neuroimaging correlates of walking and walking recovery post-stroke to provide a more comprehensive picture of neurological regions of interest. We searched the databases PubMed, CINAHL, Web of Science, and Cochrane Trials for articles published in English between January 1, 2010 and November 30, 2020 that assessed walking after stroke through neuroimaging and various clinical measures. The following key words were used: stroke, gait, walking, rehabilitation, brain mapping, neuroimaging, neural control of walking, motor recovery and motor function, and resulted in eighteen articles included in this review. These articles revealed regions of interest associated with lower extremity impairment and walking post-stroke to include the putamen, caudate, insula, pallidum, superior temporal gyrus, internal capsule, superior longitudinal fasciculus, corticospinal tract, corona radiata, and white matter associated with the pedunculopontine nucleus. This information strengthens our understanding of supraspinal control of walking post-stroke. However, future research on lesion location, functional and structural connectivity, and walking deficits is needed to confidently associate specific brain regions and white matter tracts/connectivity with specific impairments. Greater insight into neuromechanisms associated with response to neurorehabilitation post-stroke could improve treatment selection and prediction of motor recovery.

Background and purpose — In the last decade, the direct anterior approach (DAA) for total hip arthroplasty (THA) has become more popular in the Netherlands. Therefore, we investigated the learning curve and survival rate of the DAA in primary THA, using data from the Dutch Arthroplasty Register (LROI).Patients and methods — We identified all patients who received a primary THA using the DAA in several highvolume centers in the Netherlands between 2007 and 2019 (n = 15,903). Procedures were ordered per surgeon, using date of operation. Using the procedure number, operations were divided into 6 groups based on the number of previous procedures per surgeon (first 25, 26–50, 51–100, 101–150, 151–200, > 200). Data from different surgeons in different hospitals was pooled together. Revision rates were calculated using a multilevel time-to-event analysis.Results — Patients operated on in group 1–25 (hazard ratio [HR] 1.6; 95% CI 1.1–2.4) and 26–50 (HR 1.6; CI 1.1–2.5) had a higher risk for revision compared with patients operated on in group > 200 THAs. Between 50 and 100 procedures the revision risk was increased (HR 1.3; CI 0.9–1.9), albeit not statistically significant. From 100 procedures onwards the HR for revision was respectively 1.0 (CI 0.6–1.6) and 0.8 (CI 0.5–1.4) for patients in operation groups 101–150 and 151–200. Main reasons for revision were loosening of the stem (29%), periprosthetic infection (19%), and dislocation (16%).Interpretation — We found a 64% increased risk of revision for patients undergoing THA using the DAA for the first 50 cases per surgeon. Between 50 and 100 cases, this risk was 30% increased, but not statistically significant. From 100 cases onwards, a steady state had been reached in revision rate. The learning curve for DAA therefore is around 100 cases.

In 2021, a national network of multidisciplinary medical competence-centers has established itself in Germany that is committed to ensuring the care of people with thalidomide embryopathy. This article would like to draw attention to this competence network and give an overview of the most important medical care needs of aging people with thalidomide-induced body and sensory impairments. Here, the available scientific evidence and clinical peculiarities in medical care from a general medical-internal, orthopedic-paintherapeutic, sociomedical and psychosomatic-psychotherapeutic perspective will be presented and necessary tasks for the future will be discussed.In Deutschland hat sich 2021 ein nationales Netzwerk von multidisziplinären medizinischen Kompetenzzentren etabliert, das sich der Sicherstellung der Versorgung Contergan-geschädigter Menschen verpflichtet fühlt. Der vorliegende Beitrag möchte auf dieses Kompetenznetzwerk aufmerksam machen und einen Überblick über die wichtigsten medizinischen Versorgungsbedarfe von alternden Menschen mit Thalidomid-induzierten Körper- und Sinnesbeeinträchtigungen geben. Hierbei werden die vorliegende wissenschaftliche Evidenz und klinische Besonderheiten in der medizinischen Versorgung aus allgemeinmedizinisch-internistischer, orthopädisch-schmerztherapeutischer, sozialmedizinischer und psychosomatisch-psychotherapeutischer Perspektive präsentiert und zukünftige Aufgaben diskutiert.

BACKGROUND: The use of non-ionizing electric fields from low-intensity voltage sources (< 10 V) to control malignant tumor growth is showing increasing potential as a cancer treatment modality. A method of applying these low-intensity electric fields using multiple implanted electrodes within or adjacent to tumor volumes has been termed as intratumoral modulation therapy (IMT). PURPOSE: This study explores advancements in the previously established IMT optimization algorithm, and the development of a custom treatment planning system for patient-specific IMT. The practicality of the treatment planning system is demonstrated by implementing the full optimization pipeline on a brain phantom with robotic electrode implantation, postoperative imaging, and treatment stimulation. METHODS: The integrated planning pipeline in 3D Slicer begins with importing and segmenting patient magnetic resonance images (MRI) or computed tomography (CT) images. The segmentation process is manual, followed by a semi-automatic smoothing step that allows the segmented brain and tumor mesh volumes to be smoothed and simplified by applying selected filters. Electrode trajectories are planned manually on the patient MRI or CT by selecting insertion and tip coordinates for a chosen number of electrodes. The electrode tip positions and stimulation parameters (phase shift and voltage) can then be optimized with the custom semi-automatic IMT optimization algorithm where users can select the prescription electric field, voltage amplitude limit, tissue electrical properties, nearby organs at risk, optimization parameters (electrode tip location, individual contact phase shift and voltage), desired field coverage percent, and field conformity optimization. Tables of optimization results are displayed, and the resulting electric field is visualized as a field-map superimposed on the MR or CT image, with 3D renderings of the brain, tumor, and electrodes. Optimized electrode coordinates are transferred to robotic electrode implantation software to enable planning and subsequent implantation of the electrodes at the desired trajectories. RESULTS: An IMT treatment planning system was developed that incorporates patient-specific MRI or CT, segmentation, volume smoothing, electrode trajectory planning, electrode tip location and stimulation parameter optimization, and results visualization. All previous manual pipeline steps operating on diverse software platforms were coalesced into a single semi-automated 3D Slicer-based user interface. Brain phantom validation of the full system implementation was successful in preoperative planning, robotic electrode implantation, and postoperative treatment planning to adjust stimulation parameters based on actual implant locations. Voltage measurements were obtained in the brain phantom to determine the electrical parameters of the phantom and validate the simulated electric field distribution. CONCLUSIONS: A custom treatment planning and implantation system for IMT has been developed in this study and validated on a phantom brain model, providing an essential step in advancing IMT technology toward future clinical safety and efficacy investigations.

Forensic handwriting examination involves the comparison of writing samples by forensic document examiners (FDEs) to determine whether or not they were written by the same person. Here we report the results of a large-scale study conducted to assess the accuracy and reliability of handwriting comparison conclusions. Eighty-six practicing FDEs each conducted up to 100 handwriting comparisons, resulting in 7,196 conclusions on 180 distinct comparison sets, using a five-level conclusion scale. Erroneous “written by” conclusions (false positives) were reached in 3.1% of the nonmated comparisons, while 1.1% of the mated comparisons yielded erroneous “not written by” conclusions (false negatives). False positive rates were markedly higher for nonmated samples written by twins (8.7%) compared to nontwins (2.5%). Notable associations between training and performance were observed: FDEs with less than 2 y of formal training generally had higher error rates, but they also had higher true positive and true negative rates because they tended to provide more definitive conclusions; FDEs with at least 2 y of formal training were less likely to make definitive conclusions, but those definitive conclusions they made were more likely to be correct (higher positive predictive and negative predictive values). We did not observe any association between writing style (cursive vs. printing) and rates of errors or incorrect conclusions. This report also provides details on the repeatability and reproducibility of conclusions, and reports how conclusions are affected by the quantity of writing and the similarity of content.

ObjectiveTo determine the budget impact of virtual care.MethodsWe conducted a budget impact analysis of virtual care from the perspective of a large teaching hospital in the Netherlands. Virtual care included remote monitoring of vital signs and three daily remote contacts. Net budget impact over 5 years and net costs per patient per day (costs/patient/day) were calculated for different scenarios: implementation in one ward, in two different wards, in the entire hospital, and in multiple hospitals. Sensitivity analyses included best-case and worst-case scenarios, and reducing the frequency of daily remote contacts.ResultsNet budget impact over 5 years was €2 090 000 for implementation in one ward, €410 000 for two wards and €−6 206 000 for the entire hospital. Costs/patient/day in the first year were €303 for implementation in one ward, €94 for two wards and €11 for the entire hospital, decreasing in subsequent years to a mean of €259 (SD=€72), €17 (SD=€10) and €−55 (SD=€44), respectively. Projecting implementation in every Dutch hospital resulted in a net budget impact over 5 years of €−445 698 500. For this scenario, costs/patient/day decreased to €−37 in the first year, and to €54 in subsequent years in the base case.ConclusionsWith present cost levels, virtual care only saves money if it is deployed at sufficient scale or if it can be designed such that the active involvement of health professionals is minimised. Taking a greenfield approach, involving larger numbers of hospitals, further decreases costs compared with implementing virtual care in one hospital alone.

Background Enhancing propulsion during walking is often a focus in physical therapy for those with impaired gait. However, there is no consensus in the literature for assessing braking and propulsion. Both are typically measured from the anterior-posterior ground reaction force (AP-GRF). While normalization of AP-GRF force by bodyweight is commonly done in the analysis, different methods for AP-GRF time axis normalization are used. Research question Does walking speed affect propulsion and/or braking, and how do different methods for calculating propulsion and braking impact the conclusion, in both healthy adults and those with lower limb impairment? Methods We investigated three different analysis methods for assessing propulsion. 1. BW-TimeIntegration: Bodyweight (BW) normalized time integration of AP-GRF (units of BW s). 2. BW-%StanceIntegration: BW normalized AP-GRF is resampled to percent stance phase prior to integration (units of BW %Stance). 3. BW-Peak: BW normalized peak force (units of BW). We applied these methods to two data sets. One data set included AP-GRFs from trials of slow, self-selected, and fast walking speeds for 203 healthy controls (HCs); a second data set included subjects with lower limb orthopedic injuries. Results Using the BW-TimeIntegration method, we found no effect of walking speed on propulsion for HCs. Time integration over the longer stance phase of slower walking balanced the lower magnitude AP-GRFs of slower walking, resulting in a time-integrated impulse that was the same regardless of walking speed. In contrast, the other two methods that are not time integration methods found that propulsion increased with walking speed. Similarly, in the gait pathology data set, differences in results were found depending on the analysis method used. Significance For many gait studies concerning propulsion and/or braking, the impulse measure used should be related to the body’s change of momentum, necessitating an analysis method with a time integration of the AP-GRF.

Objective To assess whether ictal electric source imaging (ESI) on low-density scalp EEG can approximate the seizure onset zone (SOZ) location and predict surgical outcome in children with refractory epilepsy undergoing surgery. Methods We examined 35 children with refractory epilepsy. We dichotomized surgical outcome into seizure- and non-seizure-free. We identified ictal onsets recorded with scalp and intracranial EEG and localized them using equivalent current dipoles and standardized low-resolution magnetic tomography (sLORETA). We estimated the localization accuracy of scalp EEG as distance of scalp dipoles from intracranial dipoles. We also calculated the distances of scalp dipoles from resection, as well as their resection percentage and compared between seizure-free and non-seizure-free patients. We built receiver operating characteristic curves to test whether resection percentage predicted outcome. Results Resection distance was lower in seizure-free patients for both dipoles (p = 0.006) and sLORETA (p = 0.04). Resection percentage predicted outcome with a sensitivity of 57.1% (95% CI, 34–78.2%), a specificity of 85.7% (95% CI, 57.2–98.2%) and an accuracy of 68.6% (95% CI, 50.7–83.5%) (p = 0.01). Conclusion Ictal ESI performed on low-density scalp EEG can delineate the SOZ and predict outcome. Significance Such an application may increase the number of children who are referred for epilepsy surgery and improve their outcome.

Key points We examined the influence of cutaneous feedback from the heel and metatarsal regions of the foot sole on the soleus stretch reflex pathway during standing. We found that heel electrical stimuli suppressed and metatarsal stimuli enhanced the soleus vibration response. Follow-up experiments indicated that the interaction between foot sole cutaneous feedback and the soleus vibration response was likely not mediated by presynaptic inhibition and was contingent upon a modulation at the ⍺-motoneuron pool level. The spatially organized interaction between cutaneous feedback from the foot sole and the soleus vibration response provides information about how somatosensory information is combined to appropriately respond to perturbations during standing. Abstract Cutaneous feedback from the foot sole provides balance-relevant information and has the potential to interact with spinal reflex pathways. In this study, we examined how cutaneous feedback from the foot sole (heel and metatarsals) influenced the soleus response to proprioceptive stimuli during standing. We delivered noisy vibration (10-115 Hz) to the right Achilles tendon while we intermittently applied electrical pulse trains (five 1-ms pulses at 200 Hz, every 0.8-1.0 s) to the skin under either the heel or the metatarsals of the ipsilateral foot sole. We analysed time-dependent (referenced to cutaneous stimuli) coherence and cross-correlations between the vibration acceleration and rectified soleus EMG. Vibration-EMG coherence was observed across a bandwidth of ∼10-80 Hz, and coherence was suppressed by heel but enhanced by metatarsal cutaneous stimuli. Cross-correlations showed soleus EMG was correlated with the vibration (∼40 ms lag) and cross-correlations were also suppressed by heel (from 104-155 ms) but enhanced by metatarsal (from 76-128 ms) stimuli. To examine the neural mechanisms mediating this reflex interaction, we conducted two further experiments to probe potential contributions from (1) presynaptic inhibition, and (2) modulations at the ⍺- and γ-motoneuron pools. Results suggest the cutaneous interactions with the stretch reflex pathway required a modulation at the ⍺-motoneuron pool and were likely not mediated by presynaptic inhibition. These findings demonstrate that foot sole cutaneous information functionally tunes the stretch reflex pathway during the control of upright posture and balance.

Parkinson's disease (PD) is a progressive neurodegenerative disorder that is characterized by a range of motor and nonmotor symptoms, often with the motor dysfunction initiated unilaterally. Knowledge regarding disease‐related alterations in white matter pathways can effectively help improve the understanding of the disease and propose targeted treatment strategies. Microstructural imaging techniques, including diffusion tensor imaging (DTI), allows inspection of white matter integrity to study the pathogenesis of various neurological conditions. Previous voxel‐based analyses with DTI measures, such as fractional anisotropy and mean diffusivity have uncovered changes in brain regions that are associated with PD, but the conclusions were inconsistent, partially due to small patient cohorts and the lack of consideration for clinical laterality onset, particularly in early PD. Fixel‐based analysis (FBA) is a recent framework that offers tract‐specific insights regarding white matter health, but very few FBA studies on PD exist. We present a study that reveals strengthened and weakened white matter integrity that is subject to symptom laterality in a large drug‐naïve de novo PD cohort using complementary DTI and FBA measures. The findings suggest that the disease gives rise to tissue degeneration and potential re‐organization in the early stage., Parkinson's disease (PD) is a progressive neurodegenerative disorder that is characterized by a range of motor and nonmotor symptoms, often with the motor dysfunction initiated unilaterally. We present a study that reveals strengthened and weakened white matter integrity that is subject to symptom laterality in a large drug‐naïve de novo Parkinson's disease cohort using complementary DTI and FBA measures. The findings suggest that the disease gives rise to tissue degeneration and potential re‐organization in the early stage.

Background Health care providers, including physical therapists, need to identify the reasons for insufficient physical activity (PA) to assist the 56% to 73% of community-dwelling adults 50 years of age and older who are not performing the recommended 150 minutes of moderate to vigorous PA. Currently, there is no feasible, multifactorial tool to assess PA barriers among this population. Without a tool, health care providers must either rely on self-generated questions or collate results from multiple assessments to identify PA barriers related to personal, social, and environmental factors, which can be time-consuming and incomplete. Purpose To develop the Inventory of Physical Activity Barriers (IPAB), an assessment tool that examines personal, social, and environmental PA barriers. Methods We developed and psychometrically evaluated the IPAB using a 3-phase process. For phase 1, we used a deductive method to develop the initial scale. During phase 2, we refined the scale and explored its psychometric properties by collecting cross-sectional pilot data on community-dwelling adults 50 years of age and older. We used descriptive statistics, item-scale correlations, construct validity via Mann-Whitney U test, and internal consistency via Cronbach α to analyze the data from phase 2. After identifying the scale's potential for being valid and reliable, we implemented phase 3, a modified Delphi technique. Results Using item-scale correlations, descriptive statistics, and consensus among PA experts, we refined the initial scale from 172 items to 40 items. The 40-item IPAB demonstrated good construct validity (determined by the scale's ability to differentiate between individuals who did and did not meet 150 min/wk of moderate to vigorous PA; P = .01) and internal consistency (Cronbach α of 0.97). Conclusion Our preliminary results suggest that the IPAB is valid and reliable. Using the IPAB, health care providers will be able to identify patients' PA barriers and thus develop individualized PA prescriptions, an evidence-based method of increasing PA.

Background: Antibody tests are critical in elucidating the epidemiology of the rapidly evolving Coronavirus Disease 2019 (COVID-19) global pandemic and in developing effective infection control measures. To avoid the significant risks posed by the use of tests with poor performance characteristics and associated supply chain disruptions, we developed an in-house SARS-CoV-2 total antibody test. The performance of our robustly validated test was compared with that of three commercial antibody tests, and our test was used to determine the seroprevalence of COVID-19 among healthcare workers and outpatients in Minnesota. Methods: To evaluate the clinical performance of our SARS-CoV-2 total antibody assay, 63 plasma and serum samples were analyzed from 34 SARS-CoV-2 PCR positive patients 4 - 35 days after symptom onset. Positive samples were analyzed for IgG titers in a follow up assay. Samples were analyzed from PCR negative (n=30) and presumed true negative pre-pandemic (n=207) patients. Among samples collected from patients >14 days after symptom onset, the assay had 100% diagnostic sensitivity (95% CI: 85·7 - 100·0%), 100% diagnostic specificity (95%CI: 98·5 - 100·0%), 100% positive predictive value (95% CI: 86·2 - 100·0%), and 100% negative predictive value (95%CI: 98·6 - 100·0%). The analytical specificity was 99·8% (95% CI: 98·92 - 99·97%), indicating minimal cross-reactivity. A screening study was conducted to ascertain the seroprevalence of COVID-19 among healthcare workers and outpatients in Minnesota. Findings: Serum collected from 1,282 healthcare workers (1,000 females, 280 males, 2 gender unreported; median age 41 years [range 18 - 73]) and 2,379 outpatients (1,460 females, 916 males, 3 gender unreported; median age 49 years [range 2 months - 93 years]) between April 13 and May 21, 2020 was analyzed using our SARS-CoV-2 total antibody assay. The COVID-19 seroprevalence was 2·96% (95% CI: 2·04 - 3·89%) among healthcare workers and 4·46% (95% CI: 3·63 - 5·28%) among outpatients from 35 clinics who had a previous COVID-19 exposure or symptoms. Interpretation: Rigorously validated serology tests with robust clinical and analytical performance, such as our in-house SARS-CoV-2 total antibody test, are of critical importance when conducting epidemiological studies to inform public health decisions during the COVID-19 pandemic. Funding: University of Minnesota Department of Laboratory Medicine and Pathology Declaration of Interests: The authors do not declare any competing interests. Ethics Approval Statement: The University of Minnesota Institutional Review Board (IRB) determined that this study was not considered human research.

Background Extremity weakness, fatigue, and postural instability often contribute to mobility deficits in persons after stroke. Wearable technologies are increasingly being utilized to track many health-related parameters across different patient populations. The purpose of this systematic review was to identify how wearable technologies have been used over the past decade to assess gait and mobility in persons with stroke. Methods We performed a systematic search of Ovid MEDLINE, CINAHL, and Cochrane databases using select keywords. We identified a total of 354 articles, and 13 met inclusion/exclusion criteria. Included studies were quality assessed and data extracted included participant demographics, type of wearable technology utilized, gait parameters assessed, and reliability and validity metrics. Results The majority of studies were performed in either hospital-based or inpatient settings. Accelerometers, activity monitors, and pressure sensors were the most commonly used wearable technologies to assess gait and mobility post-stroke. Among these devices, spatiotemporal parameters of gait that were most widely assessed were gait speed and cadence, and the most common mobility measures included step count and duration of activity. Only 4 studies reported on wearable technology validity and reliability metrics, with mixed results. Conclusion The use of various wearable technologies has enabled researchers and clinicians to monitor patients’ activity in a multitude of settings post-stroke. Using data from wearables may provide clinicians with insights into their patients’ lived-experiences and enrich their evaluations and plans of care. However, more studies are needed to examine the impact of stroke on community mobility and to improve the accuracy of these devices for gait and mobility assessments amongst persons with altered gait post-stroke.

Background Persistent genital arousal disorder (PGAD), a condition of unwanted, unremitting sensations of genital arousal, is associated with a significant, negative psychosocial impact that may include emotional lability, catastrophization, and suicidal ideation. Despite being first reported in 2001, PGAD remains poorly understood. Aim To characterize this complex condition more accurately, review the epidemiology and pathophysiology, and provide new nomenclature and guidance for evidence-based management. Methods A panel of experts reviewed pertinent literature, discussed research and clinical experience, and used a modified Delphi method to reach consensus concerning nomenclature, etiology, and associated factors. Levels of evidence and grades of recommendation were assigned for diagnosis and treatment. Outcomes The nomenclature of PGAD was broadened to include genito-pelvic dysesthesia (GPD), and a new biopsychosocial diagnostic and treatment algorithm for PGAD/GPD was developed. Results The panel recognized that the term PGAD does not fully characterize the constellation of GPD symptoms experienced by patients. Therefore, the more inclusive term PGAD/GPD was adopted, which maintains the primacy of the distressing arousal symptoms and acknowledges associated bothersome GPD. While there are diverse biopsychosocial contributors, there is a common underlying neurologic basis attributable to spontaneous intense activity of the genito-pelvic region represented in the somatosensory cortex and its projections. A process of care diagnostic and treatment strategy was developed to guide the clinician, whenever possible, by localizing the symptoms as originating in any of five regions: (i) end organ, (ii) pelvis/perineum, (iii) cauda equina, (iv) spinal cord, and (v) brain. Psychological treatment strategies were considered critical and should be performed in conjunction with medical strategies. Pharmaceutical interventions may be used based on their site and mechanism of action to reduce patients’ symptoms and the associated bother and distress. Clinical Implications The process of care for PGAD/GPD uses a personalized, biopsychosocial approach for diagnosis and treatment. Strengths and Limitations Strengths and Limitations: Strengths include characterization of the condition by consensus, analysis, and recommendation of a new nomenclature and a rational basis for diagnosis and treatment. Future investigations into etiology and treatment outcomes are recommended. The main limitations are the dearth of knowledge concerning this condition and that the current literature consists primarily of case reports and expert opinion. Conclusion We provide, for the first time, an expert consensus review of the epidemiology and pathophysiology and the development of a new nomenclature and rational algorithm for management of this extremely distressing sexual health condition that may be more prevalent than previously recognized. Goldstein I, Komisaruk BR, Pukall CF, et al. International Society for the Study of Women’s Sexual Health (ISSWSH) Review of Epidemiology and Pathophysiology, and a Consensus Nomenclature and Process of Care for the Management of Persistent Genital Arousal Disorder/Genito-Pelvic Dysesthesia (PGAD/GPD). J Sex Med 2021;18:665–697.

Middle-range nursing theories provide a bridge between the more abstract grand nursing theories, research, and clinical practice. As such, middle-range nursing theories derived from extant nursing theories are critical for developing and advancing both nursing science and practice. This paper describes the strategy used in developing a middle-range theory of heart failure self-care. After integrating theoretical and empirical literature, a hypothetico-deductive approach was used to develop the middle-range theory of heart failure self-care from Orem’s theory of self-care. Theoretical substruction was used to provide a graphic representation of the conceptual-theoretical-empirical structure demonstrating the congruence between the theoretical and operational systems.

This study aims to assess how clinical outcomes of immunotherapy in real-world (effectiveness) correspond to outcomes in clinical trials (efficacy) and to look into factors that might explain an efficacy-effectiveness (EE) gap. All patients diagnosed with stage IV non-small cell lung cancer (NSCLC) in 2015–2018 in six Dutch large teaching hospitals (Santeon network) were identified and followed-up from date of diagnosis until death or end of data collection. Progression-free survival (PFS) and overall survival (OS) from first-line (1L) pembrolizumab and second-line (2L) nivolumab were compared with clinical trial data by calculating hazard ratios (HRs). From 1950 diagnosed patients, 1005 (52%) started with any 1L treatment, of which 83 received pembrolizumab. Nivolumab was started as 2L treatment in 141 patients. For both settings, PFS times were comparable between real-world and trials (HR 1.08 (95% CI 0.75–1.55), and HR 0.91 (95% CI 0.74–1.14), respectively). OS was significantly shorter in real-world for 1L pembrolizumab (HR 1.55; 95% CI 1.07–2.25). Receiving subsequent lines of treatment was less frequent in real-world compared to trials. There is no EE gap for PFS from immunotherapy in patients with stage IV NSCLC. However, there is a gap in OS for 1L pembrolizumab. Fewer patients proceeding to a subsequent line of treatment in real-world could partly explain this.

Author(s): Pezzella, Andrea; McCrery, Rebecca; Lane, Felicia; Benson, Kevin; Taylor, Chris; Padron, Osvaldo; Blok, Bertil; de Wachter, Stefan; Gruenenfelder, Jennifer; Pakzad, Mahreen; Perrouin-Verbe, Marie-Aimee; van Kerrebroeck, Philip; Mangel, Jeffrey; Peters, Kenneth; Kennelly, Michael; Shapiro, Andrew; Lee, Una; Comiter, Craig; Mueller, Margaret; Goldman, Howard B | Abstract: AimsSacral neuromodulation (SNM) is a guideline-recommended treatment with proven therapeutic benefit for urinary urgency incontinence (UUI) patients. The Axonics® System is the first Food and Drug Administration-approved rechargeable SNM system and is designed to deliver therapy for a minimum of 15 years. The ARTISAN-SNM study was designed to evaluate UUI participants treated with the Axonics System. Two-year follow-up results are presented.MethodsOne hundred and twenty-nine UUI participants underwent implantation with the Axonics System. Therapeutic response rate, participant quality of life (QoL), and satisfaction were determined using 3-day voiding diaries, ICIQ-OABqol, and satisfaction questionnaires. Participants were considered responders if they had a 50% or greater reduction in UUI episodes post-treatment. As-treated and Completers analyses are presented.ResultsAt 2 years, 93% of the participants (n = 121 Completers at 2 years) were therapy responders, of which 82% achieved ≥ 75% reduction in UUI episodes and 37% were dry (100% reduction). Daily UUI episodes reduced from 5.6 ± 0.3 at baseline to 1.0 ± 0.2 at 2 years. Statistically significant improvements in ICIQ-OABqol were reported. All participants were able to recharge their devicenand 94% of participants reported that the recharging frequency and duration were acceptable. Participant demographics nor condition severity were correlated with clinical outcomes or recharging experience. No unanticipated or serious device-related adverse eventsnoccurred.ConclusionsAt 2 years, participants treated with the Axonics System demonstrated sustained safety and efficacy, high levels of satisfaction with therapy and recharging. Participant-related factors were not associated with efficacy or recharging outcomes, indicating the reported results are applicable to a diverse population.

Helical alignments within the heart’s musculature have been speculated to be important in achieving physiological pumping efficiencies. Testing this possibility is difficult, however, because it is challenging to reproduce the fine spatial features and complex structures of the heart’s musculature using current techniques. Here we report focused rotary jet spinning (FRJS), an additive manufacturing approach that enables rapid fabrication of micro/nanofiber scaffolds with programmable alignments in three-dimensional geometries. Seeding these scaffolds with cardiomyocytes enabled the biofabrication of tissue-engineered ventricles, with helically aligned models displaying more uniform deformations, greater apical shortening, and increased ejection fractions compared with circumferential alignments. The ability of FRJS to control fiber arrangements in three dimensions offers a streamlined approach to fabricating tissues and organs, with this work demonstrating how helical architectures contribute to cardiac performance.

To assess the association of nocturnal hypoglycemia prevention strategies (NH-PS) and diabetes technology usage (insulin pump and/or continuous glucose monitors [CGM]) in people with type 1 diabetes (PWT1D).Logistic regression models were used to describe associations between self-reported NH-PS and diabetes technology (pump with intermittently-scanned or real-time CGM (isCGM or rtCGM), or automated insulin delivery (AID)), hypoglycemia history, and fear of hypoglycemia (FOH).Among 831 adults (65 % female, aged 44 ± 15 years, T1D duration 26 ± 15 years), 32 % reported HbA1c ≤ 7.0 %, 88 % used ≥ 1 diabetes technology, 66 % reported ≥ 1 symptomatic NH in the past month, and 64 % used ≥ 2 NH-PS. Compared to multiple daily injections (MDI) + capillary blood glucose (CBG), bedtime snack consumption was less likely among pump + isCGM (OR [95 %CI]: 0.55 [0.31, 0.98]), pump + rtCGM (0.40 [0.20, 0.81]), and AID (0.34 [0.17, 0.66]) users, while evening insulin basal reduction was associated with CSII + CBG (3.15 [1.25, 7.99]), pump + isCGM 4.00 [1.99, 8.01]), and pump + rtCGM 2.89 [1.28, 6.50] use. Elevated FOH was associated with snack consumption (1.37 [1.00, 1.89]), evening bolus insulin avoidance (1.77 [1.11, 2.83]), limiting exercise (2.50 [1.30, 4.82]), and limiting alcohol consumption (2.33 [1.15, 4.70]) as NH-PS.Technology use and elevated FOH might influence PWT1D' choice of NH-PS.

Complete tumor coverage by the thermal ablation zone and with a safety margin (5 or 10 mm) is required to achieve the entire tumor eradication in liver tumor ablation procedures. However, 2D ultrasound (US) imaging has limitations in evaluating the tumor coverage by imaging only one or multiple planes, particularly for cases with multiple inserted applicators or irregular tumor shapes. In this paper, we evaluate the intra-procedural tumor coverage using 3D US imaging and investigate whether it can provide clinically needed information. Using data from 14 cases, we employed surface- and volume-based evaluation metrics to provide information on any uncovered tumor region. For cases with incomplete tumor coverage or uneven ablation margin distribution, we also proposed a novel margin uniformity -based approach to provide quantitative applicator adjustment information for optimization of tumor coverage. Both the surface- and volume-based metrics showed that 5 of 14 cases had incomplete tumor coverage according to the estimated ablation zone. After applying our proposed applicator adjustment approach, the simulated results showed that 92.9% (13 of 14) cases achieved 100% tumor coverage and the remaining case can benefit by increasing the ablation time or power. Our proposed method can evaluate the intra-procedural tumor coverage and intuitively provide applicator adjustment information for the physician. Our 3D US-based method is compatible with the constraints of conventional US-guided ablation procedures and can be easily integrated into the clinical workflow.

Concurrent genital-anal human papillomavirus (HPV) infections may impose an increased anal cancer risk in women with HPV-related genital lesions. High viral load may facilitate genital-anal HPV concurrence. Genital and anal HPV is reduced by a bivalent HPV16/18 vaccine, yet the effect on concurrent genital-anal HPV remains unclear. This study analyzed viral load in concurrent genital-anal HPV infections, relative to genital-only and anal-only HPV infections and the impact of vaccination in young women. We included 1074 women, who provided both genital and anal swabs. HPV detection and genotyping was performed using the SPF10-DEIA-LiPA25. HPV copy numbers were measured with type-specific qPCRs and corrected for cellular content to obtain the viral load. Concurrent genital-anal HPV often had significantly higher genital viral load (0.09–371 c/cell) than genital-only HPV (3.17E-04-15.9 c/cell, p, Highlights • Concurrent genital-anal HPV infections may impose a higher risk of anal cancer. • These infections have increased genital viral load. • The genital site is likely the main source of a concurrent genital-anal HPV infection. • Vaccination effectively reduces concurrent genital-anal HPV infections.

There is a well-established inverse relationship between age and positive psychotic symptoms, both in patients with psychotic disorders and in general population samples with psychotic experiences. The reason for this inverse relationship is unclear. We hypothesized that life-course developmental changes in borderline personality traits, which also typically decline with age, might explain the inverse relationship between age and positive psychotic symptoms.We tested this hypothesis with data from 19,980 adults who completed 2000, 2007, and 2014 UK Adult Psychiatric Morbidity Survey studies. Hallucinations and delusions were assessed with the Psychosis Screening Questionnaire. Borderline features were assessed with the Structured Clinical Interview for DSM-IV Axis II Personality Disorders Screening Questionnaire. Logistic regression models with effect decompositions were used to conduct the analyses.As expected, age was negatively associated with hallucinations and delusions. These effects were wholly or mostly reduced after controlling for borderline features. Similar results were found in a subgroup of participants with a probable psychotic disorder. Repeating the analysis with a broad index of psychopathology severity instead of borderline features did not produce comparable results. Borderline factor scores reflecting identity/relationship disturbance, mood instability/anger, and self-harm/suicidality were created, all of which appeared to explain part of the inverse relationship between age and psychotic experiences.Declining borderline traits throughout adulthood may account for the reduced prevalence of positive psychotic symptoms in both clinical and non-clinical populations. Future research might evaluate the impact of treatments that target borderline traits on positive psychotic symptoms.