bluuebunny/crossref_metadata_2025 huggingface dataset:
The Effects of Positive Psychological Interventions on Medical Patients’ Anxiety: A Meta-analysis
Authors: Brown Lydia , Ospina Juan Pablo , Celano Christopher M. , Huffman Jeff C.
Published: June 2019

Objective

Positive psychology interventions, which involve systematic completion of activities designed to promote well-being, are being increasingly studied in medically ill patients. However, the extent to which these interventions ameliorate patient anxiety remains unclear. Therefore, the aim of the study was to conduct a meta-analysis to determine the efficacy of positive psychology interventions in reducing anxiety in medical patients.

Methods

Electronic databases Medline, PsycINFO, SciELO, Cochrane (Central), and ClinicalTrials.gov were searched from inception to June 18, 2018, to identify studies of positive psychology interventions that included a validated measure of anxiety as an outcome measure.

Results

The search generated a total of 1024 studies. Twelve randomized controlled trials (n = 1131) delivered to medical patients were included in the review, and a further 11 nonrandomized trials (n = 300) were included in a secondary analysis. Positive psychology interventions were effective at reducing patient anxiety relative to a control with a small to medium effect size (g = −0.34, 95% confidence interval = −0.50 to −0.18), and results were maintained at a mean of 8-week follow-up (g = −0.31, 95% confidence interval = −0.54 to −0.08). Clinician-led interventions seemed to be more effective than self-administered interventions, and longer interventions were more effective than shorter interventions. Secondary analysis of nonrandomized trials also found that positive psychology interventions are associated with reduced anxiety.

Conclusions

Positive psychology interventions seem to be effective at reducing medical patient anxiety. Future research is needed to determine optimal intervention characteristics, including dose and intervention content, that maximize the observed treatment effects.
Dimensions of Depressive Symptoms and Their Association With Mortality, Hospitalization, and Quality of Life in Dialysis Patients: A Cohort Study
Authors: Schouten Robbert W. , Harmse Victor J. , Dekker Friedo W. , van Ballegooijen Wouter , Siegert Carl E.H. , Honig Adriaan
Published: June 2019

Objective

Unraveling specific dimensions of depressive symptoms may help to improve screening and treatment in dialysis patients. We aimed to identify the best-fitting factorial structure for the Beck Depression Inventory-II (BDI) in dialysis patients and to assess the relation of these structure dimensions with quality of life (QoL), hospitalization, and mortality.

Methods

This prospective study included chronic dialysis patients from 10 dialysis centers in five hospitals between 2012 and 2017. Dimensions of depressive symptoms within the BDI were analyzed using confirmatory factor analysis. To investigate the clinical impact of these dimensions, the associations between symptom dimensions and QoL, hospitalization rate, and mortality were investigated using logistic, Poisson, and Cox proportional hazard regression models. Multivariable regression models included demographic, social, and clinical variables.

Results

In total, 687 dialysis patients were included. The factor model that included a general and a somatic factor provided the best-fitting structure of the BDI-II. Only the somatic dimension scores were associated with all-cause mortality (hazard ratio of 1.7 [1.2–2.5],p< .007) in the multivariable model. All dimensions were associated with increased hospitalization rate and reduced QoL.

Conclusions

The somatic dimension of the BDI-II in dialysis patients was associated with all-cause mortality, increased hospitalization rate, and reduced QoL. Other dimensions were associated with hospitalization rate and decreased QoL. These findings show that symptom dimensions of depression have differential association with adverse clinical outcomes. Future studies should take symptom dimensions into account when investigating depression-related pathways, screening, and treatment effects in dialysis patients.
Comprehensive Assessment of Vascularized Composite Allotransplantation Patient-Oriented Online Resources
Authors: Noel Daphney Y. , Kimberly Laura L. , DeMitchell-Rodriguez Evellyn M. , Levy-Lambert Dina , Ramly Elie P. , Alfonso Allyson R. , Jacoby Adam , Gelb Bruce E. , Diaz-Siso J. Rodrigo , Kantar Rami S. , Rodriguez Eduardo D.
Published: June 2019

Introduction

Online resources have become a major source of medical information for the general public. To date, there has not been an assessment of patient-oriented online resources for face and upper extremity transplantation candidates and patients. The goal of this study is to perform a comprehensive assessment of these resources.

Methods

Our analysis relied on 2 dimensions: comprehensiveness and readability. Comprehensiveness was evaluated using 14 predetermined variables. Readability was evaluated using 8 different readability scales through the Readability Studio Professional Edition Software (Oleander Software, Ltd, Vandalia, Ohio). Data were also collected from solid organ transplantation (SOT), specifically kidney and liver, programs for comparison.

Results

Face and upper extremity transplantation programs were significantly more likely to list exclusion criteria (73.9% vs 41.2%; P = 0.02), the need for life-long immunosuppression (87.0% vs 58.8%; P = 0.02), and benefits of transplantation (91.3% vs 61.8%; P = 0.01) compared with SOT programs. The average readability level of online resources by all face and upper extremity transplantation programs exceeded the sixth grade reading level recommended by the National Institutes of Health and the American Medical Association. The average reading grade level of online resources by these programs was also significantly higher than those of SOT with both exceeding the recommended reading level (13.95 ± 1.55 vs 12.60 ± 1.65; P = 0.003).

Conclusions

Future efforts in face and upper extremity transplantation should be directed toward developing standardized, comprehensive, and intelligible resources with high-quality content and simple language.
Isolated Fat Grafting for Reconstruction of Lower Face Volumetric Asymmetry in Skeletally Immature Patients
Authors: Denadai Rafael , Raposo-Amaral Cesar Augusto , Buzzo Celso Luiz , Raposo-Amaral Cassio Eduardo
Published: June 2019

Background

The purpose of this study was to assess the objective and subjective outcomes of lower face volumetric (contour) asymmetry correction with isolated fat grafting in skeletally immature patients.

Methods

A prospective analysis was conducted of skeletally immature patients (n = 73) with craniofacial microsomia and Parry-Romberg syndrome who underwent isolated fat grafting (with no previous or concomitant bone surgery) using anatomical surgical principles (facial subunits and fat compartments) for the reconstruction of lower face volumetric asymmetry. Objective ultrasound and photogrammetric lower face symmetry analyses were blindly performed preoperatively and at 3 and 12 months postoperatively. A panel assessment of blinded surgical professionals and laypersons was also obtained to grade the subjective lower face symmetry.

Results

There were significant (allP< 0.05) postoperative objective and subjective lower face symmetry enhancements (preoperative < postoperative) after isolated fat grafting, with no differences (allP> 0.05) between 3 versus 12 months' postoperative comparisons.

Conclusions

Growing patients with unilateral lower face volumetric asymmetries presented with improvement of objective and subjective symmetry after a single isolated fat grafting procedure.
Long-Term Follow-up of Full-Awake Hand Surgery in Major Flexor Tendon Injury of the Hand and Forearm
Authors: Prasetyono Theddeus O. H. , Tunjung Narottama
Published: June 2019

Background

Full-awake hand surgery (FAHS) has been gaining attention in recent years. However, the extent of full-awake approach for longer and more complicated major surgeries for the hand in trauma cases remains unclear. This study aimed to report the clinical nature of major flexor tendon trauma cases with subsequent repair under FAHS.

Methods

Retrospective study was performed on 9 male patients with an average age of 32.22 (SD, 9.67) years who experienced surgery for major flexor tendon ruptures under FAHS. Besides involving 3 digits in fingers, hand, or forearm, extensive surgery involved 3 cases with surgical dissection similar to the one needed to repair flexor tendons of 3 digits in zone 2.

Results

The assessment that was performed at least 3 years after surgery included not only the efficacy of FAHS but also the total active range of motion, opposition function, Medsger severity scale, and Disabilities of Arm, Shoulder, and Hand score. All repairs and explorations were performed under FAHS with 2 subjects who needed conversion to general anesthesia owing to intraoperative visual analog scale score of greater than 4. Average surgery duration under FAHS was 225 (170–309) minutes. Through an average follow-up of 4.1 years, all patients showed normal Medsger scale, with 7 cases that had excellent total active range of motion and 8 cases, excellent opposition. Median Disabilities of Arm, Shoulder, and Hand score was 15 (9–28.5).

Conclusions

Full-awake hand surgery is potential surgical approach for major flexor tendon trauma cases resulting in satisfactory long term functional outcome.
Extraoral Versus Intraoral Botulinum Toxin Type A Injection for Management of Temporomandibular Joint Disc Displacement With Reduction
Authors: Altaweel Alaa A. , Elsayed Shadia Abdel-Hameed , Baiomy Abdel Aziz Baiomy Abdullah , Abdelsadek Seham E. , Hyder AbdElkader A.
Published: June 2019

The present study was conducted to compare between extraoral and intraoral approach for botulinum toxin type A (BTX-A) injection into the lateral pterygoid muscle (LPM) in patients suffering from anterior disc displacement with reduction (ADDWR).

Fourteen patients suffering from ADDWR were included in this prospective cohort study. Patients were enrolled randomly into 2 groups according to injection approach; where extraoral used in group I, while intraoral approach used in group II. The LPM was injected with 20 IU BTX-A under electromyography (EMG) guidance. Postoperative evaluation of the patients included: mouth opening assessment, LPM tenderness, temporomandibular joint TMJ (clicking), and tenderness. The LPM insertional EMG activity was assessed. Also, magnetic resonance imaging (MRI) was performed to evaluate disc position. Descriptive and inferential analysis was conducted to compare between groups.

There was significant patient's convenience during injection and significant injection time reduction in group II. A slight decrease in mouth opening immediate post-injection followed by significant improvement from 8th weeks post-injection was reported in both approaches. There was a significant improvement in TMJ clicking from 1st-week post-injection with no group difference. The EMG assessment documented LPM hyperactivity pre-injection followed by significantly decreased muscle activity at 8 and 16 weeks post-injection without statistical difference. The MRI showed no change in disc position after injection.

Conclusion:

The BTX-A injection into LPM is a simple technique that can be used with high success and low complication rate for treatment of ADDWR. The intraoral approach was superior to the extraoral concerning patient convenience and injection duration with no statistical difference regarding other clinical outcomes.
Treatment of Deformational Plagiocephaly With Physiotherapy
Authors: Di Chiara Anna , La Rosa Enrica , Ramieri Valerio , Vellone Valentino , Cascone Piero
Published: June 2019

Non-synostotic plagiocephaly consists in an asymmetry of the skull due to mechanical forces applied in utero or postnatally: main differential diagnosis is with true synostotic asymmetry, which is caused by the premature closure of a suture. The correction of positional forms is mostly conservative, with 3 main strategies: counterpositioning, physiotherapy and helmet therapy. There is no synthesized evidence on which is the most effective.
1,2
The Authors evaluate the modification of antropometric measurments before and after a pediatric physical therapy program in a sample of patients with non-synostotic skull asymmetry, in order to evaluate the improvements in the skull shape. The hypothesis being tested was that physical therapy alone could improve the antropometric measurments. The authors enrolled in this study 24 patients diagnosed of non-synostotic asymmetry, clinically and with ultrasound, referred to the Maxillo-facial Unit of Policlinico Umberto I, Rome, within 2013 and 2016. A standardized pediatric physical therapy intervention program was designed: it consisted in a combination of excercises and manipulative procedures to reduce positional preference, musculoskeletal disorders and cranial deformity. Infants received 16 sessions of physical therapy, of 40 minutes each, once a week, for four months.
3,4
The Authors evaluate the variation of four anthropometric measurments, performed before and after the physical therapy program: Argenta scale, Oblique Diameter Difference Index (ODDI), Cranial Proportional Index (CPI) or Cephalic Ratio (CR), Cranial Vault Asymmetry Index (CVAI).
5,6
Craniometric evaluations were extrapolated by standardized 2D digital photographs of frontal, sagittal and transverse planes, by the same physician to minimize bias. The management of positional cranial deformities is still controversially discussed and especially the effects of physiotherapy and osteopathy have been only marginally researched. Statistical analysis revealed the effectiveness of the protocol: all anthropometric measurements improved with a high rate, major in youngest children (P < 0.5) and in more severe first presentations (P < 0.05 or P < 0.01). The results suggest manipulative approach may improve the outcome in the long term follow up of cranial asymmetries.
Eyelid Melanoma in the United States: A National Cancer Database Analysis
Authors: Oliver Jeremie D. , Boczar Daniel , Sisti Andrea , Huayllani Maria T. , Restrepo David J. , Spaulding Aaron C. , Gabriel Emmanuel , Bagaria Sanjay , Rinker Brian D. , Forte Antonio J.
Published: June 2019

Background:

Eyelid melanoma (EM) is a rare condition that accounts for <1% of all cutaneous melanomas. In this analysis, patients diagnosed with EM in the United States were compared to those with other melanomas in the head and neck.

Methods:

The National Cancer Database was used to select patients with head and neck melanoma from 2004 to 2015.

Results:

A total of 137,233 patients met the criteria of the study. Among them, 2694 were diagnosed with EM (2%) and 134,539 in other head and neck locations (98%). Regarding the patients with EM, the mean age was 68.56 years (standard deviation 14.04). A greater number of them were treated in Academic/Research Programs (53.6%), insured by Medicare (55.7%), tumor in situ (52.2%), stage 0 (49%), and without ulceration (75.9%). The mean time to treatment commencement was 18.96 days for EM compared to 14.4 days for other melanoma in the head and neck regions (P < 0.001). There was a greater proportion of EM in female patients (odds ratio [OR] 2.371 [2.191–2.566], P < 0.001), compared to male; age greater than 80 years (OR 1.622 [1.360–1.934], P < 0.001) compared to 0 to 49 years. Moreover, EM was an independent predictor for treatment in Academic/Research Programs (OR 1.258 [1.160–1.365], P < 0.001) and diagnosis at autopsy (OR 1.414 [1.083–1.847], P = 0.011) compared to other melanoma in the head and neck region.

Conclusion:

These novel findings have the potential to guide clinical decision making in head and neck melanoma management.
Ketamine and lidocaine infusions decrease opioid consumption during vaso-occlusive crisis in adolescents with sickle cell disease
Authors: Puri Latika , Morgan Kyle J. , Anghelescu Doralina L.
Published: June 2019

Purpose of review

Recurrent exposure to opioids can lead to development of opioid tolerance and opioid-induced hyperalgesia through activation of N-methyl-D-aspartate receptors. N-methyl-D-aspartate receptor antagonists ketamine and lidocaine can modulate development of opioid tolerance and OIH. This study evaluated the utility of ketamine and/or lidocaine in decreasing opioid consumption during acute pain episodes in adolescents with sickle cell disease. There has been an increased effort to promote opioid-sparing pain relieving methods given the ongoing opioid epidemic.

Recent findings

There have been six studies published over the past decade that highlight the ability of ketamine to reduce opioid consumption in the management of sickle cell disease-related pain, primarily in adult patients. There has been one study (2015) that demonstrated a similar benefit with lidocaine, however this was also in adult patients.

We retrospectively evaluated treatment with ketamine and/or lidocaine infusions in adolescents hospitalized for vaso-occlusive crisis (VOC). Patients served as self-controls using a comparison with a previous control admission for VOC. The use of ketamine and/or lidocaine as adjuncts to opioids resulted in lower daily opioid consumption in three of four patients. Our study suggests that ketamine and/or lidocaine infusions may be useful adjuncts in reducing opioid exposure during VOC pain.
Gene-targeting approaches for movement disorders: recent advances
Authors: Kaplitt Michael G.
Published: June 2019

Purpose of review

To summarize the current state of art of gene therapy for Parkinson's disease.

Recent findings

Introduction of the gene for glutamic acid decarboxylase (GAD) into the subthalamic nucleus was successful in a randomized, double-blind clinical trial and recent data from PET imaging identified novel brain networks underlying both sham surgery and therapeutic responses in treated participants. Two other approaches use viral vectors to increase dopamine transmission in the striatum. Both strategies are being studied in active trials and have recently reported promising responses in human participants. New strategies in Parkinson's disease are focused upon targeting the underlying pathogenesis in those with genetic defects thought to be the cause of disease. Finally, noninvasive focused ultrasound is currently being tested for lesioning in Parkinson's disease patients, but this same technology can be used to transiently open the blood–brain barrier, raising the potential for noninvasive delivery of gene therapy vectors to specific brain targets.

Parkinson's disease gene therapy has moved from purely animal research three decades ago, to initial human studies two decades ago to many applications moving into late stage trials, currently. Recent successes and promising new technology should only accelerate the advance of gene therapy into active clinical practice.
Repetitive Behaviors Treated With N-Acetylcysteine: Case Series
Authors: Kiliç Faruk , Keleş Süleyman
Published: June 2019

Objectives

Skin-picking disorders, trichotillomania, and nail biting are all characterized by repetitive behaviors resulting in functional deterioration and remarkable changes in physical appearance with repeated attempts to stop or decrease the behavior. While standard pharmacotherapy for obsessive-compulsive disorder and related disorders consists of serotonergic reuptake inhibitors, their moderate efficacy pushed researchers to find alternative treatment approaches. Some of these alternatives are glutamate-modulating agents. The most widely studied of these glutamate modulator agents is N-acetylcysteine (NAC), which is a derivative of the amino acid cysteine.

Methods

This report describes a case series of 3 patients in whom skin-picking disorders, trichotillomania, and nail biting were diagnosed at a center in Turkey.

Results

First case was a 42-year-old female patient who had been picking her skin from her arm area, especially in stressful times. Second case was a 31-year-old female patient who has a habit of pulling her hair for the last 20 years. The third case was 24-year-old male patient with a habit of eating his own nails that he has had for as long as he could remember. We successfully treated 3 of our patients who suffer from previously mentioned disorders with NAC.

Conclusions

Outcome of our cases demonstrates the efficacy of NAC, which is effective and well tolerated on the treatment of obsessive-compulsive disorder–related disorders.
Endocrine-exocrine signaling drives obesity-associated pancreatic ductal adenocarcinoma
Authors: Chung Katherine Minjee , Singh Jaffarguriqbal , Lawres Lauren , Dorans Kimberly Judith , Garcia Cathy , Burkhardt Daniel B. , Robbins Rebecca , Bhutkar Arjun , Cardone Rebecca , Zhao Xiaojian , Babic Ana , Vayrynen Sara A. , Costa Andressa Dias , Nowak Jonathan A. , Chang Daniel T. , Dunne Richard F. , Hezel Aram F. , Koong Albert C. , Wilhelm Joshua J. , Bellin Melena D. , Nylander Vibe , Gloyn Anna L. , McCarthy Mark I. , Kibbey Richard G. , Krishnaswamy Smita , Wolpin Brian M. , Jacks Tyler , Fuchs Charles S. , Muzumdar Mandar Deepak
Published: June 2019

Obesity is a major modifiable risk factor for pancreatic ductal adenocarcinoma (PDAC), yet how and when obesity contributes to PDAC progression is not well understood. Leveraging an autochthonous mouse model, we demonstrate a causal and reversible role for obesity in early PDAC progression, showing that obesity markedly enhances tumorigenesis, while genetic or dietary induction of weight loss intercepts cancer development. Bulk and single cell molecular analyses of human and murine samples define microenvironmental consequences of obesity that promote tumor development rather than new driver gene mutations. We observe increased inflammation and fibrosis and also provide evidence for significant pancreatic islet cell adaptation in obesity-associated tumors. Specifically, we identify aberrant islet beta cell expression of the peptide hormone cholecystokinin (CCK) in tumors as an adaptive response to obesity. Furthermore, beta cell CCK expression promotes oncogenicKras-driven pancreatic ductal tumorigenesis. Our studies argue that PDAC progression is driven by local obesity-associated changes in the tumor microenvironment – rather than systemic effects – and implicate endocrine-exocrine signaling beyond insulin in PDAC development. Furthermore, our demonstration that these obesity-associated adaptations are reversible supports the use of anti-obesity strategies to intercept PDAC early during progression.
Targeting the Autonomic Nervous System Balance in Patients with Chronic Low Back Pain using Transcranial Alternating Current Stimulation: A Randomized, Crossover, Double-Blind, Placebo-Controlled Pilot Study
Authors: Prim Julianna H. , Ahn Sangtae , Davila Maria I. , Alexander Morgan L. , McCulloch Karen L. , Fröhlich Flavio
Published: June 2019

Background

Chronic low back pain (CLBP) is characterized by an alteration in pain processing by the central nervous system that may affect autonomic nervous system (ANS) balance. Heart rate variability (HRV) reflects the balance of parasympathetic and sympathetic ANS activation. In particular, respiratory sinus arrhythmia (RSA) solely reflects parasympathetic input and is reduced in CLBP patients. Yet, it remains unknown if non-invasive brain stimulation can alter ANS balance in CLBP patients.

Objective

To evaluate if non-invasive brain stimulation modulates the ANS, we analyzed HRV metrics collected in a previously published study of transcranial alternating current stimulation (tACS) for the modulation of CLBP through enhancing alpha oscillations. We hypothesized that tACS would increase RSA.

Methods

A randomized, crossover, double-blind, sham-controlled pilot study was conducted to investigate the effects of 10Hz-tACS on metrics of ANS balance calculated from electrocardiogram (ECG). ECG data were collected for 2 minutes before and after 40 minutes of 10Hz-tACS or sham stimulation.

Results

There were no significant changes in RSA or other frequency-domain HRV components from 10Hz-tACS. However, exploratory time-domain HRV analysis revealed a significant increase in the standard deviation of normal RR intervals (SDNN) for 10Hz-tACS relative to sham.

Conclusion(s)

Although tACS did not significantly increase RSA, we found in an exploratory analysis that tACS modulated an integrated HRV measure of both ANS branches. These findings support the further study of how the ANS and alpha oscillations interact and are modulated by tACS.
Disrupting the Transmembrane Domain Oligomerization of Protein Tyrosine Phosphatase Receptor J Promotes its Activity in Cancer Cells
Authors: Bloch Elizabeth , Sikorski Eden L. , Pontoriero David , Day Evan K. , Berger Bryan W. , Lazzara Matthew J. , Thévenin Damien
Published: June 2019

Despite the critical regulatory roles that receptor protein tyrosine phosphatases (RPTP) play in mammalian signal transduction, the detailed structural basis for the regulation of their catalytic activity is not fully understood, nor are they generally therapeutically targetable. It is due, in part, to the lack of known natural ligands or selective agonists. In contrast to conventional structure-function relationship for receptor tyrosine kinases (RTKs), the activity of RPTPs has been reported to be suppressed by dimerization, which may prevent their access to their RTK substrates. We report here that: (i) homodimerization of PTPRJ (also known as DEP-1) is regulated by specific transmembrane (TM) residues, and (ii) disrupting these interactions can destabilize full-length PTPRJ homodimerization in cells, reduce the phosphorylation of EGFR (a known substrate) and downstream signaling effectors, antagonize EGFR-driven cell phenotypes, and promote substrate access. We demonstrate these points in human cancer cells using both mutational studies and through the identification of a peptide designed to bind to the PTPRJ TM domain. This peptide is the first example of such allosteric agonist of RPTPs. This study, therefore, provides not only fundamental structure-function insights on how PTPRJ activity is tuned by TM interactions in cells but also opportunities to develop a unique class of agents that could be used as tools to probe RPTPs signaling regulating mechanisms or for therapeutic purposes in cancers driven by RTK signaling.
Functional connectivity changes with rapid remission from moderate-to-severe major depressive disorder
Authors: Xiao Xiaoqian , Bentzley Brandon S. , Cole Eleanor J. , Tischler Claudia , Stimpson Katy H. , Duvio Dalton , Bishop James H. , DeSouza Danielle D. , Schatzberg Alan , Keller Corey , Sudheimer Keith D. , Williams Nolan R.
Published: June 2019

Major depressive disorder (MDD) is prevalent and debilitating, and development of improved treatments is limited by insufficient understanding of the neurological changes associated with disease remission. In turn, efforts to elucidate these changes have been challenging due to disease heterogeneity as well as limited effectiveness, delayed onset, and significant off-target effects of treatments. We developed a form of repetitive transcranial magnetic stimulation of the left dorsolateral prefrontal cortex (lDLPFC) that in an open-label study was associated with remission from MDD in 90% of individuals in 1-5 days (Stanford Accelerated Intelligent Neuromodulation Therapy, SAINT). This provides a tool to begin exploring the functional connectivity (FC) changes associated with MDD remission. Resting-state fMRI scans were performed before and after SAINT in 18 participants with moderate-to-severe, treatment-resistant MDD. FC was determined between regions of interest defined a priori by well-described roles in emotion regulation. Following SAINT, FC was significantly decreased between subgenual cingulate cortex (sgACC) and 3 of 4 default mode network (DMN) nodes. Significant reductions in FC were also observed between the following: DLPFC-striatum, DLPFC-amygdala, DMN-amygdala, DMN-striatum, and amygdala-striatum. Greater clinical improvements were correlated with larger decreases in FC between DLPFC-amygdala and DLPFC-insula, as well as smaller decreases in FC between sgACC-DMN. Greater clinical improvements were correlated with lower baseline FC between DMN-DLPFC, DMN-striatum, and DMN-ventrolateral prefrontal cortex. The multiple, significant reductions in FC we observed following SAINT and remission from depression support the hypothesis that MDD is a state of hyper-connectivity within these networks, and rapid decoupling of network nodes may lead to rapid remission from depression.

Significance statement

Major depressive disorder is common and debilitating. It has been difficult to study the brain changes associated with recovery from depression, because treatments take weeks-to-months to become effective, and symptoms fail to resolve in many people. We recently developed a type of magnetic brain stimulation called SAINT. SAINT leads to full remission from depression in 90% of people within 5 days. We used SAINT and functional magnetic resonance imaging to determine how the brain changes with rapid remission from depression. We found changes in areas of the brain associated with emotion regulation. This provides a significantly clearer picture of how the non-depressed brain differs from the depressed brain, which can be used to develop rapid and effective treatments for depression.
Probabilistic Cause-of-disease Assignment using Case-control Diagnostic Tests: A Latent Variable Regression Approach
Authors: Wu Zhenke , Chen Irena
Published: June 2019

Optimal prevention and treatment strategies for a disease of multiple causes, such as pneumonia, must be informed by the population distribution of causes among cases, or cause-specific case fractions (CSCFs). CSCFs may further depend on additional explanatory variables. Existing methodological literature in disease etiology research does not fully address the regression problem, particularly under a case-control design. Based on multivariate binary non-gold-standard diagnostic data and additional covariate information, this paper proposes a novel and unified regression modeling framework for estimating covariate-dependent CSCF functions in case-control disease etiology studies. The model leverages critical control data for valid probabilistic cause assignment for cases.We derive an efficient Markov chain Monte Carlo algorithm for flexible posterior inference. We illustrate the inference of CSCF functions using extensive simulations and show that the proposed model produces less biased estimates and more valid inference of the overall CSCFs than analyses that omit covariates. A regression analysis of pediatric pneumonia data reveals the dependence of CSCFs upon season, age, HIV status and disease severity. The paper concludes with a brief discussion on model extensions that may further enhance the utility of the regression model in disease etiology research.
Class of antiretroviral drugs and anemia risk in the current treatment era
Authors: Harding B.N. , Whitney B.M. , Nance R.M. , Crane H.M. , Burkholder G. , Moore R.D. , Mathews W.C. , Eron J.J. , Hunt P.W. , Volberding P. , Rodriguez B. , Mayer K.H. , Saag M.S. , Kitahata M.M. , Heckbert S.R. , Delaney J.A.C.
Published: June 2019

OBJECTIVES

Anemia is common among people living with HIV (PLWH) and has been associated with certain, often older, antiretroviral medications. Information on current antiretroviral therapy (ART) and anemia is limited. The objectives were to compare associations between anemia incidence or hemoglobin change with core ART classes in the current ART era.

DESIGN

Retrospective cohort study.

SETTING

U.S.-based prospective clinical cohort of PLWH aged 18 and above receiving care at 8 sites between 1/2010-3/2018.

PARTICIPANTS

16,505 PLWH were included in this study.

MAIN OUTCOME MEASURES

Anemia risk and hemoglobin change were measured for person-time on a protease inhibitor (PI) or an integrase strand transfer inhibitor (INSTI), relative to a non-nucleoside reverse transcriptase inhibitor (NNRTI) reference. We also examined PLWH on multiple core classes. Cox proportional hazards regression analyses were conducted to measure associations between time-updated ART classes and incident anemia or severe anemia. Linear mixed effects models were used to examine relationships between ART classes and hemoglobin change.

RESULTS

During a median of 4.9 years of follow-up, 1,040 developed anemia and 488 developed severe anemia during. Compared to NNRTI use, INSTI-based regimens were associated with an increased risk of anemia (adjusted hazard ratio [aHR] 1.17, 95% confidence interval [CI] 0.94-1.47) and severe anemia (aHR1.55 95%CI 1.11-2.17), and a decrease in hemoglobin level. Time on multiple core classes was also associated with increased anemia risk (aHR 1.30, 95%CI 1.06-1.60) and severe anemia risk (aHR 1.35, 95%CI 0.99-1.85), while no associations were found for PI use.

CONCLUSION

These findings suggest INSTI use may increase the risk of anemia. If confirmed, screening for anemia development in users of INSTIs may be beneficial. Further research into underlying mechanisms is warranted.

Strengths and limitations of this study

This study utilized a large and geographically diverse population of PLWH in care across the U.S.

This study leveraged comprehensive clinical data, including information on diagnoses, medication use, laboratory test results, demographic information, and medical history.

This study investigated associations between specific types of ART core regimens and anemia risk.

This observational study is subject to residual confounding.

This study focused on anemia assessed from hemoglobin lab values taken at regular medical care visits without excluding participants with conditions strongly associated with hemoglobin level through non-traditional HIV mechanisms.
Multiple Drug Resistance in the canine hookwormAncylostoma caninum: an Emerging Threat
Authors: Jimenez Castro Pablo D. , Howell Sue , Schaefer John. J. , Avramenko Russell. W. , Gilleard John. S. , Kaplan Ray M.
Published: June 2019

In the past few years, diagnoses by veterinarians of recurrent canine hookworm infections have dramatically increased, suggesting that anthelmintic resistance (AR) may have evolved in the parasiteAncylostoma caninum. To investigate this, we established three “suspected-resistant” and two susceptibleA. caninumisolates in research dogs for further study. The egg hatch assay (EHA) and the larval development assay (LDA) were used for detecting resistance to benzimidazoles, and macrocyclic lactones, respectively. Resistance ratios ranged from 6.0 to >100 and 5.5-69.8 for the EHA and LDA, respectively. Following treatments with fenbendazole, pyrantel and milbemycin oxime, reduction in faecal egg counts ranged from 64–86%, 0–72% and 58–92%, respectively. Deep amplicon sequencing of the isotype-1 β tubulin gene identified a high frequency of resistance-associated single nucleotide polymorphisms at codon 167 in the resistant isolates and clinical cases.. These data conclusively demonstrate multiple anthelmintic resistance inA. caninum, and provide pivotal evidence that this is an emerging problem in the United States. Consequently, these findings should provide some concern to the global health community, as the scale-up of mass drug administration for soil-transmitted helminths (STH) is now placing similar selection pressures for benzimidazole resistance in human hookworms.
Lateral Subunit Coupling Determines Intermediate Filament Mechanics
Authors: Lorenz Charlotta , Forsting Johanna , Schepers Anna V. , Kraxner Julia , Bauch Susanne , Witt Hannes , Klumpp Stefan , Köster Sarah
Published: June 2019

The cytoskeleton is a composite network of three types of protein filaments, among which in-termediate filaments (IFs) are the most extensible ones. Two very important IFs are keratin and vimentin, which have similar molecular architectures, but different mechanical behaviors. Here we compare the mechanical response of single keratin and vimentin filaments using optical tweezers. We show that the mechanics of vimentin strongly depends on the ionic strength of the buffer and that its force-strain curve suggests a high degree of cooperativity between subunits. Indeed, a computational model indicates that in contrast to keratin, vimentin is characterized by strong lateral subunit coupling of its charged monomers during unfolding ofα-helices. We conclude that cells can tune their mechanics by differential use of keratin versus vimentin.
De novoDNA methyltransferase activity in colorectal cancer is directed towards H3K36me3 marked CpG islands
Authors: Ali Masalmeh Roza H. , Rubio-Ramon Cristina , Taglini Francesca , Higham Jonathan , Davidson-Smith Hazel , Clark Richard , Wills Jimi , Finch Andrew J. , Murphy Lee , Sproul Duncan
Published: June 2019

The aberrant gain of DNA methylation at CpG islands (CGIs) is frequently observed in colorectal tumours and may silence the expression of tumour suppressors such asMLH1. Current models propose that these CGIs are targeted byde novoDNA methyltransferases (DNMTs) in a sequence-specific manner but this has not been tested. Using ectopically integrated CGIs, we find that aberrantly methylated CGIs are subject to low levels ofde novoDNMT activity in colorectal cancer cells. By delineating DNMT targets, we find that insteadde novoDNMT activity is targeted primarily to CGIs marked by the histone modification H3K36me3, a mark associated with transcriptional elongation. These H3K36me3 marked CGIs are heavily methylated in colorectal tumours and the normal colon suggesting thatde novoDNMT activity at CGIs in colorectal cancer is focused on similar targets to normal tissues and not greatly remodelled by tumourigenesis.
hunchbackPromoters Can Readout Morphogenetic Positional Information in Less Than a Minute
Authors: Desponds Jonathan , Vergassola Massimo , Walczak Aleksandra M.
Published: June 2019

The first cell fate decisions in the developing fly embryo are made very rapidly:hunchbackgenes decide in a few minutes whether a given nucleus follows the anterior or the posterior developmental blueprint by reading out the positional information encoded in the Bicoid morphogen. This developmental system constitutes a prototypical instance of the broad spectrum of regulatory decision processes that combine speed and accuracy. Traditional arguments based on fixed-time sampling of Bicoid concentration indicate that an accurate readout is not possible within the short times observed experimentally. This raises the general issue of how speed-accuracy tradeoffs are achieved. Here, we compare fixed-time sampling strategies to decisions made on-the-fly, which are based on updating and comparing the likelihoods of being at an anterior or a posterior location. We found that these more efficient schemes can complete reliable cell fate decisions even within the very short embryological timescales. We discuss the influence of promoter architectures on the mean decision time and decision error rate and present concrete promoter architectures that allow for the fast readout of the morphogen. Lastly, we formulate explicit predictions for new experiments involving Bicoid mutants.
Mycobacterial OtsA structures unveil substrate preference mechanism and allosteric regulation by 2-oxoglutarate and 2-phosphoglycerate
Authors: Mendes Vítor , Acebrón-García-de-Eulate Marta , Verma Nupur , Blaszczyk Michal , Dias Márcio V. B. , Blundell Tom L.
Published: June 2019

Trehalose is an essential disaccharide for mycobacteria and a key constituent of several cell wall glycolipids with fundamental roles in pathogenesis. Mycobacteria possess two pathways for trehalose biosynthesis. However, only the OtsAB pathway was found to be essential inM. tuberculosis, with marked growth and virulence defects of OtsA mutants and strict essentiality of OtsB2. Herein, we report the first mycobacterial OtsA structures fromM. thermoresistibilein both apo and ligand-bound forms. Structural information reveals three key residues in the mechanism of substrate preference that were further confirmed by site-directed mutagenesis. Additionally, we identify 2-oxoglutarate and 2-phosphoglycerate as allosteric regulators of OtsA. The structural analysis in this work strongly contributed to define the mechanisms for feedback inhibition, show different conformational states of the enzyme and map a new allosteric site.
Quantifying eco-evolutionary contributions to trait divergence in spatially structured systems
Authors: Govaert Lynn , Pantel Jelena H. , De Meester Luc
Published: June 2019

Ecological and evolutionary processes can occur at similar time scales, and hence influence one another. There has been much progress in the development of metrics that quantify contributions of ecological and evolutionary components to trait change over time. However, many empirical evolutionary ecology studies document genetic differentiation among populations structured in space. In both time and space, the observed differentiation in trait values among populations and communities can be the result of interactions between non-evolutionary (phenotypic plasticity, changes in the relative abundance of species) and evolutionary (genetic differentiation among populations) processes. However, the tools developed so far to quantify ecological and evolutionary contributions to trait change are implicitly addressing temporal dynamics because they require directionality of change from an ancestral to a derived state. Identifying directionality from one site to another in spatial studies of eco-evolutionary dynamics is not always possible and often not desired. We here suggest three modifications to existing metrics so they allow the partitioning of ecological and evolutionary contributions to changes in population and community trait values across landscapes. Applying these spatially modified metrics to published empirical examples shows how these metrics can be used to generate new empirical insights and to facilitate future comparative analyses. The possibility to apply eco-evolutionary partitioning metrics to populations and communities in real landscapes is critical as it will broaden our capacity to quantify eco-evolutionary interactions as they occur in nature.
Architecture and modular assembly ofSulfolobusS-layers revealed by electron cryo-tomography
Authors: Gambelli Lavinia , Meyer Benjamin , McLaren Mathew , Sanders Kelly , Quax Tessa E.F. , Gold Vicki , Albers Sonja-Verena , Daum Bertram
Published: June 2019

Surface protein layers (S-layers) often form the only structural component of the archaeal cell wall and are therefore important for cell survival. S-layers have a plethora of cellular functions including maintenance of cell shape, osmotic and mechanical stability, the formation of a semi-permeable protective barrier around the cell, cell-cell interaction, as well as surface adhesion. Despite the central importance of the S-layer for archaeal life, their three-dimensional architecture is still poorly understood. Here we present the first detailed 3D electron cryo-microscopy maps of archaeal S-layers from three differentSulfolobusstrains. We were able to pinpoint the positions and determine the structure of the two subunits SlaA and SlaB. We also present a model describing the assembly of the mature S-layer.
Intramolecular Communication and Allosteric Sites in Enzymes Unraveled by Time-Dependent Linear Response Theory
Authors: Huang Bang-Chieh , Cheng Yi-Yun , Chang-Chein Chi-Hong , Yao Chao-Ling , Yang Lee-Wei
Published: June 2019

It has been an established idea in recent years that protein is a physiochemically connected network. Allostery, understood in this new context, is a manifestation of residue communicating between remote sites in this network, and hence a rising interest to identify functionally relevant communication pathways and the frequent communicators within. However, there have been limited computationally trackable general methods to discover proteins' allosteric sites in atomistic resolution with good accuracy. In this study, we devised a time-dependent linear response theory (td-LRT) integrating intrinsic protein dynamics and perturbation forces that excite protein's temporary reconfiguration at the non-equilibrium state, to describe atom-specific time responses as the propagating mechanical signals and discover that the most frequent remote communicators can be important allosteric sites, mutation of which could deteriorate the hydride transfer rate in DHFR by 3 orders. The preferred directionality of the signal propagation can be inferred from the asymmetric connection matrix (CM), where the coupling strength between a pair of residues is suggested by their communication score (CS) in the CM, which is found consistent with experimentally characterized nonadditivity of double mutants. Also, the intramolecular communication centers (ICCs), having high CSs, are found evolutionarily conserved, suggesting their biological importance. We also identify spatially clustered top ICCs as the newly found allosteric site in ATG4B. Among 2016 FDA-approved drugs screened to target the site, two interacting with the site most favorably, confirmed by MD simulations, are found to inhibit ATG4B biochemically and be tumor suppressive in colorectal, pancreatic and breast cancer cell lines with an observed additive therapeutic effect when co-used with an active-site inhibitor.