bluuebunny/crossref_metadata_2025 huggingface dataset:
Quality of Life in Patients With Breast Cancer
Authors: An Yuanyuan , Fu Gan , Yuan Guangzhe
Published: September 2019

Previous research showed that family caregiver's perception of burden can influence patient's report on their quality of life (QoL). The present study investigated the relationship between the two variables by considering the role of patient's anxiety and depression. A total of 382 dyads of Chinese breast cancer patients and their family caregivers participated in this study. The results showed that the mediation model fitted the data well (χ2= 49.859;df= 16; χ2/df= 3.116; RMSEA = 0.05; TLI = 0.928; CFI = 0.959). It indicated that family caregiver's burden influenced patient's QoL negatively, and this relationship was partially mediated by patient's anxiety and depression.
Doctor-Diagnosed Arthritis and Self-Reported Physical Health Function Among Middle-Aged and Older Adults With Serious Mental Illness
Authors: Brooks Jessica M. , Umucu Emre , Sánchez Jennifer , Seehusen Carol , Fortuna Karen L. , Chiu Chungyi , Bartels Stephen J.
Published: September 2019

Arthritis is one of the most common chronic conditions in aging adults, with both physical and mental health issues and consequences. However, there is insufficient arthritis research among aging adults with serious mental illness (SMI). This study examined rates of doctor-diagnosed arthritis and its cross-sectional associations with self-reported physical health function among adults aged 50 years and older with SMI. Community-based mental health center participants (n= 176) reported clinical and sociodemographic data (e.g., physical health function, sex), whereas diagnostic information (i.e., arthritis, psychiatric, and medical diagnoses) was retrieved from medical records. Arthritis prevalence was high (43.8%) and had an independent, negative association with physical health function. Findings suggest that arthritis evaluations and intervention services need to be prioritized in middle-aged and older adults with SMI. Future research should focus on further testing arthritis self-management programs and other nonpharmacological psychosocial approaches for arthritis in aging adults with SMI.
Interindividual Balance Adaptations in Response to Perturbation Treadmill Training in Persons With Parkinson Disease
Authors: Klamroth Sarah , Gaßner Heiko , Winkler Jürgen , Eskofier Björn , Klucken Jochen , Pfeifer Klaus , Steib Simon
Published: September 2019

Background and Purpose:

Perturbation training is a promising approach to reduce fall incidence in persons with Parkinson disease (PwPD). This study aimed to evaluate interindividual differences in balance adaptations in response to perturbation treadmill training (PTT) and identify potential outcome predictors.

Methods:

PwPD (n = 43, Hoehn & Yahr stage 1-3.5) were randomly assigned to either 8 weeks of PTT or conventional treadmill training (CTT) without perturbations. At baseline and following intervention, data from 4 domains of balance function (reactive, anticipatory, dynamic postural control, and quiet stance) were collected. Using responder analysis we investigated interindividual differences (responder rates and magnitude of change) and potential predictive factors.

Results:

PTT showed a significantly higher responder rate in the Mini Balance Evaluation Systems Test (Mini-BESTest) subscore reactive postural control, compared with CTT (PTT = 44%; CTT = 10%; risk ratio = 4.22, confidence interval = 1.03-17.28). Additionally, while between-groups differences were not significant, the proportion of responders in the measures of dynamic postural control was higher for PTT compared with CTT (PTT: 22%-39%; CTT: 5%-10%). The magnitude of change in responders and nonresponders was similar in both groups. PTT responders showed significantly lower initial balance performance (4/8 measures) and cognitive function (3/8 measures), and were older and at a more advanced disease stage, based on descriptive evaluation.

Discussion and Conclusions:

Our findings suggest that PTT is beneficial to improve reactive balance in PwPD. Further, PTT appeared to be effective only for a part of PwPD, especially for those with lower balance and cognitive function, which needs further attention.

Video Abstract available for more insights from the authors (see the Video, Supplemental Digital Content 1, http://links.lww.com/JNPT/A1).
Transgender Women Have Higher Human Papillomavirus Prevalence Than Men Who Have Sex With Men—Two U.S. Cities, 2012–2014
Authors: Singh Vidisha , Gratzer Beau , Gorbach Pamina M. , Crosby Richard A. , Panicker Gitika , Steinau Martin , Amiling Raiza , Unger Elizabeth R. , Markowitz Lauri E. , Meites Elissa
Published: September 2019

Background

Human papillomavirus (HPV) prevalence is high among men who have sex with men (MSM), yet little is known about HPV among transgender women (TGW). We assessed HPV prevalence and knowledge among TGW compared with MSM.

Methods

We enrolled TGW and MSM aged 18 to 26 years from clinics in Chicago and Los Angeles during 2012 to 2014. Participants self-reported gender identity, HIV status, HPV knowledge, and vaccination status. Self-collected anal and oral specimens were tested for HPV DNA (37 types); serum was tested for HPV antibodies (4 vaccine types). Prevalence among unvaccinated TGW and MSM was compared using prevalence ratios (PRs) and 95% confidence intervals (CIs). Participants without DNA or serologic evidence of HPV were considered naïve.

Results

Among 1033 participants, 49 were TGW. Among 44 TGW and 855 MSM who were unvaccinated, any HPV DNA was detected in anal specimens from 39 (88.6%) TGW and 606 (70.9%) MSM (PR, 1.3; 95% CI, 1.1–1.4), and oral specimens from 4 (9.1%) TGW and 81 (9.5%) MSM (PR, 1.0; 95% CI, 0.4–2.5). Antibodies were detected among 37 (84.1%) TGW and 467 (54.6%) MSM (PR, 1.5; 95% CI, 1.3–1.8). Most participants were naïve to 1 or more HPV vaccine type/s, including 29 (65.9%) TGW and 775 (90.6%) MSM (PR, 0.7; 95% CI, 0.6–0.9). Most TGW (55.1%) had never heard of HPV vaccine.

Conclusions

Among TGW, HPV prevalence was high and knowledge was low. Most were still naïve to 1 or more HPV vaccine type. Although vaccination ideally occurs prior to exposure, findings support existing national recommendations to vaccinate TGW and MSM, and suggest additional outreach might increase vaccination.
A Co-Located Continuity Clinic Model to Address Healthcare Needs of Women Living Unhoused With Opioid Use Disorder, Who Engage in Transactional Sex in North Seattle
Authors: Stewart Jenell , Stadeli Kathryn M. , Green Margaret L. , Etter-Carlson Lisa , Dahl Elizabeth , Davidson Giana H. , Golden Matthew , Dhanireddy Shireesha
Published: September 2019

This is a review of the first 50 patients attending a colocated continuity clinic with harm reduction services to women experiencing homelessness in north Seattle. Among those tested, patients had high rates of curable sexually transmitted infections (44%), injection opioid use (36%), transactional sex (69%), unintended pregnancy (10%), and human immunodeficiency virus infections (10%).
Oropharyngeal and Genital Gonorrhea Infections Among Women and Heterosexual Men Reporting Sexual Contact With Partners With Gonorrhea: Implication for Oropharyngeal Testing of Heterosexual Gonorrhea Contacts
Authors: Chow Eric P.F. , Chen Marcus Y. , Williamson Deborah A. , Bradshaw Catriona S. , Vodstrcil Lenka A. , Trumpour Sabrina , Howden Benjamin P. , Fairley Christopher K.
Published: September 2019

Background

There have been very limited studies of oropharyngeal gonorrhea in heterosexuals. Routine screening of oropharyngeal gonorrhea is not recommended in heterosexual contacts of gonorrhea. This study aimed to examine oropharyngeal gonorrhea positivity among heterosexuals reporting contact with a partner with gonorrhea.

Methods

At the Melbourne Sexual Health Centre (MSHC), all heterosexual individuals reporting contact with sexual partners with gonorrhea are tested for genital gonorrhea. In May 2017, MSHC also included screening for oropharyngeal gonorrhea in heterosexual contacts of gonorrhea. All contacts of gonorrhea among women and heterosexual men between May 2017 and November 2018 were reviewed. Site-specific gonorrhea positivity was also calculated.

Results

One hundred ninety-one gonorrhea contacts (102 heterosexual men and 89 women) were reviewed. The median age was 28 (interquartile range, 24–33) years. The gonorrhea positivity in males was significantly higher at the oropharynx compared with urethra (18%; 95% confidence interval [CI], 11% to 26% vs 2%; 95% CI, 0% to 7%; P < 0.001); and higher at the oropharynx compared with cervicovaginal site in women (46%; 95% CI, 35% to 57% vs 36%; 95% CI, 26% to 47%; P = 0.056). Of the 100 men who did not have genital gonorrhea, 17 (18%; 95% CI, 10% to 26%) tested positive at the oropharynx. Of the 55 women who did not have genital gonorrhea, 21 (24%; 95% CI, 15% to 34%) tested positive at the oropharynx. Infection at both the oropharynx and genital sites was not associated with sex worker status in women. Overall, 89% and 40% of gonorrhea in heterosexual men and women were only in the oropharynx, respectively.

Conclusions

Oropharyngeal gonorrhea testing among heterosexual contacts of gonorrhea may be indicated given a substantial proportion of gonorrhea contacts are only infected at this site.
Bleeding and Thrombosis With Pediatric Extracorporeal Life Support: A Roadmap for Management, Research, and the Future From the Pediatric Cardiac Intensive Care Society: Part 2*
Authors: Penk Jamie S. , Reddy Sushma , Polito Angelo , Cisco Michael J. , Allan Catherine K. , Bembea Melania , Giglia Therese M. , Cheng Henry H. , Thiagarajan Ravi R. , Dalton Heidi J.
Published: September 2019

Objectives:

To make recommendations on improving understanding of bleeding and thrombosis with pediatric extracorporeal life support including future research directions.

Data Sources:

Evaluation of literature and consensus conferences of pediatric critical care and extracorporeal life support experts.

Study Selection:

A team of 10 experts with pediatric cardiac and extracorporeal membrane oxygenation experience and expertise met through the Pediatric Cardiac Intensive Care Society to review current knowledge and make recommendations for future research to establish “best practice” for anticoagulation management related to extracorporeal life support.

Data Extraction/Data Synthesis:

This white paper focuses on clinical understanding and limitations of current strategies to monitor anticoagulation. For each test of anticoagulation, limitations of current knowledge are addressed and future research directions suggested.

Conclusions:

No consensus on best practice for anticoagulation monitoring exists. Structured scientific evaluation to answer questions regarding anticoagulation monitoring and bleeding and thrombotic events should occur in multicenter studies using standardized approaches and well-defined endpoints. Outcomes related to need for component change, blood product administration, healthcare outcome, and economic assessment should be incorporated into studies. All centers should report data on patient receiving extracorporeal life support to a registry.
Clinicopathologic Association and Prognostic Value of MELF Pattern in Invasive Endocervical Adenocarcinoma (ECA) as Classified by IECC
Authors: Segura Sheila E. , Hoang Lien , Boros Monica , Terinte Cristina , Pesci Anna , Aviel-Ronen Sarit , Kiyokawa Takako , Alvarado-Cabrero Isabel , Oliva Esther , Park Kay J. , Soslow Robert A. , Stolnicu Simona
Published: September 2019

Microcystic, elongated, and fragmented (MELF) pattern of myometrial invasion is correlated with lymphovascular invasion (LVI) and lymph node metastases in uterine endometrioid carcinoma but has not been described in endocervical adenocarcinoma (ECA). A total of 457 ECAs were collected, and clinical/morphologic parameters correlated with follow-up data. Potential associations between MELF pattern and age, human papillomavirus status, tumor size/grade, LVI, lymph node metastases, Silva pattern were analyzed. Statistical analyses of overall survival (OS), disease-free survival, progression-free survival (PFS) were conducted using Kaplan-Meier analysis, and compared using the Log-rank test. Of 292 ECAs analyzed, 94 (32.19%) showed MELF invasion pattern (MELF-positive). Significant statistical correlation was found between MELF-positive and tumor size (P=0.0017), LVI (P=0.007), Silva pattern (P=0.0005); age, human papillomavirus status, tumor grade, lymph node metastases did not correlate. Fifty-five of 292 patients recurred (18.83%): 18/94 (19.14%) MELF-positive, 37/198 (18.68%) MELF-negative. PFS in MELF-positive: 77.2% and 64.5% at 5 and 10 yr, respectively; PFS in MELF-negative: 82% and 68.5% at 5 and 10 yr, respectively. On multivariate analysis for PFS and other prognostic parameters, only LVI was statistically significant (P=0.001). OS in MELF-positive was 86% and 74.1% at 5 and 10 yr, respectively; OS in MELF-negative, was 89.7% and 86% at 5 and 10 yr, respectively. Median survival was worse in MELF-positive (199.8 mo) versus MELF-negative (226.1 mo); this was not statistically significant. On multivariate analysis for OS and other prognostic parameters, only tumor stage was statistically significant (P=0.002). In ECAs, MELF is not independently associated with survival. Pathologic characteristics of MELF-positive (size, LVI, Silva pattern) versus MELF-negative tumors differ significantly.
Relationship Between Shear Wave Elastography Findings and Histologic Prognostic Factors of Invasive Breast Cancer
Authors: Gemici Aysegul Akdogan , Ozal Safiye Tokgoz , Hocaoglu Elif , Inci Ercan
Published: September 2019

Objective

Shear wave elastography (SWE) is an adjunct to grayscale ultrasound examinations for evaluating breast masses. This study aimed to determine the SWE features that correlated with prognostic parameters for breast cancer.

Methods

Between January 2018 and May 2018, 80 patients who were confirmed to have invasive cancers by core-needle biopsy and who were scheduled for surgery were imaged using B-mode ultrasound and SWE. Measurements were taken from a region of interest positioned over the stiffest part of the peripheral zone and mass. Three measurements were taken, and the average of the mean stiffness value was used for analysis.

Results

The mean tumor size, elasticity value of tumors, and elasticity of the peripheral zone were 2.9 ± 1.48 cm (range, 0.6–8 cm), 154.8 ± 8.55 kPa (range, 116.25–179 kPa), and 171.34 ± 5.22 kPa (range, 150.95–182.43 kPa), respectively. The types of breast cancer included were invasive ductal carcinoma (n = 71 [88.75%]; 69 invasive ductal carcinoma not otherwise specified, 1 solid papillary carcinoma, and 1 invasive micropapillary carcinoma), invasive lobular carcinoma (n = 2 [2.5%]), mixed invasive ductal and lobular carcinoma (n = 4 [5%]), mucinous carcinoma (n = 2 [2.5%]), and metaplastic cancer (n = 1 [1.25%]). A strong correlation was found between mean elasticity values and tumor grade (P= 0.018) and between mean elasticity values and lymphovascular invasion (LVI) positivity (P= 0.008). There were no significant differences between SWE values and tumor diameter or between histological tumor characteristics and SWE.

Conclusions

We found that some clinicohistopathologic features of poor prognosis had higher elasticity values than those of favorable prognosis.
Coagulation System Disorders and Thrombosis Prophylaxis During Laparoscopic Fundoplications
Authors: Zostautiene Indre , Skrodeniene Erika , Vitkauskiene Astra , Zviniene Kristina , Mickevicius Antanas , Gerbutavicius Rolandas , Gerbutaviciene Rima , Kiudelis Mindaugas
Published: September 2019

Background:

The aim of this study was to assess and recommend the optimal deep vein thrombosis (DVT) prophylaxis regimen during and after laparoscopic fundoplication according to the blood coagulation disorders and the rate of DVT in 2 patient groups, receiving different DVT prophylaxis regimens.

Materials and Methods:

This was a prospective randomized, single-center clinical study. The study population, 121 patients, were divided into 2 groups: group I received low–molecular-weight heparin 12 hours before the operation; group II received low–molecular-weight heparin only 1 hour before the laparoscopic fundoplication. Both groups received intermittent pneumatic compression during the entire procedure. Bilateral Doppler ultrasound to exclude DVT was performed before the surgery. Venous phase computed tomographic images were acquired from the ankle to the iliac tubercles on the third postoperative day to determine the presence and location of DVT. Hypercoagulation state was assessed by measuring the prothrombin fragment F1+2 (F1+2), the thrombin-antithrombin complex (TAT), and tissue factor microparticles activity (MP-TF) in plasma. The hypocoagulation effect was evaluated by measuring plasma free tissue factor pathway inhibitor (fTFPI).

Results:

F1+2, TAT, and MP-TF indexes increased significantly, whereas fTFPI levels decreased significantly during and after laparoscopic fundoplication, when molecular-weight heparin was administered 12 hours before the operation. Computed tomography venography revealed peroneal vein thrombosis in 2 group I patients on the third postoperative day. Total postsurgical DVT frequency was 1.65%: 3.6% in group I, with no DVT in group II.

Conclusion:

Molecular-weight heparin and intraoperative intermittent pneumatic compression controls the hypercoagulation effect more efficiently when it is administered 1 hour before surgery: it causes significant reduction of F1+2, TAT, and MP-TF indexes and significant increases of fTFPI levels during and after laparoscopic fundoplication.
Impact of Menopausal Status on Uropathogen Prevalence and Antimicrobial Resistance Profiles
Authors: Venuti Kristen , Cabrera Camila , Burkett Linda S. , Bradley Megan S.
Published: September 2019

Objectives

The unique factors associated with urinary tract infections (UTIs) in postmenopausal (PMP) women have been significantly less investigated as compared with premenopausal (PreMP) women. Our objective was to compare the prevalence of uropathogens and antibiotic resistance patterns between PreMP and PMP women with UTIs.

Methods

This was a cross-sectional analysis of PreMP and PMP women treated for a UTI in a urogynecologic practice between November 2016 and November 2017. Diagnostic criteria for UTI included lower urinary tract symptoms and a positive urine culture. Our primary outcome was proportion of non–Escherichia coli UTIs between groups.

Results

We had 370 women with mean (SD) age of 66.7 (12.8) years and body mass index of 29.1 (7.1) kg/m2. Most women were PMP (88.6%). Postmenopausal status did not increase the proportion of non–E. coli UTI (42.7% PMP vs 33.3% PreMP, P = 0.25) or decrease the proportion of pansensitive UTI (36.0% PMP vs 42.9% PreMP, P = 0.38).

In multivariable analysis, women with a history of rUTI were at higher odds of having a non–E. coli UTI (adjusted odds ratio, 1.93; 95% confidence interval, 1.21–3.08; P = 0.01) and at lower odds of pansensitive urine culture (adjusted odds ratio, 0.37; 95% confidence interval, 0.22–0.63; P < 0.01) as compared with those without rUTI, when controlling for confounders. Postmenopausal women with a history of rUTI had the highest proportion of non–E. coli UTIs (51.1%, P < 0.01) and lowest proportion of pansensitive uropathogens (29.1%, P < 0.01) as compared with other PMP women and PreMP without a history of rUTI.

Conclusions

In a urogynecologic population, a history of rUTI, more than menopausal status, significantly impacted the prevalence of specific uropathogens and resistant organisms.
Impact of Donor Hepatitis C Virus on Kidney Transplant Outcomes for Hepatitis C-positive Recipients in the Direct-acting Antiviral Era: Time to Revise the Kidney Donor Risk Index?
Authors: Cannon Robert M. , Locke Jayme E. , Orandi Babak J. , Anderson Douglas J. , Davis Eric G. , Mackelaite Lina , Dave Hitarth , Eng Mary , Jones Christopher M.
Published: September 2019

Background.

Kidneys from donors with hepatitis C virus (HCV) infection are traditionally considered to be at risk for poorer survival outcomes, as reflected in the kidney donor profile index (KDPI). Modern direct-acting antivirals may modify this risk.

Methods.

Using United Network for Organ Sharing data, HCV-infected adult first-time kidney transplant recipients from 2014 to 2017 were examined. Graft and patient survival were compared in a propensity-matched cohort of recipients of HCV antibody (Ab)(+) kidneys versus Ab(-) kidneys. Subsequent analysis was performed in a propensity-matched cohort of recipients of HCV-viremic (RNA positive) versus HCV-naïve kidneys.

Results.

There were 379 recipients each in the matched cohort of recipients of HCV Ab(+) versus HCV Ab(-) kidneys. Despite a higher KDPI (58.2% for HCV Ab[+] versus 38.8% for HCV Ab[-]), 1-year patient and graft survival were similar in the HCV(+) and HCV(-) groups (95.4% and 94.9% versus 97.9% and 96.0%, P = 0.543 and P = 0.834, respectively). There were 200 recipients each in the cohort of recipients of HCV-viremic versus HCV-naïve kidneys, with the KDPI again higher in the HCV-viremic group (56.8% versus 35.2%). Baseline hazard ratios (HRs) for graft failure (HR, 4.69; P = 0.009) and death (HR, 7.60; P = 0.003) were significantly elevated in the viremic group, but crossed 1 at 21 and 24 months, respectively.

Conclusions.

In the modern direct-acting antiviral era, calculated likely KDPI overestimates risk kidneys from HCV (+) donors. Donor viremia conveys an early risk which appears to subside over time. These results suggest that it may be time to revise the kidney donor risk index.
A Comprehensive Review of Outcome Predictors in Low MELD Patients
Authors: Mazumder Nikhilesh R. , Atiemo Kofi , Kappus Matthew , Cullaro Giuseppe , Harinstein Matthew E. , Ladner Daniela , Verna Elizabeth , Lai Jennifer , Levitsky Josh
Published: September 2019

Risk scoring for patients with cirrhosis has evolved greatly over the past several decades. However, patients with low Model for End-Stage Liver Disease–Sodium scores still suffer from liver-related morbidity and mortality. Unfortunately, it is not clear which of these low Model for End-Stage Liver Disease–Sodium score patients would benefit from earlier consideration of liver transplantation. This article reviews the literature of risk prediction in patients with cirrhosis, identifies which patients may benefit from earlier interventions, such as transplantation, and proposes directions for future research.
Clinical Relevance of Arteriolar C4d Staining in Patients With Chronic-active Antibody-mediated Rejection: A Pilot Study
Authors: Snijders Malou L.H. , Sablik Kasia A. , van den Bosch Thierry P.P. , Hesselink Dennis A. , Betjes Michiel G.H. , Batal Ibrahim , Clahsen-van Groningen Marian C.
Published: September 2019

Background.

C4d staining in peritubular capillaries is a well-established feature of antibody-mediated rejection (AMR). The relevance of C4d staining outside peritubular capillaries is not well understood. We investigated the significance of arteriolar C4d staining in chronic-active AMR (c-aAMR).

Methods.

All for-cause renal allograft biopsies performed in 2007–2014 at the Erasmus MC and meeting the criteria for suspicious/diagnostic c-aAMR using the Banff Classification 2015 were included. For comparison, renal allograft biopsies from a matched control group and native renal biopsies were analyzed. Arteriolar C4d staining was semiquantitatively scored as negative (0), small deposits in 1 arteriole (1+), small/large deposits in >1 arterioles (2+), or at least extensive deposits in most arterioles (3+).

Results.

Thirty-four of 40 (85%) patients with c-aAMR showed arteriolar C4d staining. A significant difference in arteriolar C4d score was observed between cases and matched controls (P = 0.01) and a trend toward significance difference between cases and native renal biopsies (P = 0.05). In the cases, arteriolar C4d staining was significantly associated with severity of arteriolar hyalinosis (P = 0.004) and ≥2 arteriolar C4d staining was independently associated with better graft outcome in a multivariate Cox regression analysis (hazard ratio, 0.260; 95% CI, 0.104-0.650; P = 0.004).

Conclusions.

This pilot study shows that arteriolar C4d staining is more common in biopsies with c-aAMR compared with those without and that it is associated with arteriolar hyalinosis and ≥2 arteriolar C4d staining is associated with superior graft outcome. However, larger studies are needed to examine these findings in more detail to asses if arteriolar C4d staining is truly related to antibody-mediated injury.
Psychoeducational Interventions for Adults With Level 3 Autism Spectrum Disorder: A 50-Year Systematic Review
Authors: Davis Katie S. , Kennedy Sandra A. , Dallavecchia Alessandra , Skolasky Richard L. , Gordon Barry
Published: September 2019

There is face validity to the expectation that adults with level 3 autism spectrum disorder (ASD–3) will benefit from a range of psychoeducational interventions. This paper reviews the empirical evidence supporting the effectiveness of these interventions, many of which are currently used in clinical settings. We reviewed 56 peer-reviewed studies of psychoeducational interventions for adults with ASD–3, written in English and since 1968, that met our criteria. The reviewing team included educators, clinicians, researchers, and a biostatistician. The available literature was limited, and most, if not all, of the studies presented some significant methodological limitations. When using Cochrane’s criteria to assess seven key outcome domains—activities of daily living, aggressive/destructive behaviors, emotional functioning, language/communication skills, self-injurious behaviors, stereotypy/mannerisms, and vocational skills—we found only moderately reliable evidence to support the effectiveness of interventions designed to improve emotional functioning in adults with ASD–3. The reliability of evidence relevant to the six other outcome domains was rated as low or very low. Based on this review, we suggest directions for future study of interventions for adults with ASD–3, including topics, subpopulations, and approaches that should be explored. We also propose some crucial changes in how future studies regarding this population should be designed, analyzed, and documented, while balancing clinical considerations with scientific/educational utility.
Relationship Between mTOR Signaling Activation and Postoperative Neurocognitive Disorder in Aged Rats
Authors: Wang Bin , Dong Rui , Lin Xu , Sun Xiaopeng , Chen Huailong , Zhou Jiahui , Li Xiaoxiao , Wang Mingshan , Bi Yanlin
Published: September 2019

Background:

Although incidence rates of postoperative neurocognitive disorder (PND) in aged individuals following noncardiac major surgery are rising as individuals are living longer, the mechanism of PND remains poorly understood. We wondered if mammalian target of rapamycin (mTOR) signaling might be associated with PND since mTOR controls some essential intracellular events.

Objective:

To investigate whether surgery activates the mTOR signaling pathway in aged rats, leading to PND, and whether the mTOR inhibitor, rapamycin, can be used to alleviate PND.

Methods:

We randomly assigned aged rats to four groups: normal control (C), isoflurane (I), surgery (S), and rapamycin (R). Then, we anesthetized Groups I, S, and R, following which, Groups S and R underwent a splenectomy. After surgery, Group R was administered rapamycin. We used the Morris water maze to test the rats’ spatial learning and memory after surgery.

Results:

In Group S, escape latency (ie, the time to find the platform) was markedly higher, and the ratio of swimming time in the target quadrant was lower, compared to the other groups. In Group R, escape latency was markedly lower as compared with Group S, and the ratio of swimming time in the target quadrant was higher.

Conclusions:

Our results indicate that an altered mTOR signaling pathway after a splenectomy causes PND in aged rats, which can be alleviated by rapamycin.
Alcohol use and cognitive functioning in young adults: improving causal inference
Authors: Mahedy Liam , Suddell Steph , Skirrow Caroline , Fernandes Gwen S. , Field Matt , Heron Jon , Hickman Matthew , Wootton Robyn , Munafò Marcus R.
Published: September 2019

Background and Aims

There have been few longitudinal studies of association between alcohol use and cognitive functioning in young people. We aimed to examine whether alcohol use is a causal risk factor for deficient cognitive functioning in young adults.

Design

Linear regression was used to examine the relationship between longitudinal latent class patterns of binge drinking and subsequent cognitive functioning. Two-sample Mendelian randomisation (MR) tested evidence for the causal relationship between alcohol use and cognitive functioning.

Setting

South West England.

Participants

The observational study included 3,155 adolescents and their parents (fully adjusted models) from the Avon Longitudinal Study of Parents and Children (ALSPAC). Genetic instruments for alcohol use were based on almost 1,000,000 individuals from the GWAS & Sequencing Consortium of Alcohol and Nicotine use (GSCAN). Genome-wide association studies for cognitive outcomes were based on 2,500 individuals from ALSPAC.

Measurements

Binge drinking was assessed at approximately 16, 17, 18, 21, and 23 years. Cognitive functioning comprised working memory, response inhibition, and emotion recognition assessed at 24 years of age. Ninety-nine independent genome-wide significant SNPs associated with ‘number of drinks per week’ were used as the genetic instrument for alcohol consumption. Potential confounders were included in the observational analyses.

Findings

Four binge drinking classes were identified: ‘low-risk’ (41%), ‘early-onset monthly’ (19%), ‘adult frequent’ (23%), and ‘early-onset frequent’ (17%). The association between early-onset frequent binge drinking and cognitive functioning: working memory (b=0.09, 95%CI=-0.10 to 0.28), response inhibition (b=0.70, 95%CI=-10.55 to 11.95), and emotion recognition (b=0.01, 95%CI=-0.01 to 0.02) in comparison to low-risk drinkers were inconclusive as to whether a difference was present. Two-sample MR analyses similarly provided little evidence that alcohol use is associated with deficits in working memory using the inverse variance weight (b=0.29, 95%CI=-0.42 to 0.99), response inhibition (b=-0.32, 95%CI=-1.04 to 0.39), and emotion recognition (b=0.03, 95%CI=-0.55 to 0.61).

Conclusions

Binge drinking in adolescence and early adulthood may not be causally related to deficiencies in working memory, response inhibition, or emotion recognition in youths.
Inferring the role of the microbiome on survival in patients treated with immune checkpoint inhibitors: causal modeling, timing, and classes of concomitant medications
Authors: Spakowicz Daniel , Hoyd Rebecca , Muniak Mitchell , Husain Marium , Bassett James S. , Wang Lei , Tinoco Gabriel , Patel Sandip H. , Burkart Jarred , Miah Abdul , Li Mingjia , Johns Andrew , Grogan Madison , Carbone David P. , Verschraegen Claire F. , Kendra Kari L. , Otterson Gregory A. , Li Lang , Presley Carolyn J. , Owen Dwight H.
Published: September 2019

The microbiome has been shown to affect the response to Immune Checkpoint Inhibitors (ICIs) in a small number of cancers. Here, we sought to more broadly survey cancers to identify those in which the microbiome will play a role using retrospective analyses. We created a causal model for the relationship between medications, the microbiome and ICI response and used it to guide the abstraction of electronic health records of 690 patients who received ICI therapy for advanced cancer. Medications associated with changes to the microbiome including antibiotics, corticosteroids, proton pump inhibitors, histamine receptor blockers, non-steroid anti-inflammatories and statins were abstracted. We tested the effect of medication timing on overall survival (OS) and evaluated the robustness of medication effects in each cancer. Finally, we compared the size of the effect observed for antibiotics classes to taxa correlated with ICI response and a literature review of culture-based antibiotic susceptibilities. Of the medications assessed, only antibiotics and corticosteroids significantly associated with lower OS. The hazard ratios (HRs) for antibiotics and corticosteroids were highest near the start of ICI treatment but remained significant when given prior to ICI. Antibiotics and corticosteroids remained significantly associated with OS even when controlling for multiple factors such as Eastern Cooperative Oncology Group performance status, Charlson Comorbidity Index score, and stage. When grouping antibiotics by class, β-lactams showed the strongest association with OS across all tested cancers. The timing and strength of these effects after controlling for confounding factors are consistent with role for the microbiome in response to ICIs.
Multifocal breast cancers are more prevalent inBRCA2versusBRCA1mutation carriers
Authors: McCrorie Alan D , Ashfield Susannah , Begley Aislinn , Mcilmunn Colin , Morrison Patrick J. , Boyd Clinton , Eccles Bryony , Greville-Heygate Stephanie , Copson Ellen R , Cutress Ramsey I. , Eccles Diana M , Savage Kienan I. , McIntosh Stuart A
Published: September 2019

Multifocal/multicentric breast cancer is generally considered to be where two or more breast tumours are present within the same breast, and is seen in ∼10% of breast cancer cases. This study investigates the prevalence of multifocality/multicentricity in a cohort ofBRCA1/2mutation carriers with breast cancer from Northern Ireland via cross-sectional analysis. Data from 211 women withBRCA1/2mutations (BRCA1- 91), (BRCA2- 120), with breast cancer were collected including age, tumour focality, size, type, grade, and receptor profile. The prevalence of multifocality/multicentricity within this group was 25%, but within subgroups, prevalence amongstBRCA2carriers was more than double that ofBRCA1carriers (p=0.001). Women affected by multifocal/multicentric tumours had proportionately higher oestrogen receptor positivity (p=0.001) and lower triple negativity (p=0.004). These observations are likely to be driven by the higher BRCA2 mutation prevalence observed within this cohort. Odds of aBRCA2carrier developing multifocal/multicentric cancer were almost four-fold higher than aBRCA1carrier (OR: 3.71, CI: 1.77-7.78, p=0.001). These findings were subsequently validated in a second, large independent cohort of patients withBRCA-associated breast cancers from a UK-wide multicentre study. This confirmed a significantly higher prevalence of multifocal/multicentric tumours amongstBRCA2mutation carriers compared withBRCA1mutation carriers. This has important implications for clinicians involved in the treatment of BRCA2-associated breast cancer, both in the diagnostic process, in ensuring that tumour focality is adequately assessed to facilitate treatment decision-making, and for breast surgeons, particularly if breast conserving surgery is being considered as a treatment option for these patients.
Village-scale persistence and elimination of gambiense human African trypanosomiasis
Authors: Davis Christopher N. , Rock Kat S. , Miaka Erick Mwamba , Keeling Matt J.
Published: September 2019

Gambiense human African trypanosomiasis (gHAT) is one of several neglected tropical diseases that is targeted for elimination by the World Health Organization. Recent years have seen a substantial decline in the number of globally reported cases, largely driven by an intensive process of screening and treatment. However, this infection is highly focal, continuing to persist at low prevalence even in small populations. Regional elimination, and ultimately global eradication, rests on understanding the dynamics and persistence of this infection at the local population scale. Here we develop a stochastic model of gHAT dynamics, which is underpinned by screening and reporting data from one of the highest gHAT incidence regions, Kwilu Province, in the Democratic Republic of Congo. We use this model to explore the persistence of gHAT in villages of different population sizes and subject to different patterns of screening. Our models demonstrate that infection is expected to persist for long periods even in relatively small isolated populations. We further use the model to assess the risk of recrudescence following local elimination and consider how failing to detect cases during active screening events informs the probability of elimination. These quantitative results provide insights for public health policy in the region, particularly highlighting the difficulties in achieving and measuring the 2030 elimination goal.

Author summary

Gambiense human African trypanosomiasis (gHAT) is a vector-borne infectious disease that causes sleeping sickness across many African countries. Reported gHAT cases show a continued decline, but it is unclear if this is sufficient to reach the WHO goal of stopping transmission by 2030. We develop a stochastic model necessary to address the critical question of persistence of gHAT infection at the local-scale. In contrast to other commonly studied infections, we predict long-term persistence of gHAT in small populations (< 1, 000 people) despite very low prevalence. Our local-scale predictions (together with previous larger-scale studies) suggest that, to achieve regional elimination, controls need to be widespread and intensified in the worst affected regions, while the movement of infected people could rapidly lead to re-emergence.
Genetic liability to schizophrenia is associated with exposure to traumatic events in childhood
Authors: Sallis Hannah M , Croft Jazz , Havdahl Alexandra , Jones Hannah J , Dunn Erin C , Smith George Davey , Zammit Stanley , Munafò Marcus R
Published: September 2019

Background

There is a wealth of literature on the observed association between childhood trauma and psychotic illness. However, the relationship between childhood trauma and psychosis is complex and could be explained, in part, by gene-environment correlation.

Methods

The association between schizophrenia polygenic scores (PGS) and experiencing childhood trauma was investigated using data from the Avon Longitudinal Study of Parents and Children (ALSPAC) and the Norwegian Mother, Father and Child Cohort Study (MoBa). Schizophrenia PGS were derived in each cohort for children, mothers, and fathers where genetic data were available. Measures of trauma exposure were derived based on data collected throughout childhood and adolescence (0-17 years; ALSPAC) and at age 8 years (MoBa).

Results

Within ALSPAC, we found a positive association between schizophrenia PGS and exposure to trauma across childhood and adolescence; effect sizes were consistent for both child or maternal PGS. We found evidence of an association between the schizophrenia PGS and the majority of trauma subtypes investigated, with the exception of bullying. These results were comparable in MoBa. Within ALSPAC, genetic liability to a range of additional psychiatric traits was also associated with a greater trauma exposure.

Conclusions

Results from two international birth cohorts indicate that genetic liability for a range of psychiatric traits is associated with experiencing childhood trauma. GWAS of psychiatric phenotypes may also reflect risk factors for these phenotypes. Our findings also suggest that youth at higher genetic risk might require greater resources/support to ensure they grow-up in a healthy environment.
Complete characterization of the human immune cell transcriptome using accurate full-length cDNA sequencing
Authors: Cole Charles , Byrne Ashley , Adams Matthew , Volden Roger , Vollmers Christopher
Published: September 2019

The human immune system relies on highly complex and diverse transcripts and the proteins they encode. These include transcripts forHumanLeukocyteAntigen (HLA) class I and II receptors which are essential for self/non-self discrimination by the immune system as well as transcripts encoding B cell and T cell receptors (BCR and TCR) which recognize, bind, and help eliminate foreign antigens.

HLA genes are highly diverse within the human population with each individual possessing two of thousands of different alleles in each of the 9 major HLA genes. Determining which combination of alleles an individual possesses for each HLA gene (high-resolution HLA-typing) is essential to establish donor-recipient compatibility in organ and bone-marrow transplantations. BCR and TCR genes in turn are generated by recombining a diverse set of gene segments on the DNA level in each maturing B and T cell, respectively. This process generatesadaptiveimmunereceptorrepertoires (AIRR) of composed of unique transcripts expressed by each B and T cells. These repertoires carry a vast amount of health relevant information. Both short-read RNA-seq based HLA-typing1and adaptive immune receptor repertoire sequencing2–5currently rely heavily on our incomplete knowledge of the genetic diversity at HLA6and BCR/TCR loci7,8.

Here we used our nanopore sequencing basedRolling CircletoConcatemericConsensus (R2C2) protocol9to generate over 10,000,000 full-length cDNA sequences at a median accuracy of 97.9%. We used this dataset to demonstrate that deep and accurate full-length cDNA sequencing can - in addition to providing isoform-level transcriptome analysis for over 9,000 loci - be used to generate accurate sequences of HLA alleles for HLA allele typing and discovery as well as detailed AIRR data for the analysis of the adaptive immune system without requiring specific knowledge of the diversity at HLA and BCR/TCR loci.
Open source 3D printable replacement parts for the WHO insecticide susceptibility bioassay system
Authors: Tomlinson Sean , Yates Henrietta C. , Oruni Ambrose , Njoroge Harun , Weetman David , Donnelly Martin J. , Van’t Hof Arjen E
Published: September 2019

Background

Malaria vector control and research rely heavily on monitoring mosquito populations for the development of resistance to public health insecticides. One standard method for determining susceptibility in adult mosquito populations is the World Health Organization test (WHO bioassay). The WHO bioassay kit consists of several acrylic pieces that are assembled into a unit. Parts of the kit commonly break, reducing the capacity of insectaries to carry out resistance profiling. Since there is at present only a single supplier for the test kits, replacement parts can be hard to procure in a timely fashion. Here, we present 3D printable versions for all pieces of the WHO bioassay kit.

Results

Using widely available polylactic acid (PLA) filament as a printing material, we were able to design and print functional replacements for each piece of the WHO bioassay kit. We note no significant difference in mortality results obtained from PLA printed tubes and WHO acrylic tubes. Additionally, we observed no degradation of PLA in response to prolonged exposure times of commonly used cleaning solutions.

Conclusions

Our designs can be used to produce replacement parts for the WHO bioassay kit in any facility with a 3D printer, which are becoming increasingly widespread. 3D printing technologies can affordably and rapidly address equipment shortages and be used to develop bespoke equipment in laboratories.
Dynamic clamp constructed phase diagram of the Hodgkin-Huxley action potential model
Authors: Ori Hillel , Hazan Hananel , Marder Eve , Marom Shimon
Published: September 2019

Excitability – a threshold governed transient in transmembrane voltage – is a fundamental physiological process that controls the function of the heart, endocrine, muscles and neuronal tissues. The 1950’s Hodgkin and Huxley explicit formulation provides a mathematical framework for understanding excitability, as the consequence of the properties of voltage-gated sodium and potassium channels. The Hodgkin-Huxley model is more sensitive to parametric variations of protein densities and kinetics than biological systems whose excitability is apparently more robust. It is generally assumed that the model’s sensitivity reflects missing functional relations between its parameters or other components present in biological systems. Here we experimentally construct excitable membranes using the dynamic clamp and voltage-gated potassium ionic channels (Kv1.3) expressed inXenopusoocytes. We take advantage of a theoretically derived phase diagram, where the phenomenon of excitability is reduced to two dimensions defined as combinations of the Hodgkin-Huxley model parameters. This biological-computational hybrid enabled us to explore functional relations in the parameter space, experimentally validate the phase diagram of the Hodgkin-Huxley model, and demonstrate activity-dependence and hysteretic dynamics due to the impacts of slow inactivation kinetics. The experimental results presented here provide new in-sights into the gap between technology-guided high-dimensional descriptions, and a lower, physiological dimensionality, within which biological function is embedded.
Representations of complex contexts: A role for hippocampus
Authors: Dimsdale-Zucker Halle R. , Montchal Maria E. , Reagh Zachariah M. , Wang Shao-Fang , Libby Laura A. , Ranganath Charan
Published: September 2019

The hippocampus plays a critical role in supporting episodic memory, in large part by binding together experiences and items with surrounding contextual information. At present, however, little is known about the roles of different hippocampal subfields in supporting this item-context binding. To address this question, we constructed a task in which items were affiliated with differing types of context – cognitive associations that vary at the local, item level and membership in temporally organized lists that linked items together at a global level. Participants made item recognition judgments while undergoing high-resolution fMRI imaging. We performed voxel pattern similarity analyses to answer the question of how human hippocampal subfields represent retrieved information about cognitive states and the time at which a past event took place. As participants recollected previously presented items, activity patterns in the CA23DG subregion carried information about prior cognitive states associated with these items. We found no evidence to suggest reinstatement of information about temporal context at the level of list membership, but exploratory analyses revealed representations of temporal context at a coarse level in conjunction with representations of cognitive contexts. Results are consistent with characterizations of CA23DG as a critical site for binding together items and contexts in the service of memory retrieval.
Alternative splicing regulation by GWAS risk loci for breast cancer
Authors: Machado Juliana , Magno Ramiro , Xavier Joana M , Maia Ana-Teresa
Published: September 2019

Recent genome-wide association studies (GWAS) have revealed the association of hundreds of single nucleotide polymorphisms (SNPs) with breast cancer (BC) risk, which mostly locate in non-coding regions, suggesting regulatory roles to the causal variants. Functional characterisation of GWAS loci has been biased towards the effect of regulatory SNPs on transcription factor binding. Here we set out to determine the extent of the contribution of breast cancer risk-associated SNPs to alternative splicing (AS).

We screened genome-wide significant (P≤ 5 × 10−8) BC risk SNPs for association with AS, using expression and genotype data from normal breast samples, from the GTEx project. We identified four splicing quantitative trait loci (sQTL). In locus 6p22.1,rs6456883is a significant cis-sQTL for the expression ofZNF311gene isoforms. Three SNPs in locus 8p23.3,rs6682326,rs3008282andrs2906324, were also identified as significant cis-sQTLs/svQTLs for the expression ofRPL23AP53gene isoforms. In-silico functional analysis revealed that these variants can potentially alter enhancer splicing elements within the target genes.

Our work shows that BC risk-associated variants at two loci are associated with AS isoforms in normal breast tissue, thus demonstrating that AS plays an important role in breast cancer susceptibility. Furthermore, it supports that all cis-regulatory mechanisms should be considered in the functional characterisation of risk loci.