bluuebunny/crossref_metadata_2025 huggingface dataset:
Incidence and clinical features of patients with peritoneal dialysis peritonitis complicated by bacteremia
Authors: Tsai Chang-Chih , Hsu Chien-Chin , Chen Kuo-Tai
Published: December 2018

The standard treatment of peritoneal dialysis peritonitis (PD peritonitis) is intraperitoneal antibiotic therapy. In patients with PD peritonitis complicated by bacteremia, intraperitoneal antibiotics combined with elective removal of the infected intraperitoneal catheter may be inadequate.

We collected data of all patients with PD peritonitis admitted to Chi-Mei Medical Center during a 4-year period. We reviewed the medical records of the study cohort and collected their in-hospital details. Patients with positive blood culture results were assigned to the bacteremia group, whereas those with negative blood culture results were assigned to the peritonitis-only group.

We discovered that 11.0% of patients with PD peritonitis had bacteremia complications, and immunocompromised comorbidities were more common in the bacteremia group than in the peritonitis-only group (66.7% vs 37.2%, P = .022). Additionally, the bacteremia group exhibited higher temperatures, greater respiratory rates, and lower serum sodium levels than the peritonitis-only group (temperature, 37.7 vs 37.2 °C, P = .014; respiratory rate, 19.1 vs 17.9 rate/min, P = .008; serum sodium level, 130.3 vs 132.7 mEq/L, P = .031). No mortality was found in patients with PD peritonitis complicated by bacteremia after intravenous and intraperitoneal antibiotic therapy.

More than 1 in 10 patients with PD peritonitis was complicated by bacteremia, which resulted in extensive systemic derangements. Patients with immunocompromised comorbidities carried a higher risk of developing bacteremia, resulting in prolonged hospital stays. Combination of intraperitoneal and intravenous antibiotics therapies achieved fair prognoses in patients with PD peritonitis complicated by bacteremia.
Laparoscopic transabdominal preperitoneal technique versus open surgery with the ULTRAPRO Hernia System for the repair of female primary femoral hernias—an observational retrospective study
Authors: Chen Dongfeng , Su Nana , Wang Weijia , Zhang Zhaoyong , Guo Mingxiao , Lu Chunlei , Zhang Haifeng
Published: December 2018

Femoral hernias (FHs), predominantly seen in females, require surgery for cure. To date, surgical repair of primary FHs in female patients with either open surgery or laparoscopic operation has been poorly documented. We retrospectively investigated the treatment of female primary FHs with open surgery using the ULTRAPRO Hernia System (UHS procedure) or the laparoscopic procedure, namely, the transabdominal preperitoneal (TAPP) technique. A total of 41 female patients with primary FHs who had undergone UHS or TAPP were included in this study. The procedural parameters, post-surgical complications, treatment expense, and follow-up results were analyzed. The vast majority of patients (39/41) underwent elective operations: 15 received UHS (including 2 emergency cases) and 26 had TAPP (P = .08). The UHS group had a greater average age, due to the fact that FHs occur often in people with advanced age who tend to have systemic disease, limiting the use of general anesthesia required for TAPP. Compared with UHS, TAPP took a significantly shorter time to complete and patients undergoing TAPP had a dramatically shorter hospital stay. While no recurrence was observed in both groups, post-procedure pain and foreign body sensation were reported by significantly more patients in UHS group. The cost was greater with TAPP. Taken together, we concluded that both UHS and TAPP are effective in the management of female FHs. In view of the advantages and disadvantages between the open and the laparoscopic operation, surgeons can select a procedure according to their skills and patients’ situation.
UGT1A1 genotypes and unconjugated hyperbilirubinemia phenotypes in post-neonatal Chinese children
Authors: Abuduxikuer Kuerbanjiang , Fang Ling-Juan , Li Li-Ting , Gong Jing-Yu , Wang Jian-She
Published: December 2018

To retrospectively analyze and quantitatively correlate UGT1A1 (bilirubin UDP- glucuronosyltransferase gene) genotypes and unconjugated hyperbilirubinemia (UCH) phenotypes among Chinese children.

We retrospectively reviewed UCH patients, quantitatively analyzed genotype–phenotype correlation by comparing with healthy controls. Pfam database, SWISS-model, and Pymol were used for UGT1A1 protein domain analysis and protein modeling for assessing the effect of novel missense variants on protein structure.

Seventy four cases, including 21 prolonged unconjugated hyperbilirubinemia (PUCH), 30 Gilbert syndrome (GS), 22 Crigler-Najjar syndrome type II (CNS-II), and 1 Crigler-Najjar syndrome type I (CNS-I) phenotypes were analyzed. Total of 21 variants, including 7 novel variants (c.764T>A/p.L255Q, c.1112C>T/p.T371I, c.1028C>A/p.S343X, c.1047delG/p.I350YfsX16, c.996 + 5G>C/g.6923G>C, c.287G>A/p.G96E, and c.1142G>A/p.S381N) were found. In the multiple regression model, heterozygous A(TA)7TAA, G71R/P364L, and Y486D/other mutations were significantly associated with increased risk of GS, PUCH, and CNS-II, respectively. Total allele number is significantly associated with GS and CNS-II, with each increase in total allele number, the odds ratio (OR) of having GS and CNS-II increased by 1.46 and 4.47 fold, respectively. Having only functional polymorphisms in UGT1A1 gene is associated with increased risk of PUCH, and GS with OR values of 5.67 (95% CI: 1.52–21.13), and 3.88 (95% CI: 1.02–14.78), respectively. Having only mutation is associated with significantly increased risk of having GS phenotype (OR: 34.00, 95% CI: 4.65–248.37), but not CNS-II. Polymorphism plus mutation had the strongest association with CNS-II with OR value of 64.80 (95% CI: 7.68–546.41), followed by GS (OR: 4.53, 95% CI: 1.08–19.08).

We detected 7 novel variants, and quantitatively calculated risks of having specific phenotypes using genetic data. Among Chinese children, G71R and P364L is independently associated with PUCH, A(TA)7TAA is associated with GS, and Y486D or other disease-causing mutations were associated with CNS-II. Multiple alleles were associated with more severe phenotypes. Combined variant of G71R+Y486D is a common occurrence among Chinese children with UCH.
Pulmonary embolism caused by myasthenia gravis
Authors: Lin Shan , Wang Yan , Guan Wei , Shi Yingqing
Published: December 2018

Rationale:

Pulmonary embolism (PE) is a relatively common disease; however, myasthenia gravis leading to PE has been rarely reported in the literature. We report a case of PE in a patient with myasthenia gravis and discuss the possible mechanism underlying the development of PE. We hypothesize that inflammatory mediators may lead to endothelial injury, resulting in PE or deep venous thrombosis (DVT) in patients with myasthenia gravis.

Patient concerns:

A 45-year-old woman had a 9-year history of myasthenia gravis. She was receiving neostigmine bromide for symptomatic relief and had never been on immunosuppressive therapy.

Diagnoses:

Myasthenia gravis and pulmonary embolism.

Interventions:

Our patient was treated with low-molecular-weight heparin immediately after hospital admission. Thrombolytic therapy was later initiated as her condition deteriorated.

Outcomes:

After 2 weeks, the pulmonary artery systolic pressure on echocardiography reduced to 60 mm Hg, and venous ultrasonography showed no evidence of DVT. Her computed tomography pulmonary angiogram revealed a mural thrombus in both the main pulmonary arteries. She refused to undergo immunosuppressive therapy; hence, she was discharged on neostigmine bromide and warfarin. There was no recurrence of PE or DVT at 3- and 6-month follow-ups.

Lessons:

Patients with an autoimmune-mediated disease may have an increased risk of DVT and PE. We hypothesize that the risk may increase in the absence of immunosuppressive therapy. Hence, anticoagulant therapy may be administered early to reduce mortality from acute PE.
Retrospective observational study of micro-monovision small incision lenticule extraction (SMILE) for the correction of presbyopia and myopia
Authors: Kim Jung Sub , Ra Ho , Rho Chang Rae
Published: December 2018

This study was aimed to evaluate refractive and visual outcomes after micro-monovision small incision lenticule extraction (SMILE) in patients with presbyopia and myopia. In total, 72 patients (144 eyes) with a mean age of 46.0 ± 4.9 years were included in this study. The dominant eye was treated for distance vision and the nondominant eye for near vision by targeting between −0.50 and −1.75 diopters (D). Treatment efficacy, safety, and refractive stability were calculated from postoperative data including refraction, binocular uncorrected distance visual acuity (UDVA), binocular uncorrected near visual acuity, monocular uncorrected distance visual acuity, and monocular corrected distance visual acuity (CDVA). Six months post-surgery, binocular UDVA was better than or equal to 20/20 in 88% of patients. No loss in 2 or more lines was observed in the Snellen lines of corrected distance visual acuity. Mean spherical equivalent (SE) for the distance eye was −0.18 ± 0.37 D, whereas the attempted and achieved SE in the near eye were −0.90 ± 0.44 and −0.99 ± 0.54 D, respectively. In total, 79% of eyes were within ±0.50 D, and 98% within ±1.00 D, of the intended refraction. A UDVA of 0.0 logMAR (20/20) or better, and an uncorrected near visual acuity of Jaeger (J) of 3 (20/32) or better, were observed in 83% of patients. Micromonovision refractive surgery using SMILE enhanced functional near vision in presbyopic patients.
Ambient air pollution in gastrointestinal endoscopy unit; rationale and design of a prospective study
Authors: Bang Chang Seok , Lee Keunwook , Choi Jae Ho , Soh Jae Seung , Hong Ji Young , Baik Gwang Ho , Kim Dong Joon
Published: December 2018

Background:

A gastrointestinal endoscopy unit is frequently exposed to gastrointestinal gas expelled from patients and electrocoagulated tissue through carbonation for the treatment of gastrointestinal neoplasms or hemostasis of gastrointestinal bleeding. This can be potentially harmful to the health of not only the healthcare personnel but also patients who undergo endoscopic examinations. However, there has been scarce data on air quality in the endoscopy unit. This study aimed to measure the air quality in the gastrointestinal endoscopy unit.

Methods:

This is a prospective study using conventional portable passive air quality monitoring sensors in the gastrointestinal endoscopy unit. We will check the 6 main indoor air quality indices, as well as the atmospheric temperature, pressure, and humidity in the endoscopy unit of a single hospital in Korea. These indices are as follows: carbon dioxide (CO2), total volatile organic compounds (VOCs), particulate matter that has a diameter of <2.5 μm, nitrogen dioxide (NO2), carbon monoxide (CO), and ozone. The indices will be checked in the endoscopy unit, including the procedural area, recovery area, and area for disinfection and cleansing of equipment, at 1-minute intervals for at least 1 week, and the type and number of endoscopic procedures will also be recorded. The primary outcome of this study is to determine whether the air quality indices exceed safety thresholds and whether there is any association between ambient air pollution and the type and number of endoscopic procedures.

Conclusion:

The results of this study will provide evidence for health-related protective strategies for medical practitioners and patients in the endoscopy unit.
Risk Factors for Early Disenrollment From Colorado’s Affordable Care Act Marketplace
Authors: Gordon Sarah H. , Sommers Benjamin D. , Wilson Ira B. , Galarraga Omar , Trivedi Amal N.
Published: December 2018

Background:

Midyear disenrollment from Marketplace coverage may have detrimental effects on continuity of care and risk pool stability of individual health insurance markets.

Objective:

The main objective of this study was to assess associations between insurance plan characteristics, individual and area-level demographics, and disenrollment from Marketplace coverage.

Data:

All payer claims data from individual market enrollees, 2014–2016.

Study Design:

We estimated Cox proportional hazards models to assess the relationship between plan actuarial value and Marketplace enrollment. The primary outcome was disenrollment from Marketplace coverage before the end of the year. We also calculated the proportion of enrollees who transitioned to other coverage after leaving the Marketplace, and identified demographic and area-level factors associated with early disenrollment. Finally, we compared monthly utilization rates between those who disenrolled early and those who maintained coverage.

Results:

Nearly 1 in 4 Marketplace beneficiaries disenrolled midyear. The hazard rate of disenrollment was 30% lower for individuals in plans receiving cost-sharing reductions and 21% lower for those enrolled in gold plans, compared with silver plans without cost-sharing subsidies. Young adults had a 70% increased hazard of disenrollment compared with older adults. Those who disenrolled midyear had greater hospital and emergency department utilization before disenrollment compared with those who maintained continuous coverage.

Conclusions:

Plan generosity is significantly associated with lower disenrollment rates from Marketplace coverage. Reducing churning in Affordable Care Act Marketplaces may improve continuity of care and insurers’ ability to accurately forecast the health care costs of their enrollees.
Six Lessons to Guide Intentional Career Action: Homage to the Queen of Soul and a Maverick Senator
Authors: Fink-Samnick Ellen
Published: December 2018

Independent of political perspective or musical preferences, the deaths of two individuals who played a major role in history was worthy of a moment of pause. The life lessons inspired by the efforts of these icons, plus the work of motivational author Jon Acuff together serve to empower the intentional action of professional case managers in defining a successful career path.
Cognitive Impairment in Zambians With HIV Infection and Pulmonary Tuberculosis
Authors: Hestad Knut A. , Chinyama Jonathan , Anitha Menon J. , Ngoma Mary S. , McCutchan J. Allen , Franklin Donald R. , Heaton Robert K.
Published: December 2018

Background:

HIV infection may result in neurocognitive deficits, but the effects of pulmonary tuberculosis (TB+), a common comorbid condition in HIV infection, on cognition in HIV infections are unknown. Accordingly, we examined the effects of TB+, on neurocognitive functioning in HIV-infected (HIV+) Zambian adults.

Setting:

All participants were drawn from HIV clinics in and around Lusaka, the capital of Zambia.

Methods:

Participants were 275 HIV+, of whom 237 were HIV+ and TB-negative (HIV+/TB−), and 38 also had pulmonary TB+ (HIV+/TB+). Controls were 324 HIV- and TB-uninfected (HIV−) healthy controls. All HIV+ participants were prescribed combination antiretroviral treatment (cART). Published, demographically corrected Zambian neuropsychological norms were used to correct for effects of age, education, sex, and urban/rural residence.

Results:

Neuropsychological deficits, assessed by global deficit scores, were more prevalent in this order: 14% (46 of 324) of HIV− controls, 34% (80 of 237) of HIV+/TB−, and 55% (21 of 38) of HIV+/TB+ group. Thus, both HIV-infected groups evidenced more impairment than HIV− controls, and the HIV+/TB+ group had a higher rate of neurocognitive impairment than the HIV+/TB− group. HIV+/TB+ patients were more likely to be male, younger, less-educated, and have lower CD4 counts and detectable HIV RNA in blood compared with the HIV+/TB− patients.

Conclusions:

In HIV infection, TB may contribute to cognitive impairment, even after controlling for lower CD4 counts and viral load. Thus, systemic inflammation from HIV and TB and more advanced immune deficiency at diagnosis of HIV may contribute to impaired cognition in HIV+/TB+ patients.
Does Incident Circumcision Lead to Risk Compensation? Evidence From a Population Cohort in KwaZulu-Natal, South Africa
Authors: Ortblad Katrina F. , Harling Guy , Chimbindi Natsayi , Tanser Frank , Salomon Joshua A. , Bärnighausen Till
Published: December 2018

Background:

Voluntary medical male circumcision reduces men's risk of HIV acquisition and may thus increase HIV risk-related sexual behaviors through risk compensation. We analyze longitudinal data from one of Africa's largest population cohorts using fixed-effects panel estimation to measure the effect of incident circumcision on sexual behaviors.

Setting:

KwaZulu-Natal, South Africa.

Methods:

An open population cohort of men was followed from 2009 to 2015. Men self-reported their circumcision status and sexual behavior annually. We used linear regression models with individual-level fixed effects to measure the effect of incident circumcision on recent sex (past 12 months) and sexual behaviors that increase HIV risk (not using a condom at last sex, never using condoms with the most recent sexual partner, concurrent sexual partners at present, and multiple sexual partners in the past 12 months). We controlled for potential time-varying confounders: calendar year, age, education, and sexual debut.

Results:

The 5127 men in the cohort had a median age of 18 years (interquartile range 16–24) at cohort entry. Over the study period, almost 1 in 5 of these men (19.4%) became newly circumcised. Incident circumcision affected neither recent sex [percentage point (PP) change 0.0, 95% confidence interval: −1.2 to 1.3] nor sexual behaviors that increase HIV risk (PP −1.6, 95% confidence interval: −4.5 to 1.4).

Conclusions:

The data from this study strongly reject the hypothesis that circumcision affects sexual risk-taking. Risk compensation should not serve as an argument against increased and accelerated scale-up of circumcision in this and similar communities in South Africa.
Vulnerable Periods: Characterizing Patterns of Sexual Risk and Substance Use During Lapses in Adherence to HIV Pre-exposure Prophylaxis Among Men Who Have Sex With Men
Authors: Wray Tyler B. , Chan Philip A. , Kahler Christopher W. , Simpanen Erik M. , Liu Tao , Mayer Kenneth H.
Published: December 2018

Background:

Pre-exposure prophylaxis (PrEP) is highly efficacious, but some groups of men who have sex with men may have difficulty adhering to daily dosing. Prevention-effective adherence suggests that PrEP's efficacy depends on adherence at the time of HIV exposure; yet, few studies have examined how exposures (ie, high-risk sex) overlap with periods of consecutive missed PrEP doses. Substance use may also play a role in these vulnerable periods.

Methods:

We used digital pill bottles to monitor the daily adherence of 40 PrEP-experienced patients recruited from an outpatient clinic in the Northeastern US over a six-month period. Participants also completed detailed online diaries every 2 weeks during this time that surveyed their sexual behavior and substance use each day.

Results:

Daily adherence was high overall (M = 83.9%, SD = 18.0%), but 53% (N = 21) had a lapse of > 3 consecutive daily PrEP doses over 6 months. Participants' rate of engaging in high-risk condomless anal sex (CAS) did not differ across lapse days versus continuously adherent days. Alcohol use was not associated with engaging in CAS during a PrEP lapse. However, participants reported engaging in CAS significantly more often during a PrEP adherence lapse on days when they also used stimulant drugs.

Conclusions:

Men who have sex with men may have periodic difficulty adhering to PrEP at the specific times when they are at risk. Stimulant drug use could play an important role in increasing HIV risk specifically during adherence lapses.
Serological Assessment of 18 Pathogens and Risk of AIDS-Associated Non-Hodgkin Lymphoma
Authors: Halec Gordana , Waterboer Tim , Brenner Nicole , Butt Julia , Hardy W. David , D'Souza Gypsyamber , Wolinsky Steven , Macatangay Bernard J. , Pawlita Michael , Detels Roger , Martínez-Maza Otoniel , Hussain Shehnaz K.
Published: December 2018

Background:

HIV infection is associated with increased susceptibility to common pathogens, which may trigger chronic antigenic stimulation and hyperactivation of B cells, events known to precede the development of AIDS-associated non-Hodgkin lymphoma (AIDS-NHL).

Methods:

To explore whether cumulative exposure to infectious agents contributes to AIDS-NHL risk, we tested sera from 199 AIDS-NHL patients (pre-NHL, average lead time 3.9 years) and 199 matched HIV-infected controls from the Multicenter AIDS Cohort Study, for anti-IgG responses to 18 pathogens using multiplex serology. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using conditional logistic regression models.

Results:

We found no association between cumulative exposure to infectious agents and AIDS-NHL risk (OR 1.01, 95% CI: 0.91 to 1.12). However, seropositivity for trichodysplasia spinulosa polyomavirus (TSPyV), defined as presence of antibodies to TSPyV capsid protein VP1, was significantly associated with a 1.6-fold increase in AIDS-NHL risk (OR 1.62, 95% CI: 1.02 to 2.57). High Epstein–Barr virus (EBV) anti-VCA p18 antibody levels closer to the time of AIDS-NHL diagnosis (<4 years) were associated with a 2.6-fold increase in AIDS-NHL risk (OR 2.59, 95% CI: 1.17 to 5.74). In addition, high EBV anti-EBNA-1 and anti-ZEBRA antibody levels were associated with 2.1-fold (OR 0.47, 95% CI: 0.26 to 0.85) and 1.6-fold (OR 0.57, 95% CI: 0.35 to 0.93) decreased risk of AIDS-NHL, respectively.

Conclusions:

Our results do not support the hypothesis that cumulative exposure to infectious agents contributes to AIDS-NHL development. However, the observed associations with respect to TSPyV seropositivity and EBV antigen antibody levels offer additional insights into the pathogenesis of AIDS-NHL.
Human Immunodeficiency Virus Increases the Risk of Incident Heart Failure
Authors: Yen Yung-Feng , Ko Ming-Chung , Yen Muh-Yong , Hu Bor-Shen , Wang Teng-Ho , Chuang Pei-Hung , Lai Hsin-Hao , Chen Chu-Chieh , Deng Chung-Yeh
Published: December 2018

Background:

Although the HIV can cause myocardial inflammation, the association of HIV infection with subsequent development of heart failure (HF) has not been extensively studied. This nationwide cohort study aimed to determine the risk of incident HF in people living with HIV/AIDS (PLWHA).

Methods:

We identified PLWHA using the Taiwan Centers for Disease Control and Prevention HIV Surveillance System. An age- and sex-matched control group without HIV infection was selected from the Taiwan National Health Insurance Research Database for comparison. All patients were followed up until December 2014 and were observed for a new diagnosis of HF. A time-dependent Cox proportional hazards model was used to determine the association of HIV and highly active antiretroviral therapy with incident HF, with death as a competing risk event.

Results:

Of the 120,765 patients (24,153 PLWHA and 96,612 matched controls), 641 (0.53%) had incident HF during a mean follow-up period of 5.84 years, including 192 (0.79%) PLWHA and 449 (0.46%) controls. Time to diagnosis of incident HF was significantly shorter in PLWHA than in those without HIV infection (P < 0.001, the log-rank test). After adjusting for age, sex, and comorbidities, HIV infection was found to be an independent risk factor for incident HF (adjusted hazard ratio, 1.52; 95% confidence interval: 1.27 to 1.82). As the duration of highly active antiretroviral therapy increased, the risk of HF decreased (P = 0.014).

Conclusions:

HIV infection was an independent risk factor for incident HF. Clinicians need to be aware of the higher risk of HF in PLWHA.
Early and Late Virologic Failure After Virologic Suppression in HIV-Infected Asian Children and Adolescents
Authors: Mu Weiwei , Bartlett Adam W. , Bunupuradah Torsak , Chokephaibulkit Kulkanya , Kumarasamy Nagalingeswaran , Ly Penh Sun , Hansudewechakul Rawiwan , Nguyen Lam Van , Lumbiganon Pagakrong , Sudjaritruk Tavitiya , Mohamed Thahira A. Jamal , Yusoff Nik Khairulddin Nik , Truong Khanh Huu , Do Viet Chau , Fong Moy Siew , Nallusamy Revathy , Kurniati Nia , Wati Dewi Kumara , Sohn Annette H. , Kariminia Azar , Zhang Fujie ,   for the TREAT Asia Pediatric HIV Observational Database of IeDEA Asia-Pacific
Published: December 2018

Background:

Virologic failure is a major threat to maintaining effective combination antiretroviral therapy, especially for children in need of lifelong treatment. With efforts to expand access to HIV viral load testing, our understanding of pediatric virologic failure is evolving.

Setting:

An Asian cohort in 16 pediatric HIV services across 6 countries.

Methods:

From 2005 to 2014, patients younger than 20 years who achieved virologic suppression and had subsequent viral load testing were included. Early virologic failure was defined as a HIV RNA ≥1000 copies per milliliter within 12 months of virologic suppression, and late virologic as a HIV RNA ≥1000 copies per milliliter after 12 months following virologic suppression. Characteristics at combination antiretroviral therapy initiation and virologic suppression were described, and a competing risk time-to-event analysis was used to determine cumulative incidence of virologic failure and factors at virologic suppression associated with early and late virologic failure.

Results:

Of 1105 included in the analysis, 182 (17.9%) experienced virologic failure. The median age at virologic suppression was 6.9 years, and the median time to virologic failure was 24.6 months after virologic suppression. The incidence rate for a first virologic failure event was 3.3 per 100 person-years. Factors at virologic suppression associated with late virologic failure included older age, mostly rural clinic setting, tuberculosis, protease inhibitor–based regimens, and early virologic failure. No risk factors were identified for early virologic failure.

Conclusions:

Around 1 in 5 experienced virologic failure in our cohort after achieving virologic suppression. Targeted interventions to manage complex treatment scenarios, including adolescents, tuberculosis coinfection, and those with poor virologic control are required.
A Clinical Prediction Rule for Protease Inhibitor Resistance in Patients Failing Second-Line Antiretroviral Therapy
Authors: Cohen Karen , Stewart Annemie , Kengne Andre P. , Leisegang Rory , Coetsee Marla , Maharaj Shavani , Dunn Liezl , Hislop Michael , van Zyl Gert , Meintjes Graeme , Maartens Gary
Published: December 2018

Background:

Most adults with virological failure on second-line antiretroviral therapy (ART) in resource-limited settings have no major protease inhibitor (PI) resistance mutations. Therefore, empiric switches to third-line ART would waste resources. Genotypic antiretroviral resistance testing (GART) is expensive and has limited availability. A clinical prediction rule (CPR) for PI resistance could rationalize access to GART.

Setting:

A private sector ART cohort, South Africa.

Methods:

We identified adults with virologic failure on ritonavir-boosted lopinavir/atazanavir-based ART and GART. We constructed a multivariate logistic regression model including age, sex, PI duration, short-term adherence (using pharmacy claims), concomitant CYP3A4-inducing drugs, and viral load at time of GART. We selected variables for the CPR using a stepwise approach and internally validated the model by bootstrapping.

Results:

148/339 (44%) patients had PI resistance (defined as ≥ 1 major resistance mutation to current PI). The median age was 42 years (interquartile range 36–48), 212 (63%) were females, 308 (91%) were on lopinavir/ritonavir, and median PI duration was 2.6 years (interquartile range 1.6–4.7). Variables associated with PI resistance and included in the CPR were age {adjusted odds ratio (aOR) 1.96 (95% confidence interval [CI]: 1.42 to 2.70) for 10-year increase}, PI duration (aOR 1.14 [95% CI: 1.03 to 1.26] per year), and adherence (aOR 1.22 [95% CI: 1.12 to 1.33] per 10% increase). The CPR model had a c-statistic of 0.738 (95% CI: 0.686 to 0.791).

Conclusions:

Older patients with high adherence and prolonged PI exposure are most likely to benefit from GART to guide selection of a third-line ART regimen. Our CPR to select patients for GART requires external validation before implementation.
Brief Report: Surveillance of Congenital Anomalies After Exposure to Raltegravir or Elvitegravir During Pregnancy in the United Kingdom and Ireland, 2008–2018
Authors: Rasi Virginia , Cortina-Borja Mario , Peters Helen , Sconza Rebecca , Thorne Claire
Published: December 2018

Background:

The indisputable benefits of antiretroviral therapy (ART) in the reduction of mother-to-child-transmission of HIV have to be carefully balanced with the risks of embryo–fetal toxicities due to fetal exposure to maternal ART. The recent report of a potential safety signal with dolutegravir use in pregnancy and potential increased rate of neural tube defects has raised the question of a potential class effect for integrase strand inhibitors. To contribute real-world evidence, we evaluated data on pregnant women receiving raltegravir (RAL) or elvitegravir (EVG) in the United Kingdom and Ireland.

Methods:

The National Study of HIV in Pregnancy and Childhood is a comprehensive population-based surveillance study collecting data on all HIV-positive pregnant women and their children. We collected data on all pregnancies exposed to an ART regimen containing RAL or EVG resulting in live birth, stillbirth, and induced abortion with an expected date of delivery between September 2008 and April 2018. Pregnancies were stratified into 3 groups of earliest exposure.

Results:

A total of 908 pregnancies were exposed to a RAL- or EVG-based regimen (875 to RAL and 33 to EVG). There were 886 live-born infants exposed to RAL, 8 pregnancies ended in stillbirth, and 9 in induced abortions. Among the 886 live-born infants, there were 23 (2.59%, 95% confidence interval: 1.65 to 3.86) reported congenital anomalies, 2 nervous system defects but no reported neural tube defects. Of the 33 pregnancies exposed to EVG, 31 resulted in live-born infants with no congenital anomaly and the remaining 2 pregnancies ended in induced abortion.

Conclusions:

The prevalence of congenital anomalies is consistent with national population estimates for 2008–2016 in the United Kingdom. More data are needed on safety of RAL and EVG in pregnancy.
Peripheral Blood Mitochondrial DNA Copy Number Obtained From Genome-Wide Genotype Data Is Associated With Neurocognitive Impairment in Persons With Chronic HIV Infection
Authors: Hulgan Todd , Kallianpur Asha R. , Guo Yan , Barnholtz-Sloan Jill S. , Gittleman Haley , Brown Todd T. , Ellis Ronald , Letendre Scott , Heaton Robert K. , Samuels David C. ,   for the CHARTER Study
Published: December 2018

Background:

Mitochondrial DNA (mtDNA) copy number varies by cell type and energy demands. Blood mtDNA copy number has been associated with neurocognitive function in persons without HIV. Low mtDNA copy number may indicate disordered mtDNA replication; high copy number may reflect a response to mitochondrial dysfunction. We hypothesized that blood mtDNA copy number estimated from genome-wide genotyping data is related to neurocognitive impairment (NCI) in persons with HIV.

Methods:

In the CNS HIV Antiretroviral Therapy Effects Research (CHARTER) study, peripheral blood mtDNA copy number was obtained from genome-wide genotyping data as a ratio of mtDNA single-nucleotide polymorphism probe intensities relative to nuclear DNA single-nucleotide polymorphisms. In a multivariable regression model, associations between mtDNA copy number and demographics, blood cell counts, and HIV disease and treatment characteristics were tested. Associations of mtDNA copy number with the global deficit score (GDS), GDS-defined NCI (GDS ≥ 0.5), and HIV-associated neurocognitive disorder (HAND) diagnosis were tested by logistic regression, adjusting for potential confounders.

Results:

Among 1010 CHARTER participants, lower mtDNA copy number was associated with longer antiretroviral therapy duration (P < 0.001), but not with d-drug exposure (P = 0.85). mtDNA copy number was also associated with GDS (P = 0.007), GDS-defined NCI (P < 0.001), and HAND (P = 0.002). In all analyses, higher mtDNA copy number was associated with poorer cognitive performance.

Conclusions:

Higher mtDNA copy number estimated from peripheral blood genotyping was associated with worse neurocognitive performance in adults with HIV. These results suggest a connection between peripheral blood mtDNA and NCI, and may represent increased mtDNA replication in response to mitochondrial dysfunction.
Copy-Years Viremia and Risk of Virological Failure in Long-Term–Treated HIV Patients
Authors: Falasca Francesca , De Vito Corrado , Mazzuti Laura , di Carlo Daniele , Celani Luigi , Fimiani Caterina , d'Ettorre Gabriella , Mezzaroma Ivano , Antonelli Guido , Turriziani Ombretta
Published: December 2018

Background:

Viremia copy-years (VCY) is associated with mortality and disease outcome prediction. This study evaluated the association of VCY with virological failure (VF), defined as a plasma viral load (pVL) >400 copies/mL, and with single levels of viremia.

Methods:

Eight hundred and fifty antiretroviral therapy (ART)-treated patients with pVL < 37 copies/mL [target not detected or target detected (TD)] or >37, but less than 200 copies/mL (low-level viremia), and at least 6-pVL measures during 54 months of follow-up were selected. VCY was calculated individually over the follow-up as the area under pVL curve. Pearson's χ2 test was used to analyze differences in VCY quartiles distribution between groups.

Results:

Higher VCY values were detected in patients with low-level viremia {294 copy-years [interquartile range (IQR): 99–1870]} than in TD [52 copy-years (IQR: 53–153)] and target not detected groups [19 copy-years (IQR: 8–54)]. VCY was also significantly different between patients with undetectable viremia and patients with basal pVL TD (P < 0.001). Pearson's χ2 test revealed a significant association between VCY and basal levels of viremia (P < 0.0001). In addition, the risk of VF rose with increasing VCY (Hazard ratio 1.01, 95% confidence interval: 1.01 to 1.02).

Conclusions:

This study revealed the association of VCY with VF and with single levels of viremia suggesting that, despite the success of ART, minimal residual viremia may cause the cumulative viral burden to rise. Full viral load suppression during ART is crucial to limit the increase in VCY.
Climate explains population divergence in drought-induced plasticity of functional traits and gene expression in a South AfricanProtea
Authors: Akman Melis , Carlson Jane E. , Latimer Andrew M.
Published: December 2018

Long term environmental variation often drives local adaptation and leads to trait differentiation across populations. Additionally, when traits change in an environment-dependent way through phenotypic plasticity, the genetic variation underlying plasticity will also be under selection. These processes could create a landscape of differentiation across populations in traits and their plasticity. Here, we studied drought responses in seedlings of a shrub species from the Cape Floristic Region, the common sugarbush (Protea repens). We measured morphological and physiological traits, and sequenced whole transcriptomes in 8 populations that represent both the climatic and the geographic distribution of this species. We found that there is substantial variation in how populations respond to drought, but we also observed common patterns such as reduced leaf size and leaf thickness, and upregulation of stress- and down-regulation of growth-related gene groups. Both high environmental heterogeneity and milder source site climates were associated with higher plasticity in various traits and co-expression gene networks. Associations between traits, trait plasticity, gene networks and the source site climate suggests that temperature may play a bigger role in shaping these patterns when compared to precipitation, in line with recent changes in the region due to climate change. We also found that traits respond to climatic variation in an environment dependent manner: some associations between traits and climate were apparent only under certain growing conditions. Together, our results uncover common responses ofP. repenspopulations to drought, and climatic drivers of population differentiation in functional traits, gene expression and their plasticity.
Metagenome-wide measurement of protein synthesis in the human fecal microbiota using MetaRibo-Seq
Authors: Fremin Brayon J. , Bhatt Ami S.
Published: December 2018

The healthy human fecal microbiota is too diverse to comprehensively study with the current throughput of proteomic methods. Shotgun sequencing technologies allow for much more comprehensive profiling. Here, we develop and apply MetaRibo-Seq, a method for simultaneous ribosome profiling of multiple taxa within a complex bacterial community. This approach captures taxonomic diversity in fecal samples. As expected, the detected ribosome-bound transcripts are relatively enriched within coding regions and significantly correlate to detectable protein abundances. In a low diversity fecal sample, we show that MetaRibo-Seq is more strongly correlated than metatranscriptomic data to protein abundance. This significant correlation of metatranscriptomics and MetaRibo-Seq with protein levels is maintained, though with decreased strength as taxonomic diversity increases. Finally, we identify genes that are consistently regulated at the translational level across bacterial taxa within fecal communities. In conclusion, MetaRibo-Seq enables comprehensive translational profiling in complex bacterial communities for the first time.
De novo aging-related megaloneurites: alteration of NADPH diaphorase positivity in the sacral spinal cord of the aged dog
Authors: Li Yinhua , Jia Yunge , Hou Wei , Wei Zichun , Wen Xiaoxin , Tian Yu , Zhang Weijin , Bai Lu , Guo Anchen , Du Guanghui , Tan Huibing
Published: December 2018

The aging-related changes of NADPH-diaphorase (NADPH-d) in the spinal cord were studied in aged dogs. At all levels of the spinal cord examined, NADPH-d activities were present in neurons and fibers in the superficial dorsal horn, dorsal commissure and in neurons around the central canal. In addition, the sympathetic autonomic nucleus in the thoracic and rostral lumbar segments exhibited prominent NADPH-d cellular staining whereas the sacral parasympathetic nucleus (SPN) in the sacral segments was not well stained. Interestingly, we found abundant NADPH-d positive enlarged-diameter fibers termed megaloneurite, which characteristically occurred in the aged sacral segments, distributed in the dorsal gray commissure (DGC), lateral collateral pathway (LCP) the lateral fasciculi and the central canal compared with the cervical, thoracic and lumbar segments. The dense, abnormal NADPH-d megaloneurites occurred in extending from dorsal entry zone through lamina I along with the lateral boundary of the dorsal horn to the region of the SPN. These fibers were prominent in the S1-S3 segments but not in adjacent segments L5-L7 and Cx1 or in thoracolumbar segments and cervical segments. Double staining with GFAP, NeuN, CGRP, MAP2 and Iba1, NADPH-d megaloneurite colocalized with vasoactive intestinal peptide. Presumably, the megaloneurites may represent, in part, visceral afferent projections to the SPN and/or DGC. The NADPH-d megaloneurites in the aged sacral spinal cord indicated some anomalous changes in the neurites, which might account for a disturbance in the aging pathway of the autonomic and sensory nerve in the pelvic visceral organs.
HeartBioPortal: an internet-of-omics for human cardiovascular disease data
Authors: Khomtchouk Bohdan , Vand Kasra A , Koehler William C , Tran Diem-Trang , Middlebrook Kai , Sudhakaran Shyam , Gozani Or , Assimes Themistocles
Published: December 2018

Cardiovascular disease (CVD) is the leading cause of death worldwide, causing over 17M deaths per year, which outpaces global cancer mortality rates. Despite these sobering statistics, the state-of-the-art in computational infrastructure to study datasets associated with CVD has lagged far behind public resources widely available in the oncology field, where improved data science and visualization methods have led to the development of large-scale cancer genomics resources like MSKCC's cBioPortal or NCI's Genomic Data Commons (GDC) Portal. Developing a similar user-friendly computational platform could significantly lower the barriers between complex CVD data and researchers who want rapid, intuitive, and high-quality visual access to molecular profiles and clinical attributes from existing CVD projects. Here we present HeartBioPortal: a publicly available web application that provides intuitive visualization, analysis, and downloads of large-scale CVD data currently focused on gene expression, genetic association, and ancestry information. By democratizing access to anonymized CVD data, HeartBioPortal's aim is to integrate relevant omics and clinical information across the biological dataverse to support CVD clinicians and researchers.
The Biological Basis of the Experience of Constant Colour Categories
Authors: Zeki Semir , Javier Alexandre , Mylonas Dimitris
Published: December 2018

In the work reported here, we used the Land Color Mondrian experiments to test the degree to which subjects vary in their perception of color categories. Twenty subjects of different ethnic and cultural backgrounds, for all but one of whom English was not the primary language, viewed 8 patches of different color in two Mondrian displays; each patch, when viewed, was made to reflect identical ratios of long, middle and short wave light. Subjects were asked to match the color of the viewed patch with that of the Munsell chip coming closest in color to that of the viewed patch, without using language. Overall, there was no variability in categorizing colors as red, yellow, brown and green but a small variability in categorizing them as purple, blue, orange and turquoise. In terms of hue, we found significantly less variability in matching warm hues than in cool ones. We interpret the lack of significant variability between subjects in the matches made as a pointer to similar computational mechanisms being employed in different subjects to perceive colors, thus permitting subjects to assume that their categorization of colors has universal agreement and assent.
Dynamics of Cardiomyocyte Transcriptome and Chromatin Landscape Demarcates Key Events of Heart Development
Authors: Pawlak Michal , Kedzierska Katarzyna Z. , Migdal Maciej , Abu Nahia Karim , Ramilowski Jordan A. , Bugajski Lukasz , Hashimoto Kosuke , Marconi Aleksandra , Piwocka Katarzyna , Carninci Piero , Winata Cecilia L.
Published: December 2018

The development of an organ involves dynamic regulation of gene transcription and complex multipathway interactions. To better understand transcriptional regulatory mechanism driving heart development and the consequences of its disruption, we isolated cardiomyocytes (CMs) from wild-type zebrafish embryos at 24, 48 and 72 hours post fertilization corresponding to heart looping, chamber formation and heart maturation, and from mutant lines carrying loss-of-function mutations ingata5, tbx5aandhand2, transcription factors (TFs) required for proper heart development. The integration of CM transcriptomics (RNA-seq) and genome-wide chromatin accessibility maps (ATAC-seq) unravelled dynamic regulatory networks driving crucial events of heart development. These networks contained key cardiac TFs including Gata5/6, Nkx2.5, Tbx5/20, and Hand2, and are associated with open chromatin regions enriched for DNA sequence motifs belonging to the family of the corresponding TFs. These networks were disrupted in cardiac TF mutants, indicating their importance in proper heart development. The most prominent gene expression changes, which correlated with chromatin accessibility modifications within their proximal promoter regions, occurred between heart looping and chamber formation, and were associated with metabolic and hematopoietic/cardiac switch during CM maturation. Furthermore, loss of function of cardiac TFs Gata5, Tbx5a, and Hand2 affected the cardiac regulatory networks and caused global changes in chromatin accessibility profile. Among regions with differential chromatin accessibility in mutants were highly conserved non-coding elements which represent putativecisregulatory elements with potential role in heart development and disease. Altogether, our results revealed the dynamic regulatory landscape at key stages of heart development and identified molecular drivers of heart morphogenesis.
Uncovering missed indels by leveraging unmapped reads
Authors: Hasan Mohammad Shabbir , Wu Xiaowei , Zhang Liqing
Published: December 2018

In current practice, Next Generation Sequencing (NGS) applications start with mapping/aligning short reads to the reference genome, with the aim of identifying genetic mutations. While most short reads can be mapped to the reference genome accurately by existing alignment tools, a significant number remain unmapped and excluded from downstream analyses thus potentially discarding important biological information hidden in the unmapped reads. This paper describes Genesis-indel, a computational pipeline that explores the unmapped reads to identify novel indels that are initially missed in the alignment procedure. Genesis-indel is applied to the unmapped reads of 30 Breast Cancer patients from TCGA. Results show that the unmapped reads are conserved between the two subtypes of breast cancer investigated in this study and might contribute to the divergence between the subtypes. Genesis-indel is able to leverage the unmapped reads to identify 72,997 small to large novel high-quality indels previously not found in the original alignments and among them, 16,141 have not been annotated in the widely used mutation database. Statistical analysis shows that these new indels mostly altered the oncogenes and tumor suppressor genes. Functional annotation further reveals that these indels are strongly correlated to pathways of cancer and can have high to moderate impact on protein functions. Additionally, these indels overlap with the genes that are missed in the indels from the originally mapped reads and contribute to the tumorigenesis in multiple carcinomas.
In Vivo Flow Cytometry of Extremely Rare Circulating Cells
Authors: Tan Xuefei , Patil Roshani , Bartosik Peter , Runnels Judith , Lin Charles P. , Niedre Mark
Published: December 2018

Circulating tumor cells (CTCs) are of great interest in cancer research, but methods for their enumeration remain far from optimal. We developed a new small animal research tool called Diffuse in vivo Flow Cytometry (DiFC) for detecting extremely rare fluorescently- labeled circulating cells directly in the bloodstream. The technique exploits near-infrared diffuse photons to detect and count cells flowing in large superficial arteries and veins without drawing blood samples. DiFC uses custom-designed, dual fiber optic probes that are placed in contact with the skin surface approximately above a major vascular bundle. In combination with a novel signal processing, algorithm DiFC allows counting of individual cells moving in arterial or venous directions, as well as measurement of their speed and depth. We show that DiFC allows sampling of the entire circulating blood volume of a mouse in under 10 minutes, while maintaining a false alarm rate of 0.014 per minute. Hence, the unique capabilities of DiFC are highly suited to biological applications involving very rare cell types such as the study of hematogenic cancer metastasis.