bluuebunny/crossref_metadata_2025 huggingface dataset:
Diagnosis and outcome of resected solitary pulmonary nodules after liver transplantation
Authors: Tone Mari , Awano Nobuyasu , Izumo Takehiro , Yoshimura Hanako , Jo Tatsunori , Kuse Naoyuki , Inomata Minoru , Fukumoto Kento , Furuhata Yoshiaki , Hashimoto Takuya , Kumasaka Toshio , Kunitoh Hideo
Published: November 2019

Objective

Solitary pulmonary nodules after liver transplantation are challenging clinical problems. Herein, we report the causes and clinical courses of resected solitary pulmonary nodules in patients who underwent liver transplantation.

Methods

We retrospectively obtained medical records of 68 patients who underwent liver transplantation between March 2009 and June 2016. This study mainly focused on patients with solitary pulmonary nodules observed on computed tomography scans during follow-ups that were conducted until their deaths or February 2019.

Results

Computed tomography scans revealed solitary pulmonary nodules in 7 of the 68 patients. Definitive diagnoses were obtained using video-assisted lung resection in all seven patients. None experienced major postoperative complications. The final pathologic diagnoses were primary lung cancer in three patients, pulmonary metastases from hepatocellular carcinoma in one patient, invasive pulmonary aspergillosis in one patient, post-transplant lymphoproliferative disorder in one patient, and hemorrhagic infarction in one patient. The three patients with lung cancer were subsequently treated with standard curative resection.

Conclusions

Solitary pulmonary nodules present in several serious but potentially curable diseases, such as early-stage lung cancer. Patients who present with solitary pulmonary nodules after liver transplantation should be evaluated by standard diagnostic procedures, including surgical biopsy if necessary.
Comparative Vector Efficiency of Two Prevalent Mosquito Species for Dog Heartworm in North Carolina
Authors: Spence Beaulieu Meredith R , Reiskind Michael H
Published: November 2019

The dog heartworm, Dirofilaria immitis (Leidy) (Spirurida: Onchocercidae), is a devastating parasite of domestic and wild canines vectored by a multitude of mosquito species. Although many species are implicated as vectors, not all contribute equally to disease transmission, with demonstrated variation in vector efficiency between and within species. We investigated the vector efficiency of mosquitoes derived from wild-caught North Carolina populations of two known heartworm vectors: a native species, Aedes triseriatus (Say) (Diptera: Culicidae), and an invasive species, Aedes albopictus (Skuse). We compared the parasite developmental times within the mosquito, mosquito longevity and fecundity, and the vector efficiency index between the two species. We found that the tested composite North Carolina population of Ae. triseriatus was an efficient vector of D. immitis under laboratory conditions, whereas the local composite population of Ae. albopictus was a competent but relatively poor vector. Compared with Ae. triseriatus, Ae. albopictus showed a longer time for parasite development, lower infection rates, and lower vector efficiency. Additionally, Ae. albopictus was the sole species to exhibit significant parasite-induced mortality. These results are in contrast to prior studies of populations of Ae. albopictus from locations outside of North Carolina, which have implicated the species as a highly competent heartworm vector. The variation seen for different strains of the same species emphasizes the heritable nature of D. immitis vector competence and highlights the need for local infection studies for accurate transmission risk assessment in a particular locale.
The Pseudo Maximum Likelihood Estimator for Quantiles of Survey Variables
Authors: Wang Jing
Published: November 2019

The pseudo maximum likelihood approach has been employed in multilevel models for analysis of complex survey data. This approach may be inappropriate for many survey variables that are nonsymmetrically distributed with skewness and multimodality characteristics. This article intends to fill this gap in the literature by developing a pseudolikelihood estimator for quantiles of survey variables in the quantile regression framework. This approach is illustrated using a Monte Carlo simulation study and the body mass index data from the 1998–1999 Early Childhood Longitudinal Study. Results show that the proposed estimator is consistent and approximately unbiased for both informative and noninformative sampling designs.
γ-Tubulin interacts with E2FA, E2FB and E2FC transcription factors, regulates proliferation and endocycle in Arabidopsis
Authors: Kállai B M , Kourová H , Chumová J , Papdi C , Trögelová L , Kofroňová O , Hozák P , Filimonenko V , Mészáros T , Magyar Z , Bögre L , Binarová P
Published: November 2019

γ-Tubulin is associated with microtubule nucleation, but evidence is accumulating in eukaryotes that it functions also in nuclear processes and in cell division control that are independent of its canonical role. We found that in Arabidopsis thaliana γ-tubulin interacts specifically with E2FA, E2FB, and E2FC transcription factors both in vitro and in vivo. The interaction of γ-tubulin with the E2Fs is not reduced in the presence of the dimerization partners (DPs) and, in agreement, we found that γ-tubulin interaction with E2Fs does not require the dimerization domain. γ-Tubulin associates with the promoters of E2F-regulated cell cycle genes in an E2F dependent manner, likely in complex with the E2F/DP heterodimer. The upregulation of E2F targets; PCNA, ORC2, CDKB1;1 and CCS52A under γtubulin silencing suggests a repressive function for γ-tubulin at G1/S, G2/M and endocycle, which is consistent with an excess of cell division in some cells and enhanced endoreduplication in others in the shoot and young leaves of γ-tubulin RNAi plants. Altogether, our data show ternary interaction of γ-tubulin with E2F/DP heterodimer and suggest a repressive role for γ-tubulin with E2Fs in controlling mitotic activity and endoreduplication during plant development.
Optimally managing hyperkalemia in patients with cardiorenal syndrome
Authors: Wang Angela Yee-Moon
Published: November 2019

Renin–angiotensin–aldosterone system inhibitors (RAASi) are now a standard treatment in most patients with cardiovascular disease, especially in those with heart failure (HF). The European Society of Cardiology and the American College of Cardiology/American Heart Association gave a Class IA recommendation for the use of RAASi in the treatment of Classes II–IV symptomatic HF with reduced ejection fraction (HFREF), based on their strong clinical benefits of lowering all-cause mortality and HF hospitalizations in these subjects. However, RAASi therapy or adding mineralocorticoid receptor antagonists in subjects receiving background angiotensin-converting enzyme inhibitors or angiotensin receptor blockers may be associated with an increased risk of hyperkalemia (HK), especially in those with reduced kidney function. As a result, a significant proportion of these subjects either have RAASi dose reduced or more often discontinued when they develop HK. Discontinuation of RAASi in patients hospitalized with HFREF was associated with higher postdischarge mortality and rehospitalization rates, while optimal dosing of RAASi significantly reduced median hospital stays, outpatient visits and related costs. Thus, effective treatment is required to lower potassium level and maintain normokalemia in subjects with HF and reduced kidney disease who develop or are at risk of HK, thus enabling them to continue their RAASi therapy and maximize benefits from RAASi. In this review, we provide an up-to-date review of the prevalence and significance of HK in patients with cardiorenal syndrome, as well as their optimal management of HK with recent novel therapies.
Very Low Nicotine Content Cigarettes Disrupt the Feedback Loop of Affective States and Smoking Behavior
Authors: Robinson Jason D , Kypriotakis George , Al’absi Mustafa , Denlinger-Apte Rachel L , Drobes David J , Leischow Scott J , McClernon F Joseph , Pacek Lauren R , Severson Herbert H , Smith Tracy T , Donny Eric C , Luo Xianghua , Jensen Joni A , Strayer Lori G , Cinciripini Paul M , Hatsukami Dorothy K
Published: November 2019

Introduction

Smoking to reduce negative affect has been identified as a key motivational feature of tobacco use. Our recent work suggests that smoking very low nicotine content (VLNC) cigarettes reduces the relationship between negative affect and smoking behavior over a 6-week period. Here, we sought to extend our findings by evaluating whether a gradual or immediate approach to switching to VLNC cigarettes led to a differential reduction in the relationship between affect and smoking behavior over a longer (20-week) period.

Aims and Methods

Participants (n = 1250) were adult smokers from 10 US sites randomized to one of three groups: gradual nicotine reduction (15.5, 11.7, 5.2, 2.4, and 0.4 mg of nicotine per gram of tobacco [mg/g]), immediate nicotine reduction (0.4 mg/g), or standard nicotine content cigarettes (15.5 mg/g; control), for 20 weeks. We examined whether the relationship between affect—both negative and positive—and cigarettes per day differed as a function of reduction group.

Results

We found that both negative and positive affect were associated with cigarette consumption in the control group, but not in the gradual or immediate reduction groups across the 20 weeks of exposure.

Conclusions

Our results extend previous findings that switching to VLNC cigarettes disrupts the relationship between affect and cigarette consumption by showing that either gradually or immediately reducing cigarette nicotine content achieves this disruption. These findings provide further evidence that switching to VLNC cigarettes reduces nicotine-related reinforcement of cigarette smoking.

Implications

These findings support the notion that switching to very low nicotine content cigarettes reduces the association between affect and smoking behavior, and that either a gradual or immediate nicotine reduction approach achieves this reduction. This provides further evidence that switching to very low nicotine content cigarettes weakens reinforcement mechanisms associated with nicotine dependence.
Predictors of Acute Liver Failure in Patients With Acute Hepatitis A: An Analysis of the 2016–2018 San Diego County Hepatitis A Outbreak
Authors: Jiang Aiyang A , Greenwald Holly S , Sheikh Lamiya , Wooten Darcy A , Malhotra Atul , Schooley Robert T , Sweeney Daniel A
Published: November 2019

Background

Between 2016 and 2018, San Diego County experienced a hepatitis A outbreak with a historically high mortality rate (3.4%) that highlighted the need for early recognition of those at risk of developing acute liver failure (ALF).

Methods

A retrospective case series of adult hospitalized patients with acute hepatitis A.

Results

One hundred six patients with hepatitis A were studied, of whom 11 (10.4%) developed ALF, of whom 7 (6.6%) died. A history of alcohol abuse, hyperbilirubinemia, hypoalbuminemia, hyponatremia, and anemia were associated with increased odds of developing ALF. Initial Maddrey’s and Model of End-Stage Liver Disease Sodium (MELD-Na) scores were also associated with the development of ALF. Multivariable analysis showed that a higher initial MELD-Na score (odds ratio [OR], 1.205; 95% confidence interval [CI], 1.018–1.427) and a lower initial serum albumin concentration (OR, 9.35; 95% CI, 1.15–76.9) were associated with increased odds of developing ALF. Combining serum albumin and MELD-Na (SAM; C-statistic, 0.8878; 95% CI, 0.756–0.988) yielded a model that was not better than either serum albumin (C-statistic, 0.852; 95% CI, 0.675–0.976) or MELD-Na (C-statistic, 0.891; 95% CI, 0.784–0.968; P = .841). Finally, positive blood cultures were more common among patients with ALF compared with those without ALF (63.6% vs 4.3%; P < .00001).

Conclusions

Hypoalbuminemia was associated with an increased risk of ALF in patients with acute hepatitis A. Positive blood cultures and septic shock as a cause of death were common among patients with ALF. Providers caring for patients with acute hepatitis A should monitor for early signs of sepsis and consider empiric antibiotics, especially in patients presenting with hypoalbuminemia.
Microsurgical Resection of Recurrent Cavernous Sinus Hemangioma by Superior and Lateral Approach: 2-Dimensional Operative Video
Authors: Zeeshan Qazi , Hernandez Juan P Carrasco , Moore Michael K , Sekhar Laligam N
Published: November 2019

This video shows the technical nuances of microsurgical resection of recurrent cavernous sinus (CS) hemangioma by superior and lateral approach.

 A 77-yr-old woman presented with headache and difficulty in vision in right eye for 6 mo. She had previously undergone attempted resection of a right CS tumor in another hospital with partial removal, and the tumor had grown significantly. Neurological examination revealed proptosis, cranial nerve 3 palsy, and loss of vision in right eye (20/200). Left side visual acuity was 20/20.

 Brain magnetic resonance imaging (MRI) demonstrated a large CS mass with homogeneous enhancement, measuring 3.3 × 3.3 × 2.6 cm, extending into the suprasellar cistern with mass effect on the right optic nerve. It extended anteriorly to the region of the right orbital apex and abuted the basilar artery posteriorly.

 She underwent right frontotemporal craniotomy, posterolateral orbitotomy and anterior clinoidectomy as well as optic nerve decompression, and the CS tumor was removed by superior and lateral approach. An incision was made into the superior wall of the CS medial to the third nerve. On lateral aspect the tumor had extended outside the CS through the Parkinson's triangle. Posteriorly it extended through the clival dura. Anteriorly tumor encased the carotid artery and it was gradually dissected away. At the end of the operation, all of the cranial nerves were intact.

 Postoperative MRI showed near complete tumor resection with preservation of the internal carotid artery. At 6 mo follow-up her modified Rankin Scale was 1 and vision in left eye was normal.

 Informed consent was obtained from the patient prior to the surgery that included videotaping of the procedure and its distribution for educational purposes. All relevant patient identifiers have also been removed from the video and accompanying radiology slides.
DWARF WITH SLENDER LEAF1 encoding a histone deacetylase plays diverse roles in rice development
Authors: Kubo Fumika Clara , Yasui Yukiko , Ohmori Yoshihiro , Kumamaru Toshihiro , Tanaka Wakana , Hirano Hiro-Yuki
Published: November 2019

In plants, reversible histone acetylation and deacetylation play a crucial role in various biological activities, including development and the response to environmental stress. Histone deacetylation, which is generally associated with gene silencing, is catalyzed by multiple histone deacetylases (HDACs). Our understanding of HDAC function in plant development has accumulated from molecular genetic studies in Arabidopsis thaliana. By contrast, how HDACs contribute to the development of rice (Oryza sativa) is poorly understood and no rice mutants of HDAC have been reported. Here we have characterized a new rice mutant showing semi-dwarfism, which we named dwarf with slender leaf1 (dsl1). The mutant showed pleiotropic defects in both vegetative and reproductive development; for example, dsl1 produced short and narrow leaves, accompanied with a reduction in the number and size of vascular bundles. The semi-dwarf phenotype was due to suppression of the elongation of some culm (stem) internodes. Interestingly, despite this suppression of the upper internodes, the elongation and generation of lower internodes were slightly enhanced. Inflorescence and spikelet development were also affected by the dsl1 mutation. Some of the observed morphological defects were related to a reduction in cell numbers, in addition to reduced cell division in leaf primordia revealed by in situ hybridization analysis, suggesting the possibility that DSL1 is involved in cell division control. Gene cloning revealed that DSL1 encodes an HDAC belonging to the Reduced potassium dependence3/Histone Deacetylase1 (RPD3/HDA1) family. Collectively, our study shows that the HDAC DSL1 plays diverse and important roles in development in rice.
All-cause and cause-specific mortality in ANCA-associated vasculitis: overall and according to ANCA type
Authors: Wallace Zachary S , Fu Xiaoqing , Harkness Tyler , Stone John H , Zhang Yuqing  , Choi Hyon
Published: November 2019

Objective

The objective of this study was to evaluate causes of death in a contemporary inception cohort of ANCA-associated vasculitis patients, stratifying the analysis according to ANCA type.

Methods

We identified a consecutive inception cohort of patients newly diagnosed with ANCA-associated vasculitis from 2002 to 2017 in the Partners HealthCare System and determined vital status through the National Death Index. We determined cumulative mortality incidence and standardized mortality ratios (SMRs) compared with the general population. We compared MPO- and PR3-ANCA+ cases using Cox regression models.

Results

The cohort included 484 patients with a mean diagnosis age of 58 years; 40% were male, 65% were MPO-ANCA+, and 65% had renal involvement. During 3385 person-years (PY) of follow-up, 130 patients died, yielding a mortality rate of 38.4/1000 PY and a SMR of 2.3 (95% CI: 1.9, 2.8). The most common causes of death were cardiovascular disease (CVD; cumulative incidence 7.1%), malignancy (5.9%) and infection (4.1%). The SMR for infection was greatest for both MPO- and PR3-ANCA+ patients (16.4 and 6.5). MPO-ANCA+ patients had an elevated SMR for CVD (3.0), respiratory disease (2.4) and renal disease (4.5). PR3- and MPO-ANCA+ patients had an elevated SMR for malignancy (3.7 and 2.7). Compared with PR3-ANCA+ patients, MPO-ANCA+ patients had a higher risk of CVD death [hazard ratio 5.0 (95% CI: 1.2, 21.2]; P = 0.03].

Conclusion

Premature ANCA-associated vasculitis mortality is explained by CVD, infection, malignancy, and renal death. CVD is the most common cause of death, but the largest excess mortality risk in PR3- and MPO-ANCA+ patients is associated with infection. MPO-ANCA+ patients are at higher risk of CVD death than PR3-ANCA+ patients.
Auditory brainstem responses in weaning pigs and three ages of sows1
Authors: Anderson Nichole Chapel , Thomovsky Stephanie A , Lucas Jeffrey R , Kushiro-Banker Tokiko , Radcliffe John Scott , Stewart Kara R , Lay Donald C
Published: November 2019

Piglet crushing is a devastating welfare concern on swine farms; however, some sows appear unresponsive to a piglet’s call. Sow hearing ability is rarely considered despite the extensive body of research performed on crushing. In this study, pigs of four age groups (weaning, n = 7; gilts, n = 5; 2nd and 3rd parity, n = 5; 5th parity and up, n = 5) were anesthetized and auditory brainstem responses (ABRs) were performed to measure if pig hearing diminishes with age in a mechanically ventilated barn. Before testing, pigs were placed in a sound dampening box. ABRs were performed on animals using 1,000 clicks at two decibel (dB) levels: 90 and 127 dB sound pressure level. Latencies and amplitudes of waves I–V were measured and interpeak latencies for waves I–III, III–V, and I–V were calculated. Five pigs (three 2nd and 3rd parity, and two 5th parity and above) had no detectable waves at either decibel. Sows in 2nd and 3rd parities had very few distinguishable waves, with only wave I and II present in two sows. Amplitudes of waves I and V increased with increased dB (P < 0.001). Increasing dB decreased the latency of each of the recorded waves (P < 0.01). The vast majority of commercial swine are raised in noisy barn environments; it is possible that these environments directly affect the ability for pigs to hear and normal hearing development in this population of animals. Hearing has a significant effect on swine welfare as hearing is integral to successful animal handing and during moments of animal-to-animal communication. Hearing is a considerable welfare issue on farms and ways to decrease pig hearing loss should be considered.
Is there a trial bias impacting user engagement with unguided e-mental health interventions? A systematic comparison of published reports and real-world usage of the same programs
Authors: Baumel Amit , Edan Stav , Kane John M
Published: November 2019

Trial settings that include proactive recruitment, human contact, and assessment procedures may substantially impact the way users engage with unguided e-mental health programs and the generalizability of reported findings. This study examined the impact of trial setting on user behavior by directly comparing reported user engagement in trial-based research and objective measures of real-world usage of the same unguided mental health programs. The authors conducted a systematic search for papers reporting user engagement with off-the-shelf unguided e-mental health programs. Real-world usage was obtained from a panel that presents aggregated nonpersonal information on user engagement with digital programs across the world. A total of 13 papers yielding 14 comparable usage metrics met all inclusion criteria. In three papers reporting the use of programs by lay users without any proactive trial procedures, the ratios calculated by dividing the usage reported in the paper by the usage documented within the objective dataset were 0.84, 1.05, and 1.27—suggesting a sufficient criterion validity for our examination. In studies that proactively recruited users and included pre- to post-assessment procedures (11 comparisons), the median program usage rate reported was 4.06 times higher (IQR = 4.49) than the real-world usage of the same program. Severity of clinical symptoms, in-person versus remote assessment procedures, study design, and program cost had no impact on these differences. The results suggest that trial settings have a large impact on user engagement with unguided interventions and, therefore, on the generalizability of the findings to the real world.
Draft Genomic Resources for the Brown Rot Fungal Pathogen Monilinia laxa
Authors: Landi Lucia , Pollastro Stefania , Rotolo Caterina , Romanazzi Gianfranco , Faretra Francesco , De Miccolis Angelini Rita Milvia
Published: November 2019

Monilinia laxa is the causal agent of brown rot on stone fruit, and it can cause heavy yield losses during field production and postharvest storage. This article reports the draft genome assembly of the M. laxa Mlax316 strain, obtained using a hybrid genome assembly with both Illumina short-reads and PacBio long-reads sequencing technologies. The complete draft genome consists of 49 scaffolds with total size of 42.81 Mb, and scaffold N50 of 2,449.4 kb. Annotation of the M. laxa assembly identified 11,163 genes and 12,424 proteins which were functionally annotated. This new genome draft improves current genomic resources available for M. laxa and represents a useful tool for further research into its interactions with host plants and into evolution in the Monilinia genus.
PRADC1: a novel metabolic‐responsive secretory protein that modulates physical activity and adiposity
Authors: Rodriguez Susana , Stewart Ashley N. , Lei Xia , Cao Xi , Little Hannah C. , Fong Vincent , Sarver Dylan C. , Wong G. William
Published: November 2019

Interorgan communication mediated by secreted proteins plays a pivotal role in metabolic homeostasis, yet the function of many circulating secretory proteins remains unknown. Here, we describe the function of protease‐associated domain‐containing 1 (PRADC1), an enigmatic secretory protein widely expressed in humans and mice. In metabolically active tissues (liver, muscle, fat, heart, and kidney), we showed that Pradc1 expression is significantly suppressed by refeeding and reduced in kidney and brown fat in the context of obesity. PRADC1 is dispensable for whole‐body metabolism when mice are fed a low‐fat diet. However, in obesity induced by high‐fat feeding, PRADC1‐deficient female mice have reduced weight gain and adiposity despite similar caloric intake. Decreased fat mass is attributed, in part, to increased metabolic rate, physical activity, and energy expenditure in these animals. Reduced adiposity in PRADC1‐deficient mice, however, does not improve systemic glucose and lipid metabolism, insulin sensitivity, liver steatosis, or adipose inflammation. Thus, in PRADC1‐deficient animals, decreased fat mass and enhanced physical activity are insufficient to confer a healthy metabolic phenotype in the context of an obesogenic diet. Our results shed light on the physiologic function of PRADC1 and the complex regulation of metabolic health.—Rodriguez, S., Stewart, A. N., Lei, X., Cao, X., Little, H. C., Fong, V., Sarver, D. C., Wong, G. W. PRADC1: a novel metabolic‐responsive secretory protein that modulates physical activity and adiposity. FASEB J. 33, 14748‐14759 (2019). www.fasebj.org
Nonunions of Bisphosphonate Fractures of the Femur: Presentation, Etiopathogenesis, Diagnosis, and Operative Treatment
Authors: Leighton Ross K. , de Dios Robinson Juan , Giannoudis Peter V.
Published: November 2019

Patients presenting with femoral fractures and long-term use of bisphosphonate treatment are at risk of developing a delayed union and/or nonunion as a result of the atypical metabolic activity prevailing at the fracture edges of the affected extremity. The treatment of these nonunions poses a serious challenge to orthopaedic surgeons worldwide and necessitates specialized techniques and materials to design a construct that will last a long period (greater than 6 months), while still allowing weight-bearing in this elderly population. Treatment options, timing of intervention, selection of implant, and the option of bone grafting are discussed to assist the clinician to make the right decisions in these complex clinical cases.
Osteoporotic Bone: When and How to Use Augmentation?
Authors: Schuetze Konrad , Eickhoff Alexander , Röderer Goetz , Gebhard Florian , Richter Peter H.
Published: November 2019

The number of fragility fractures is rising, and treatment is a challenge for orthopaedic trauma surgeons. Various augmentation options have been developed to prevent mechanical failure. Different composites can be used based on the fracture type, patient needs, and biomechanical needs. Indications for augmentation are not limited to osteoporotic fractures but can also be performed as a salvage procedure or in pathologic fractures. Biomechanical studies have shown advantages for augmented implants in the spine, proximal femur, and humerus. Clinical studies are preliminary but promising, showing good clinical results after augmentation with reduced mechanical failure and minimal complications.
Vaccine hesitancy: Not a new phenomenon, but a new threat
Authors: Koslap-Petraco Mary
Published: November 2019

Vaccines have been recognized as one of the top 10 public health achievements of the 20th century. In 1998, a study on the connection between measles, mumps, rubella vaccine and autism was published by the now discredited Andrew Wakefield. That study was retracted in 2010, but the damage was already done. The purpose of this article is to review the history of vaccine hesitancy and discuss a successful paradigm for speaking with vaccine-hesitant parents. Discussion of immunizations related to public health law and religious exemptions will also be reviewed.
Evaluation of biomarkers for monitoring thrombogenic potential of FXaI16L
Authors: Bolt Michael W. , Hua Fei , Brenneman Karrie A. , Graves John E. , Arkin Steven , Criswell Kay
Published: November 2019

A zymogen-like activated factor X variant (FXaI16L) is being developed for treating acute bleeding conditions. Activated factor V is an essential cofactor to FXaI16L for activating prothrombin to thrombin. Thrombi/emboli formation was observed microscopically in FXaI16L toxicity studies in animals. The objective of this research was to evaluate candidate biomarkers for FXaI16L-induced thrombi/emboli formation to inform safety monitoring and dose-escalation decisions in FXaI16L clinical trials. Effects of intravenous FXaI16L administration on platelets, fibrinogen, activated partial thromboplastin time (aPTT), prothrombin time (PT), d-dimer, tissue factor pathway inhibitor, thrombin : antithrombin complex, antithrombin, and factor V, and protein C (PC) activities were evaluated in mice, rats, and monkeys. Mice had endogenous factor V activity 10× that of monkeys and were overly sensitive to FXaI16L-induced thrombi/emboli formation. In monkeys, decreases in fibrinogen and prolongation in aPTT and PT emerged as potential biomarkers for impending FXaI16L-induced thrombi/emboli formation, based on association of changes with microscopically observable thrombi/emboli (0–97 thrombi/emboli per monkey). PC decreases, measured by a clot-based assay, were also observed. A similar reduction in PC activity, when measured by clot-based assay, was observed in a phase 1 clinical trial. However, an in-vitro experiment with human plasma spiked with increasing concentrations of FXaI16L indicated dose-dependent FXaI16L-induced interference with clot-based assays and no depletion of PC or S by FXaI16L in non-clot-based assays. Nonclinical biomarker studies identified fibrinogen, aPTT and PT as potential biomarkers for monitoring the clinical safety of FXaI16L. Results of clot-based assays with FXaI16L treatment should be interpreted with caution.
A Pilot Study of an Intervention to Prevent Suicide After Psychiatric Hospitalization
Authors: Riblet Natalie B. , Shiner Brian , Schnurr Paula , Bruce Martha L. , Wasserman Danuta , Cornelius Sarah , Scott Robert , Watts Bradley V.
Published: November 2019

A prior meta-analysis found that the World Health Organization Brief Intervention and Contact Program (WHO BIC) significantly reduces suicide risk. WHO BIC has not been studied in high-income countries. We piloted an adapted version of WHO BIC on an inpatient mental health unit in the United States. We assessed the feasibility and acceptability. We also evaluated changes in suicidal ideation, hopelessness, and connectedness using a repeated measures analysis of variance. Of 13 eligible patients, 9 patients enrolled. Patients experienced significant improvements in suicidal ideation, hopelessness, and connectedness at 1 and 3 months (Beck Scale for Suicidal Ideation, F(2,16) = 14.96, p < 0.01; Beck Hopelessness Scale, F(2,16) = 5.88, p < 0.05; perceived burdensomeness subscale, F(2,16) = 10.97, p < 0.013; and thwarted belongingness subscale, F(2,16) = 4.77, p < 0.03). Patients were highly satisfied. An adapted version of WHO BIC may be feasible to implement in a high-resource setting, but trials need to confirm efficacy.
Oxygenator Impact on Ceftolozane and Tazobactam in Extracorporeal Membrane Oxygenation Circuits
Authors: Cies Jeffrey J. , Moore Wayne S. , Giliam Nadji , Low Tracy , Enache Adela , Chopra Arun
Published: November 2019

Objectives:

To determine the oxygenator impact on alterations of ceftolozane/tazobactam in a contemporary neonatal/pediatric (1/4-inch) and adolescent/adult (3/8-inch) extracorporeal membrane oxygenation circuit including the Quadrox-i oxygenator (Maquet, Wayne, NJ).

Design:

A 1/4-inch and 3/8-inch, simulated closed-loop extracorporeal membrane oxygenation circuits were prepared with a Quadrox-i pediatric and Quadrox-i adult oxygenator and blood primed. Additionally, 1/4-inch and 3/8-inch circuits were also prepared without an oxygenator in series. A one-time dose of ceftolozane/tazobactam was administered into the circuits and serial preoxygenator and postoxygenator concentrations were obtained at 5 minutes, 1, 2, 3, 4, 5, 6, and 24-hour time points. Ceftolozane/tazobactam was also maintained in a glass vial and samples were taken from the vial at the same time periods for control purposes to assess for spontaneous drug degradation

Setting:

A free-standing extracorporeal membrane oxygenation circuit.

Patients:

None.

Interventions:

Single-dose administration of ceftolozane/tazobactam into closed-loop extracorporeal membrane oxygenation circuits prepared with and without an oxygenator in series with serial preoxygenator, postoxygenator, and reference samples obtained for concentration determination over a 24-hour study period.

Measurements and Main Results:

For the 1/4-inch circuit, there was approximately 92% ceftolozane and 22–25% tazobactam loss with the oxygenator in series and 19–30% ceftolozane and 31–34% tazobactam loss without an oxygenator in series at 24 hours. For the 3/8-inch circuit, there was approximately 85% ceftolozane and 29% tazobactam loss with the oxygenator in series and 25–27% ceftolozane and 23–26% tazobactam loss without an oxygenator in series at 24 hours. The reference ceftolozane and tazobactam concentrations remained relatively constant during the entire study period demonstrating the drug loss in each size of the extracorporeal membrane oxygenation circuit with or without an oxygenator was not a result of spontaneous drug degradation.

Conclusions:

This ex vivo investigation demonstrated substantial ceftolozane loss within an extracorporeal membrane oxygenation circuit with an oxygenator in series with both sizes of the Quadrox-i oxygenator at 24 hours and significant ceftolozane loss in the absence of an oxygenator. Tazobactam loss was similar regardless of the presence of an oxygenator. Further evaluations with multiple dose in vitro and in vivo investigations are needed before specific drug dosing recommendations can be made for clinical application with extracorporeal membrane oxygenation.
Effect of Endotracheal Tube Size, Respiratory System Mechanics, and Ventilator Settings on Driving Pressure
Authors: Ilia Stavroula , van Schelven Patrick D. , Koopman Alette A. , Blokpoel Robert G. T. , de Jager Pauline , Burgerhof Johannes G. M. , Markhorst Dick G. , Kneyber Martin C. J.
Published: November 2019

Objectives:

We sought to investigate factors that affect the difference between the peak inspiratory pressure measured at the Y-piece under dynamic flow conditions and plateau pressure measured under zero-flow conditions (resistive pressure) during pressure controlled ventilation across a range of endotracheal tube sizes, respiratory mechanics, and ventilator settings.

Design:

In vitro study.

Setting:

Research laboratory.

Patients:

None.

Interventions:

An in vitro bench model of the intubated respiratory system during pressure controlled ventilation was used to obtain the difference between peak inspiratory pressure measured at the Y-piece under dynamic flow conditions and plateau pressure measured under zero-flow conditions across a range of endotracheal tubes sizes (3.0–8.0 mm). Measurements were taken at combinations of pressure above positive end-expiratory pressure (10, 15, and 20 cm H2O), airway resistance (no, low, high), respiratory system compliance (ranging from normal to extremely severe), and inspiratory time at constant positive end-expiratory pressure (5 cm H2O). Multiple regression analysis was used to construct models predicting resistive pressure stratified by endotracheal tube size.

Measurements and Main Results:

On univariate regression analysis, respiratory system compliance (β –1.5; 95% CI, –1.7 to –1.4; p < 0.001), respiratory system resistance (β 1.7; 95% CI, 1.5–2.0; p < 0.001), pressure above positive end-expiratory pressure (β 1.7; 95% CI, 1.4–2.0; p < 0.001), and inspiratory time (β –0.7; 95% CI, –1.0 to –0.4; p < 0.001) were associated with resistive pressure. Multiple linear regression analysis showed the independent association between increasing respiratory system compliance, increasing airway resistance, increasing pressure above positive end-expiratory pressure, and decreasing inspiratory time and resistive pressure across all endotracheal tube sizes. Inspiratory time was the strongest variable associated with a proportional increase in resistive pressure. The contribution of airway resistance became more prominent with increasing endotracheal tube size.

Conclusions:

Peak inspiratory pressures measured during pressure controlled ventilation overestimated plateau pressure irrespective of endotracheal tube size, especially with decreased inspiratory time or increased airway resistance.
Fidelity to Best Practices of Psychiatric Assessments in Army Behavioral Health Settings
Authors: WILLIAMS JUINELL B. , TOBLIN ROBIN L. , DUFFY FARIFTEH F. , SHANNAHOFF MOLLY E. , WILK JOSHUA E.
Published: November 2019

While civilian and military psychiatric clinical practice guidelines (CPGs) exist for psychiatric assessments, data are lacking on providers’ adherence to these criteria. This study evaluated the use of psychiatric CPGs’ assessment criteria by Army behavioral health providers (BHPs). In a weighted cross-sectional survey, 348 BHPs were evaluated on their assessment of a systematically selected patient on 15 total domains recommended by the Departments of Veterans Affairs and Defense CPGs for substance use disorders, posttraumatic stress disorder, and major depressive disorder. The proportion of BHPs providing high-quality assessment and the association between high-quality assessment and BHP and patient characteristics were examined. Using the weighted sample, 80% of BHPs provided a high-quality assessment. BHPs who saw ≥20 patients per week were significantly more likely to provide high-quality assessments compared with BHPs who saw <20 patients per week [odds ratio (OR)=1.72, 95% confidence interval (CI)=1.01-2.92]. Patients diagnosed with generalized anxiety disorder [adjusted OR (AOR)=0.42, 95% CI=0.18-0.96] or whose BHPs did not assess patients’ current overall physical health (AOR=0.26, 95% CI=0.07-0.97) or lifetime duration of treatment for mental health (AOR=0.03, 95% CI=0.01-0.20) were less likely to receive high-quality assessments. A majority of Army BHPs are conducting high-quality assessments for the 3 most common mental disorders in military populations. If recommendations to increase fidelity to assessment could be implemented, more patients could receive optimized care.
What Psychotherapists Should Understand About DNA Methylation
Authors: PLAKUN ERIC M.
Published: November 2019

This column reviews the basics of DNA methylation and how this molecular mechanism is related to the experience of trauma, the causation of mental disorders, and recovery from both trauma and mental disorders. Emerging molecular genetic findings about the role of DNA methylation in mental disorders fit well with our understanding of what is valuable about psychotherapy. DNA methylation offers a heuristically useful metaphor to broaden our understanding of how psychotherapy works.
Basal Ganglia Calcification: A Case Report of Fahr Disease With Pure Psychiatric Symptoms
Authors: KONSTANTINOU GERASIMOS , STAVRINOU ANASTASIA , MYLONA SAVVINA , PASCHALAKIS GEORGE , VASILOPOULOU POLYXENI
Published: November 2019

Fahr disease, also known as familial idiopathic basal ganglia calcification, is a rare neurodegenerative disorder, the etiology of which remains unknown. Given its various presentations, Fahr disease is presumed to be underdiagnosed and its prevalence underestimated. We present a case of Fahr disease that presented mainly with pure psychiatric symptoms. Isolated psychiatric symptoms without neurological manifestations are rarely seen in patients diagnosed with Fahr disease. Psychiatrists should consider Fahr disease as a differential diagnosis in the evaluation of psychiatric illness.
Commentary on “Basal Ganglia Calcification: A Case Report of Fahr Disease With Pure Psychiatric Symptoms”
Authors: KAHN DAVID A.
Published: November 2019

Fahr disease, also known as familial idiopathic basal ganglia calcification, is a rare neurodegenerative disorder, the etiology of which remains unknown. Given its various presentations, Fahr disease is presumed to be underdiagnosed and its prevalence underestimated. We present a case of Fahr disease that presented mainly with pure psychiatric symptoms. Isolated psychiatric symptoms without neurological manifestations are rarely seen in patients diagnosed with Fahr disease. Psychiatrists should consider Fahr disease as a differential diagnosis in the evaluation of psychiatric illness.
Commentary on “Are We Missing Subtle Forms of Anti-N-Methyl-D-Aspartate Encephalitis With the Current Diagnostic Approach? A Case Report”
Authors: KAHN DAVID A.
Published: November 2019

Encephalitis related to antibodies against the N-methyl-D-aspartate receptor (NMDAr) is a recently described clinical entity in which IgG autoantibodies against the NR1 subunit of the NMDAr lead to the appearance of complex neuropsychiatric symptoms. As psychiatric symptoms predominate in early stages, anti-NMDAr encephalitis is frequently mistaken as a primary psychiatric disorder which delays treatment and has serious consequences for patients. This report presents the case of a 24-year-old woman with a subacute onset of psychotic and catatonic symptoms in whom current diagnostic criteria for probable anti-NMDAr encephalitis were not fulfilled. On the basis of the red flags that have been proposed to raise suspicion of anti-NMDAr encephalitis, a study of fluorodeoxyglucose positron emission tomography was requested and demonstrated bilateral occipital hypometabolism consistent with clinical suspicion of anti-NMDAr encephalitis. Once the appropriate treatment was established, the patient recovered completely. This case supports the need to maintain clinical suspicion of anti-NMDAr encephalitis, even when conventional diagnostic tests have been normal. Psychiatrists should be familiar with this entity to promote timely diagnosis and prompt treatment.
Appreciating the 4 “Ts” of Loneliness When Providing Psychiatric Care for the Lonely Patient
Authors: LOBOPRABHU SHEILA , MOLINARI VICTOR
Published: November 2019

Loneliness can be evaluated from a 4-concept viewpoint of territory, threat, trauma and trust (4 Ts). Territory refers to an area of ownership that is controlled on a daily basis and is fundamental to one’s daily life. Lonely individuals often manage boundaries by gaining greater control over their physical environment by territorial behavior. They guard personal territory well as the only area where they can exert dominance and feel safe. Perceptions of social isolation or loneliness increase vigilance for threats, decrease trust, and heighten feelings of vulnerability. Clinical teams caring for the lonely must be especially attentive to a history of prior trauma. Clinicians who ask permission, who pay attention to nonverbal cues, distance, and speed as they enter the lonely person’s space, and who respect boundaries may be more successful in gaining trust. Achieving trust diminishes the risk of physical harm, while allowing lonely persons the perceived control they need to permit health care interventions. Veterans are at higher risk for loneliness. Given their military training, they may be particularly attentive to boundaries, protecting the perimeter, watching for threats, and defending their space. In this article, we discuss the successful mental health treatment of a lonely male veteran in a Veterans Affairs Medical Center, by paying attention to the 4 Ts of loneliness. We used a 4-step approach of validation, mentalization, reality testing, and socialization to decrease the sense of threat as we sought acceptance to the patient’s territory, followed by building trust and working on past trauma.
Findings From a Trial of the Smartphone and OnLine Usage-based eValuation for Depression (SOLVD) Application: What Do Apps Really Tell Us About Patients with Depression? Concordance Between App-Generated Data and Standard Psychiatric Questionnaires for Depression and Anxiety
Authors: MOUKADDAM NIDAL , TRUONG ANH , CAO JIAN , SHAH ASIM , SABHARWAL ASHUTOSH
Published: November 2019

Objective:

Depression imposes a notable societal burden, with limited treatment success despite multiple available psychotherapy and medications choices. Potential reasons may include the heterogeneity of depression diagnoses and the presence of comorbid anxiety symptoms. Despite technological advances and the introduction of many mobile phone applications (apps) claiming to relieve depression, major gaps in knowledge still exist regarding what apps truly measure and how they correlate with psychometric questionnaires. The goal of this study was to evaluate whether mobile daily mood self-ratings may be useful in monitoring and classifying depression symptoms in a clinically depressed population compared with standard psychometric instruments including the Patient Health Questionaire-9 (PHQ-9), the Hamilton Rating Scale for Depression (HAM-D), and the Hamilton Anxiety Rating Scale (HAM-A).

Method:

For this study, 22 patients with major depressive disorder with or without comorbid anxiety disorder were recruited. The diagnosis of depression was confirmed through the Mini International Neuropsychiatric Interview (MINI). Over an 8-week period, daily moods were self-reported through the Smartphone and OnLine Usage-based eValuation for Depression (SOLVD) application, a custom-designed application that was downloaded onto patients’ mobile devices. Depression and anxiety symptoms were also measured biweekly using the HAM-D, HAM-A, and PHQ-9.

Results:

Significant correlations were observed among self-evaluated mood, daily steps taken, SMS (text) frequency, average call duration, and biweekly psychometric scores (|r|>0.5, P<0.05). The correlation coefficients were higher in individuals with more severe depressive symptoms.

Conclusions:

Although this study, given its limited sample size, was exploratory in nature, it helps fill a significant gap in our knowledge of the concordance between ratings obtained on the Ham-D, Ham-A, and the PHQ-9 psychometric instruments and data obtained via a smartphone app. These questionnaires represent gold-standard, commonly used psychiatric research/clinical instruments, and, thus, this information can serve as a foundation for digital phenotyping for depression and pave the way for interventional studies using smartphone applications.
Altered monocyte phenotype and dysregulated innate cytokine responses among people living with HIV and opioid-use disorder
Authors: Underwood Michelle L. , Nguyen Thuan , Uebelhoer Luke S. , Kunkel Lynn E. , Korthuis Philip T. , Lancioni Christina L.
Published: November 2019

Background:

Opioid-use disorders (OUD) and hepatitis C or B co-infection (HEP) are common among people living with HIV (PLHIV). The impact of OUD on innate and adaptive immunity among PLHIV with and without HEP is unknown.

Objectives:

To investigate the impact of OUD on monocyte and T-cell phenotypes, cytokine responses to lipopolysaccharide (LPS) and phytohemagglutinin (PHA), and plasma inflammatory markers, among PLHIV with and without HEP.

Methods:

Cross-sectional study enrolling PLHIV receiving ART, with and without OUD. Flow cytometry determined monocyte and T-cell phenotypes; LPS and PHA-induced cytokine production was assessed following LPS and PHA stimulation by multiplex cytokine array; plasma IL-6, soluble CD163, and soluble CD14 were measured by ELISA.

Results:

Twenty-two PLHIV with OUD and 37 PLHIV without OUD were included. PLHIV with OUD exhibited higher frequencies of intermediate (CD14++CD16+) and nonclassical (CD14dimCD16+) monocytes when compared with PLHIV without OUD (P = 0.0025; P = 0.0001, respectively), regardless of HEP co-infection. Soluble CD163 and monocyte cell surface CD163 expression was increased among PLHIV with OUD and HEP, specifically. Regardless of HEP co-infection, PLHIV with OUD exhibited reduced production of IL-10, IL-8, IL-6, IL-1alpha, and TNF-alpha in response to LPS when compared with PLHIV without OUD; PHA-induced production of IL-10, IL-1alpha, IL-1beta, IL-6, and TNF-alpha were also reduced among individuals with OUD.

Conclusion:

OUD among PLHIV are associated with altered monocyte phenotypes and a dysregulated innate cytokine response. Defining underlying mechanisms of opioid-associated innate immune dysregulation among PLHIV should be prioritized to identify optimal OUD treatment strategies.