bluuebunny/crossref_metadata_2025 huggingface dataset:
Deubiquitinating enzyme USP30 maintains basal peroxisome abundance by regulating pexophagy
Authors: Riccio Victoria , Demers Nicholas , Hua Rong , Vissa Miluska , Cheng Derrick T. , Strilchuk Amy Wong , Wang Yuqing , McQuibban G. Angus , Kim Peter Kijun
Published: January 2019

The regulation of organelle abundance is critical for cell function and survival; however, the mechanisms responsible are not fully understood. In this study, we characterize a role of the deubiquitinating enzyme USP30 in peroxisome maintenance. Peroxisomes are highly dynamic, changing in abundance in response to metabolic stress. In our recent study identifying the role of USP30 in mitophagy, we observed USP30 to be localized to punctate structures resembling peroxisomes. We report here that USP30, best known as a mitophagy regulator, is also necessary for regulating pexophagy, the selective autophagic degradation of peroxisomes. We find that overexpressing USP30 prevents pexophagy during amino acid starvation, and its depletion results in pexophagy induction under basal conditions. We demonstrate that USP30 prevents pexophagy by counteracting the action of the peroxisomal E3 ubiquitin ligase PEX2. Finally, we show that USP30 can rescue the peroxisome loss observed in some disease-causing peroxisome mutations, pointing to a potential therapeutic target.
Pancreatic β cells: Gatekeepers of type 2 diabetes
Authors: Park Yoo Jin , Woo Minna
Published: January 2019

Park and Woo outline the cellular events leading to failure of the insulin-producing β cells in type 2 diabetes.
Effect of HCl cleaning on InSb–Al2O3 MOS capacitors
Authors: Vavasour Oliver J , Jefferies Richard , Walker Marc , Roberts Joseph W , Meakin Naomi R , Gammon Peter M , Chalker Paul R , Ashley Tim
Published: January 2019

In this work, the role of HCl treatments on InSb surfaces and InSb–Al2O3 dielectric interfaces is characterised. X-ray photoelectron spectroscopy measurements indicate that HCl diluted in and rinsed with isopropanol (IPA) results in a surface layer of InCl3 which is not present for similar HCl-water processes. Furthermore, this InCl3 layer desorbs from the surface between 200 °C and 250 °C. Metal–oxide–semiconductor capacitors were fabricated using atomic layer deposition of Al2O3 at 200 °C and 250 °C and the presence of InCl3 was associated with a +0.79 V flatband voltage shift. The desorption of the InCl3 layer at 250 °C reversed this shift but the increased process temperature resulted in increased interface-trapped charge (D
it) and hysteresis voltage (V

H
). This shift in flatband voltage, which does not affect other figures of merit, offers a promising route to manipulate the threshold voltage of MOS transistors, allowing enhancement-mode and depletion-mode devices to be fabricated in parallel.
Efficacy and Safety of Intravenous-to-oral Lefamulin, a Pleuromutilin Antibiotic, for the Treatment of Community-acquired Bacterial Pneumonia: The Phase III Lefamulin Evaluation Against Pneumonia (LEAP 1) Trial
Authors: File Thomas M , Goldberg Lisa , Das Anita , Sweeney Carolyn , Saviski John , Gelone Steven P , Seltzer Elyse , Paukner Susanne , Wicha Wolfgang W , Talbot George H , Gasink Leanne B
Published: January 2019

Monotherapy with lefamulin, a novel, pleuromutilin antibiotic with intravenous and oral formulation options, was noninferior to moxifloxacin for efficacy and generally safe and well tolerated for community-acquired bacterial pneumonia (CABP). Lefamulin’s spectrum of activity targets bacteria that cause CABP.
Prevalence and Factors Associated With Fatigue in Patients With Inflammatory Bowel Disease: A Multicentre Study
Authors: Chavarría C , Casanova M J , Chaparro M , Barreiro-de Acosta M , Ezquiaga E , Bujanda L , Rivero M , Argüelles-Arias F , Martín-Arranz M D , Martínez-Montiel M P , Valls M , Ferreiro-Iglesias R , Llaó J , Moraleja-Yudego I , Casellas F , Antolín-Melero B , Cortés X , Plaza R , Pineda J R , Navarro-Llavat M , García-López S , Robledo-Andrés P , Marín-Jiménez I , García-Sánchez V , Merino O , Algaba A , Arribas-López M R , Banales J M , Castro B , Castro-Laria L , Honrubia R , Almela P , Gisbert J P
Published: January 2019

Background and Aims

The aims of this study were to determine the prevalence of fatigue in patients with inflammatory bowel disease [IBD], to identify the factors associated with fatigue and its severity, to assess the impact of fatigue on quality of life [QoL], and to evaluate the relationship between fatigue and sleep disorders.

Methods

This was a prospective multicentre study conducted at 22 Spanish centres. Consecutive patients followed at IBD Units were included. Fatigue was evaluated with the Fatigue Severity Scale [FSS] and the Fatigue Impact Scale [FIS]. Quality of life and sleep quality were assessed using the IBD Questionnaire-Short Form [IBDQ-9] and the Pittsburgh Sleep Quality Index [PSQI], respectively.

Results

A total of 544 consecutive adult IBD patients were included [50% women, mean age 44 years, 61% Crohn’s disease]. The prevalence of fatigue was 41% (95% confidence interval [CI] = 37–45%). The variables associated with an increased risk of fatigue were: anxiety [OR = 2.5, 95% CI = 1.6–3.7], depression [OR = 2.4, 95% CI = 1.4–3.8], presence of extraintestinal manifestations [EIMs] [OR = 1.7, 95% CI = 1.1–2.6], and treatment with systemic steroids [OR = 2.8, 95% CI = 1.4–5.7]. The presence of EIMs [regression coefficient, RC = 8.2, 95% CI = 2.3–14.2], anxiety [RC = 25.8, 95% CI = 20.0–31.5], depression [RC = 30.6, 95% CI = 24.3–37.0], and sleep disturbances [RC = 15.0, 95% CI = 9.3–20.8] were associated with severity of fatigue. Patients with fatigue had a significantly decreased IBDQ-9 score [p < 0.001].

Conclusions

The prevalence of fatigue in IBD patients is remarkably high and has a negative impact on QoL. Therapy with systemic steroids is associated with an increased risk of fatigue. The severity of fatigue is associated with anxiety, depression, sleep disorders, and the presence of EIMs. Fatigue was not associated with anaemia, disease activity or anti-TNF therapy.
Health Professional Perspectives on Rehabilitation for People With Dementia
Authors: Cations Monica , May Natalie , Crotty Maria , Low Lee-Fay , Clemson Lindy , Whitehead Craig , McLoughlin James , Swaffer Kate , Laver Kate E
Published: January 2019

Background and Objectives

Multidisciplinary rehabilitation is not incorporated into the usual care pathway for dementia despite increasing demand from key advocates. Clinician views regarding the relevance of rehabilitation in dementia care are not well known. This qualitative study explored the perspectives of health professionals regarding barriers to provision of multidisciplinary rehabilitation programs for people with dementia.

Research Design and Methods

Sixteen health professionals from a variety of settings and professional backgrounds were purposively sampled using maximum variation sampling. Semi-structured interviews were conducted to explore attitudes toward the care of people with dementia and beliefs about the feasibility and value of multidisciplinary rehabilitation in this population. Thematic analysis was used to identify themes.

Results

Participating clinicians acknowledged problems with existing dementia care pathways in Australia but rarely conceptualized rehabilitation as relevant to this pathway. Analyses yielded two main and related themes: (i) difficulty defining worthwhile outcomes of a rehabilitation program for people with dementia and (ii) perceived barriers to participation in this population. Clinicians felt that achievable outcomes for people with dementia were not sufficiently worthwhile for investment.

Discussion and Implications

Broader acceptance of multidisciplinary rehabilitation as relevant to dementia care will require a reframing of practice that both educates emerging health professionals regarding the outcomes that may be achievable for people with dementia and persuades staff to appreciate that the investment is worthwhile.
On the Inhomogeneity of the Mandelbrot Set
Authors: Luo Yusheng
Published: January 2019

We will show that the Mandelbrot set $M$ is locally conformally inhomogeneous; the only conformal map $f$ defined in an open set $U$ intersecting $\partial M$ and satisfying $f(U\cap \partial M)=f(U)\cap \partial M$ is the identity map. The proof uses the study of local conformal symmetries of the Julia sets of polynomials; we will show in many cases that the dynamics can be recovered from the local conformal structure of the Julia sets.
Use of Aspergillus fumigatus real-time PCR in bronchoalveolar lavage samples (BAL) for diagnosis of invasive aspergillosis, including azole-resistant cases, in high risk haematology patients: the need for a combined use with galactomannan
Authors: Mikulska Malgorzata , Furfaro Elisa , De Carolis Elena , Drago Enrico , Pulzato Ilaria , Borghesi Maria Lucia , Zappulo Emanuela , Raiola Anna Maria , Grazia Carmen Di , Del Bono Valerio , Cittadini Giuseppe , Angelucci Emanuele , Sanguinetti Maurizio , Viscoli Claudio
Published: January 2019

Diagnosis of invasive aspergillosis (IA) is challenging, particularly in high-risk patients with lung lesions other than typical according to 2008-EORTC/MSG criteria. Even if microbiology is positive, they still remain unclassified according to 2008-EORTC/MSG. Quantitative polymerase chain reaction (qPCR) provides new mycological documentation of IA. This retrospective study assessed Aspergillus fumigatus real time qPCR (MycoGENIE®) in BAL to diagnose IA and identify azole-resistant strains. Clinical, radiological, and microbiological data from 114 hematology patients (69% HSCT recipients; 29% on mould active agents) from years 2012-2017 were collected; and 123 BAL samples were tested with qPCR (cutoff: Ct < 40) and galactomannan (GM, Platelia®, cutoff: 0.5 ODI). Patients were classified as proven/probable, possible, and no-IA. "Atypical-IA" referred to patients with lesions other than typical according to 2008-EORTC/MSG and positive mycology. Proven IA was diagnosed in two cases (1.6%), probable in 28 (22.8%), possible in 27 (22%), atypical in 14 (11.4%). qPCR was positive in 39 samples (31.7%). Sensitivity and specificity of qPCR for proven/probable IA (vs no-IA; atypical-IA excluded) were 40% (95% confidence interval [CI]: 23–59) and 69% (95%CI: 55–81), respectively. Sensitivity of qPCR was higher when combined with GM (83%, 95%CI: 65–94) and in those receiving mould-active agents at BAL (61%, 95%CI: 32–86). One sample had TR34/L98H mutation. In conclusion, in high-risk hematology patients with various lung lesions, A. fumigatus qPCR in BAL contributes to diagnosing IA, particularly if combined with GM and in patients receiving mould-active agents might allow detecting azole-resistant mutations in culture negative samples.
Coping with selection effects: a Primer on regression with truncated data
Authors: Mantz Adam B
Published: January 2019

The finite sensitivity of instruments or detection methods means that data sets in many areas of astronomy, for example cosmological or exoplanet surveys, are necessarily systematically incomplete. Such data sets, where the population being investigated is of unknown size and only partially represented in the data, are called ‘truncated' in the statistical literature. Truncation can be accounted for through a relatively straightforward modification to the model being fitted in many circumstances, provided that the model can be extended to describe the population of undetected sources. Here, I examine the problem of regression using truncated data in general terms, and use a simple example to show the impact of selecting a subset of potential data on the dependent variable, on the independent variable, and on a second dependent variable that is correlated with the variable of interest. Special circumstances in which selection effects are ignorable are noted. I also comment on computational strategies for performing regression with truncated data, as an extension of methods that have become popular for the non-truncated case, and provide some general recommendations.
Contribution of Human Herpesvirus 8 and Herpes Simplex Type 2 to Progression of Carotid Intima-Media Thickness in People Living With HIV
Authors: Lidón Fernando , Padilla Sergio , García Jose A , Fernández Marta , García Javier , Ortiz de la Tabla Victoria , Gutiérrez Félix , Masiá Mar
Published: January 2019

Background

Human herpesvirus 8 (HHV-8) is a lymphotropic and vasculotropic herpesvirus with potential pro-atherogenic effects. We explored the influence of coinfection with HHV-8 and other herpesviruses on the rate of progression of carotid intima-media thickness (cIMT) in virologically suppressed people living with HIV (PLWH).

Methods

Prospective cohort study including men who have sex with men (MSM) infected with HIV. At the baseline visit, IgG antibodies against HHV-8 and other herpesviruses, highly sensitive C-reactive protein (hsCRP) levels, and Framingham risk scores were measured. To evaluate the progression of cIMT, successive measurements with high-resolution carotid artery ultrasound were performed over an 8-year period. Adjusted general linear mixed models were used to assess factors associated with faster cIMT progression.

Results

One hundred forty-one participants with suppressed HIV-RNA (<200 copies/mL) at cIMT measurement during the study period were included. Forty-six (31.3%) were coinfected with HHV-8 and 76 (54%) with herpes simplex virus 2 (HSV-2). Factors associated with faster cIMT progression adjusting for CD4 cell counts, time between cIMT measurements, hepatitis C, varicella zoster virus, and cytomegalovirus coinfection were seropositivity for HHV-8 (P = .059), HSV-2+HHV-8 coinfection (P = .027), Framingham risk score (P = .057), and hsCRP (P = .027). Coinfection with HHV-8 was independently associated with higher levels of hsCRP (odds ratio, 1.09; 95% confidence interval, 1.02 to 1.17; P = .016). When hsCRP and HHV-8 were simultaneously included in the adjusted model, the relationship of HHV-8 with cIMT progression was attenuated.

Conclusions

HHV-8 might contribute to progression of cIMT with a more prominent role when it coinfects with HHV-2 in virologically suppressed PLWH, and this effect could be driven by systemic inflammation.
Is it possible to overcome the ‘long arm’ of childhood socioeconomic disadvantage through upward socioeconomic mobility?
Authors: Vable Anusha M , Gilsanz Paola , Kawachi Ichiro
Published: January 2019

Objectives

Socioeconomically disadvantaged children have worse adult health; we test if this ‘long arm’ of childhood disadvantage can be overcome through upward socioeconomic mobility in adulthood.

Methods

Four SES trajectories (stable low, upwardly mobile, downwardly mobile and stable high) were created from median dichotomized childhood socioeconomic status (SES; childhood human and financial capital) and adult SES (wealth at age 67) from Health and Retirement Study respondents (N = 6669). Healthy ageing markers, in tertiles, were walking speed, peak expiratory flow (PEF), and grip strength measured in 2008 and 2010. Multinomial logistic regression models, weighted to be nationally representative, controlled for age, gender, race, birthplace, outcome year and childhood health and social capital.

Results

Upwardly mobile individuals were as likely as the stable high SES group to be in the best health tertile for walking speed (OR = 0.81; 95% CI: 0.63, 1.05; P = 0.114), PEF (OR = 0.97; 95% CI: 0.78, 1.21; P = 0.810) and grip strength (OR = 0.97; 95%CI: 0.74, 1.27; P = 0.980).

Discussion

Findings suggest the ‘long arm’ of childhood socioeconomic disadvantage can be overcome for these markers of healthy ageing through upward socioeconomic mobility.
Developing a graduate training program in Synthetic Biology: SynBioCDT
Authors: Cazimoglu Idil , Darlington Alexander P S , Grigonyte Aurelija , Hoskin Charlotte E G , Liu Juntai , Oppenheimer Robert , Siller-Farfán Jesús A , Grierson Claire , Papachristodoulou Antonis
Published: January 2019

This article presents the experience of a team of students and academics in developing a post-graduate training program in the new field of Synthetic Biology. Our Centre for Doctoral Training in Synthetic Biology (SynBioCDT) is an initiative funded by the United Kingdom’s Research Councils of Engineering and Physical Sciences (EPSRC), and Biotechnology and Biological Sciences (BBSRC). SynBioCDT is a collaboration between the Universities of Oxford, Bristol and Warwick, and has been successfully running since 2014, training 78 students in this field. In this work, we discuss the organization of the taught, research and career development training. We also address the challenges faced when offering an interdisciplinary program. The article concludes with future directions to continue the development of the SynBioCDT.
A LAMP Protocol for the Detection of ‘Candidatus Phytoplasma pyri’, the Causal Agent of Pear Decline
Authors: Siemonsmeier A. , Hadersdorfer J. , Neumüller M. , Schwab W. , Treutter D.
Published: January 2019

Phytoplasmas are cell-wall-less bacteria that cause diseases in approximately 1,000 plant species. ‘Candidatus Phytoplasma pyri’, the causal agent of pear decline, induces various symptoms on its hosts, leading to weakening and dieback of the plants, reduced fruit size and yield, and, consequently, considerable financial losses in all pear-growing areas. Fighting this disease requires a reliable and inexpensive method for pathogen detection in propagation material as well as plant stocks in orchards and breeding facilities. Here, we present a field-suitable detection protocol for ‘Ca. P. pyri’ based on loop-mediated isothermal amplification (LAMP) targeting the phytoplasmal 16S ribosomal DNA sequence. The combination of a simplified sample preparation method based on sodium hydroxide and colorimetric visualization of LAMP results enables a laboratory-independent pathogen detection. The detection limit is comparable with analysis by polymerase chain reaction; however, the pear decline LAMP detection method is superior in terms of ease of use, cost, and time effectiveness for obtaining results.
Anterior nucleus of paraventricular thalamus mediates chronic mechanical hyperalgesia
Authors: Chang Ya-Ting , Chen Wei-Hsin , Shih Hsi-Chien , Min Ming-Yuan , Shyu Bai-Chuang , Chen Chien-Chang
Published: January 2019

Pain-related diseases are the top leading causes of life disability. Identifying brain regions involved in persistent neuronal changes will provide new insights for developing efficient chronic pain treatment. Here, we showed that anterior nucleus of paraventricular thalamus (PVA) plays an essential role in the development of mechanical hyperalgesia in neuropathic and inflammatory pain models in mice. Increase in c-Fos, phosphorylated extracellular signal–regulated kinase, and hyperexcitability of PVA neurons were detected in hyperalgesic mice. Direct activation of PVA neurons using optogenetics and pharmacological approaches were sufficient to induce persistent mechanical hyperalgesia in naive animals. Conversely, inhibition of PVA neuronal activity using DREADDs (designer receptors exclusively activated by designer drugs) or inactivation of PVA extracellular signal–regulated kinase at the critical time window blunted mechanical hyperalgesia in chronic pain models. At the circuitry level, PVA received innervation from central nucleus of amygdala, a known pain-associated locus. As a result, activation of right central nucleus of amygdala with blue light was enough to induce persistent mechanical hyperalgesia. These findings support the idea that targeting PVA can be a potential therapeutic strategy for pain relief.
Modified-Power-Piston: Short-Incudial-Process-Vibroplasty and Simultaneous Stapedotomy in Otosclerosis
Authors: Dejaco Daniel , Riedl David , Gottfried Timo , Rasse Thomas , Fischer Natalie , Prejban David , Koci Viktor , Riechelmann Herbert , Schmutzhard Joachim , Keintzel Thomas
Published: January 2019

Objective:

If mixed-hearing-loss (MHL) occurs in otosclerosis, hearing-aids (HA) in addition to conventional-stapedotomy (SDT) may be necessary. If otosclerosis progresses or technical or medical problems prevent use of HA, combining active-middle-ear-implants (AMEI) with SDT (“power-piston”) may be considered. Previously, AMEI-coupling to the long-incudial-process was suggested. Here, a “modified-power-piston” surgery (mPP) coupling to the short-incudial-process was proposed, so no coupling over the positioned stapes-piston is required. We questioned whether mPP is as safe and effective as SDT.

Methods:

Otosclerotic patients with MHL and limited satisfaction with previously worn HA receiving mPP were retrospectively reviewed at two Austrian tertiary otologic referral centers. Patients, receiving stapedotomy, were case-matched for preoperative pure-tone averages (PTA), bone-conduction (BC-PTA), air-conduction (AC-PTA), and air-bone gap (ABG-PTA). Postoperative changes in BC-PTA and in AC-PTA and ABG-PTA were defined as safety- and as efficacy outcome parameter.

Results:

Of 160 patients, 14 received mPP and 14 stapedotomy. Preoperative findings were comparable (all p = 1.000). BC-PTA improved from 38.0 to 36.7 and from 37.1 to 36.9 dB-HL for mPP and SDT, respectively (Δ –1.3 versus –0.2 dB-HL; p = 0.077). AC-PTA improved from 66.8 to 47.1 and from 66.3 to 46.5 dB-HL for mPP and SDT, respectively (Δ –19.6 versus –19.7 dB-HL; p = 0.991). ABG-PTA improved from 28.8 to 10.4 and from 29.1 to 9.6 dB-HL for mPP and SDT, respectively (Δ –18.3 versus –19.5 dB-HL; p = 0.771).

Conclusion:

In otosclerosis with MHL and limited satisfaction with HA, mPP appeared as safe and effective as SDT and may be considered a treatment alternative in these patients.
Controversy over the atherogenicity of lipoprotein-X
Authors: Miida Takashi , Hirayama Satoshi
Published: January 2019

Purpose of review

Lipoprotein-X (Lp-X) is an abnormal lipoprotein containing abundant free cholesterol and phospholipids, as well as some apolipoprotein E (apoE). Serum Lp-X increases in patients with cholestasis and lecithin–cholesterol acyltransferase deficiency, as well as in those receiving intravenous lipid emulsion. Lp-X is often associated with skin xanthomas in cholestatic patients. However, earlier studies showed that Lp-X is not taken up by murine macrophages, but exerts antiatherogenic actions. In this review, we discuss the heterogeneity of Lp-X and its potential atherogenicity.

Recent findings

Mass spectrometry revealed that Lp-X of cholestatic patients is similar in lipid composition to low-density lipoprotein (LDL) and high-density lipoprotein, but not to bile acids, suggesting that Lp-X is synthesized in the liver. Palmar xanthomas appear in patients with cholestasis, but regress over months after improvement of hypercholesterolemia. Lp-X isolated from cholestatic patients is rich in apoE, and causes more lipid accumulation than oxidized LDL and acetyl LDL in human monocyte-derived macrophages.

Lp-X is heterogeneous in apoE content. Lp-X is taken up in cholestatic patients by apoE-recognizing lipoprotein receptors. Further research is warranted to fully understand the atherogenicity of Lp-X and the clinical significance of elevated Lp-X concentrations, particularly in cholestatic patients.
Retrospective Evaluation of the Perioperative Management of Patients Undergoing Total Pancreatectomy With Islet Autotransplantation
Authors: McSwain Julie R. , Nykamp Madeline , Wolf Bethany J. , McMurray Jeffrey D. , Skorke Christopher A. , Clark Carlee A.
Published: January 2019

Objective

The aim of this retrospective descriptive study was to examine associations with the perioperative management of patients undergoing total pancreatectomy with islet autotransplantation, which may impact complication rate and hospital length of stay.

Methods

We retrospectively collected data on 165 patients, and 161 patients were included in the final analysis. Data collected included preoperative, intraoperative, and postoperative patient and procedural characteristics.

Results

Approximately 46.6% of patients experienced 1 or more complications. The occurrence of complications was associated with postoperative day 1 hemoglobin levels, use of intraoperative goal-directed therapy, estimated intraoperative blood loss, and total amount of intraoperative insulin given. Hospital length of stay was significantly associated with number of complications, use of goal-directed therapy, procedure duration, and postoperative day 1 hemoglobin levels.

Conclusions

Overall, our retrospective descriptive study adds to the emerging body of literature determining optimal perioperative management of patients undergoing total pancreatectomy with islet autotransplantation.
Adenocarcinoma of the Rete Testis
Authors: Al-Obaidy Khaleel I. , Idrees Muhammad T. , Grignon David J. , Ulbright Thomas M.
Published: January 2019

Adenocarcinoma of the rete testis is rare and its etiological and pathologic characteristics are not well studied. We therefore investigated the clinical, morphologic, and immunohistochemical features of 6 cases diagnosed at our institution and conducted a detailed review of the literature. The mean age was 64 years. All patients presented with testicular masses; 4 were right-sided. On gross examination, all tumors were centered in the hilum and had solid and cystic cut surfaces. Microscopically, all had intrarete and invasive growth and showed multiple patterns, with a variable proportion of papillary, solid and glandular morphology, the latter varying from slit-like lumens to well-formed glands and tubules. Less common patterns included corded/trabecular (n=3), cribriform (n=3), glomeruloid (n=3), nested (n=2), and micropapillary (n=2). Discrete nests of eosinophilic and clear cells were a distinctive feature in 3 cases. Geographic necrosis occurred in 3 cases. All showed at least moderate nuclear pleomorphism with ovoid nuclei. Transition from benign to malignant rete epithelium was seen in all cases. The stroma was hyalinized to partially fibrotic. On immunohistochemical study, the tumor cells were positive for CK7 (5/5), AE1/AE3 cytokeratin (5/5), EMA (5/5), vimentin (5/5), EpCAM (detected by BerEP4 anitbody) (4/5), CK5/6 (4/5), nuclear Wilms Tumor-1 (4/5), epithelial specific antigen (detected by MOC31 antibody) (3/4), PAX8 (3/5), and calretinin (2/5). OCT3/4, SALL4, CD30, NKX3.1, PSA, α-inhibin, CK20, and S100 protein were negative. Ki-67 proliferative index ranged from 5% to 60% (mean: 40, median: 43). At presentation, 5 patients had retroperitoneal lymph node metastasis and one of these also had pulmonary metastases. The sixth patient developed pulmonary metastasis within 15 months of diagnosis. Three died within 4 years of diagnosis. In summary, adenocarcinoma of the rete testis is a rare malignant tumor with poor survival and a high propensity for retroperitoneal lymph node metastasis that must be distinguished from other testicular neoplasms and metastasis to the testis. Hilar localization, transition from benign to malignant rete epithelium, and supportive immunostains aid its accurate diagnosis.
Developing Core Capabilities for Local Health Departments to Engage in Land Use and Transportation Decision Making for Active Transportation
Authors: Lemon Stephenie C. , Goins Karin Valentine , Sreedhara Meera , Arcaya Mariana , Aytur Semra A. , Heinrich Katie , Kerner Bridget , Lyn Rodney , Maddock Jay E. , Riessman Robin , Schmid Thomas L.
Published: January 2019

Objective:

To develop a core set of capabilities and tasks for local health departments (LHDs) to engage in land use and transportation policy processes that promote active transportation.

Design:

We conducted a 3-phase modified Delphi study from 2015 to 2017.

Setting:

We recruited a multidisciplinary national expert panel for key informant interviews by telephone and completion of a 2-step online validation process.

Participants:

The panel consisted of 58 individuals with expertise in local transportation and policy processes, as well as experience in cross-sector collaboration with public health. Participants represented the disciplines of land use planning, transportation/public works, public health, municipal administration, and active transportation advocacy at the state and local levels.

Main Outcome Measures:

Key informant interviews elicited initial capabilities and tasks. An online survey solicited rankings of impact and feasibility for capabilities and ratings of importance for associated tasks. Feasibility rankings were used to categorize capabilities according to required resources. Results were presented via second online survey for final input.

Results:

Ten capabilities were categorized according to required resources. Fewest resources were as follows: (1) collaborate with public officials; (2) serve on land use or transportation board; and (3) review plans, policies, and projects. Moderate resources were as follows: (4) outreach to the community; (5) educate policy makers; (6) participate in plan and policy development; and (7) participate in project development and design review. Most resources were as follows: (8) participate in data and assessment activities; (9) fund dedicated staffing; and (10) provide funding support.

Conclusions:

These actionable capabilities can guide planning efforts for LHDs of all resource levels.
Targeted Management Strategies in Multiple Myeloma
Authors: Kumar Shaji K.
Published: January 2019

There has been a paradigm shift in the treatment of myeloma triggered by intense exploration of the disease biology to understand the basis of disease development and progression and the evolution of newly diagnosed myeloma to a multidrug refractory state that is associated with poor survival. These studies have in turn informed us of potential therapeutic strategies in our ongoing effort to cure this disease, or at a minimum convert it into a chronic disease. Given the clonal evolution that leads to development of drug resistance and treatment failure, identification of specific genetic abnormalities and approaches to target these abnormalities have been on the top of the list for some time. The more recent studies examining the genome of the myeloma cell have led to development of umbrella trials that assigns patients to specific targeted agents based on the genomic abnormality. In addition, other approaches to targeting myeloma such as monoclonal antibodies are already in the clinic and are being used in all stages of disease, typically in combination with other therapies. As the therapeutic strategy evolves and we have a larger arsenal of targeted agents, we will be able to use judicious combination of drugs based on specific tumor characteristics assessed through genomic interrogation or other biologic targets. Such targeted approaches are likely to evolve to become the mainstay of myeloma therapies in the future.
Headache in Postoperative Isolated Sagittal Synostosis
Authors: van de Beeten Stephanie D. C. , Mathijssen Irene M. J. , Kamst Nathalie W. , van Veelen Marie-Lise C.
Published: January 2019

Background:

This study investigates the relationship between headache and the occurrence of signs associated with intracranial hypertension such as ophthalmic signs, restricted skull growth, and a vertex bulge in children who were operated on for sagittal synostosis.

Methods:

A total of 94 patients (aged 6 to 18 years) with sagittal synostosis were asked to indicate their headache frequency. Based on their age at referral, the patients had undergone either frontobiparietal remodeling or an extended strip craniotomy. Data on funduscopy, optical coherence tomography, occipitofrontal head circumference, and presence of vertex bulge on radiography were collected retrospectively.

Results:

Univariate analysis showed that extended strip craniotomy, the occurrence of ophthalmic signs, and a smaller occipitofrontal head circumference at last follow-up were related to more frequent headaches (p = 0.01, p = 0.04, and p < 0.01, respectively). On multivariate analysis, only type of surgery and occipitofrontal head circumference at last follow-up remained significant predictors (p = 0.04 and p < 0.01, respectively).

Conclusions:

Although the reported rate of frequent headaches in this study is within the norm reported for the normal population, this study shows that after correction for sagittal craniosynostosis, frequent headaches are independently related to type of surgery and to occipitofrontal head circumference at last follow-up. Headaches in the sagittal craniosynostosis population may be related to papilledema and/or an increased total retinal thickness. Therefore, the authors recommend that occipitofrontal head circumference be routinely measured and that patients be asked about the occurrence and frequency of headaches during their checkup at the clinic.

CLINICAL QUESTION/LEVEL OF EVIDENCE:

Therapeutic, III.
Primary progressive aphasia: a model for neurodegenerative disease
Authors: Tee Boon Lead , Gorno-Tempini Maria Luisa
Published: January 2019

Purpose of review

Knowledge on primary progressive aphasia (PPA) has expanded rapidly in the past few decades. Clinical characteristics, neuroimaging correlates, and neuropathological features of PPA are better delineated. This facilitates scientific studies on the disease pathophysiology and allows speech and language therapy to be more precisely targeted. This review article begins with a summary of the current understanding of PPA and discusses how PPA can serve as a model to promote scientific discovery in neurodegenerative diseases.

Recent findings

Studies on the different variants of PPA have demonstrated the high compatibility between clinical presentations and neuroimaging features, and in turn, enhances the understanding of speech and language neuroanatomy. In addition to the traditional approach of lesion-based or voxel-based mapping, scientists have also adopted functional connectivity and network topology approaches that permits a more multidimensional understanding of neuroanatomy. As a result, pharmacological and cognitive therapeutic strategies can now be better targeted towards specific pathological/molecular and cognitive subtypes.

Recent scientific advancement in PPA potentiates it to be an optimal model for studying brain network vulnerability, neurodevelopment influences and the effects of nonpharmacological intervention in neurodegenerative diseases.
Technical Description of Long-Term High-Density EEG Monitoring Using 128-Channel Cap Applied With a Conductive Paste
Authors: Ochoa Juan G. , Rini James , Diaz Judy , Botwell Jennifer
Published: January 2019

Purpose:

EEG is a common diagnostic tool to localize epileptic activity with excellent temporal resolution and, however, with relatively low spatial resolution. High-density EEG recording is limited in clinical practice, mainly because of electrode placement difficulties, need of high technical skills, and advanced equipment requirement.

Methods:

We described the technique of long-term EEG recording using a 128-channel neoprene cap placed with a dielectric paste in 7 patients with refractory epilepsy. We captured electrographic seizures in six of seven patients. The 128-channel EEG cap was well tolerated except for a mild headache. Daily impedance checks and reapplication of the high impedance leads maintained the recording with impedances below 10 kΩ.

Results:

Successful long-term recording of high-density EEG was able to capture seizures in six of seven patients. The time needed to apply the electrodes was approximately 1 hour and approximately 30 minutes daily for maintenance. The EEG source localization was obtained in six of seven patients, concordant within the sublobar region for both standard and high-density EEG recordings. Three patients reported a mild headache not leading to discontinuation of the recording.

Conclusions:

In general, long-term high-density scalp EEG recording with a dielectric paste is well tolerated and allows capturing both interictal and ictal data for localization. This small sample does not show a significant advantage in terms of sublobar localization when high-density EEG source is compared with standard 10 to 20 placement as long as the subtemporal areas are recorded.
Force-profile analysis of the cotranslational folding of HemK and filamin domains: Comparison of biochemical and biophysical folding assays
Authors: Kemp Grant , Kudva Renuka , Rosa Andrés de la , Heijne Gunnar von
Published: January 2019

We have characterized the cotranslational folding of two small protein domains of different folds – the a-helical N-terminal domain of HemK and the β-rich FLN5 filamin domain – by measuring the force that the folding protein exerts on the nascent chain when located in different parts of the ribosome exit tunnel (Force-Profile Analysis - FPA), allowing us to compare FPA to three other techniques currently used to study cotranslational folding: real-time FRET, PET, and NMR. We find that FPA identifies the same cotranslational folding transitions as do the other methods, and that these techniques therefore reflect the same basic process of cotranslational folding in similar ways.
Higher frequency of extra-pair offspring in urban than forest broods of great tits (Parus major)
Authors: Pipoly Ivett , Szabó Krisztián , Bókony Veronika , Preiszner Bálint , Seress Gábor , Vincze Ernő , Schroeder Julia , Liker András
Published: January 2019

Urbanization increasingly changes the ecological conditions for wild animal populations, influencing their demography, reproduction, and behaviour. While studies on the ecological consequences of urbanization frequently document a reduced number and poorer body condition of offspring in urban than in non-urban bird populations, consequences for other components of reproduction are rarely investigated. Mating with partners outside the social pair-bond is widespread in birds, and although theory predicts that the occurrence of extra-pair fertilizations (EPF) may be sensitive to the altered ecological conditions of cities, the effect of urbanization on EPF is poorly known. Here we used data from two urban and two forest populations collected over three years to test whether the frequency of extra-pair offspring (EPO) in great tit broods differed between the habitats. We found that significantly more broods contained EPO in urban habitats (48.9 %) than in forests (24.4 %). In broods with EPO, the number and proportion of EPO was similar in urban and forest broods. These results suggest that females that live in urban habitats are more likely to engage in EPF than those living in forests. Urban environments may either 1) provide more spatiotemporal opportunities to EPF because of higher breeding density and lower or more constant caterpillar supply in cities compared to natural habitats, or 2) enhance the benefits of EPF via increased fertility or due to disrupted quality signals caused by anthropogenic pollution. In addition, 3) females with higher propensity to engage in EPF may more likely settle in urban habitats.
Global phylogeography and ancient evolution of the widespread human gut virus crAssphage
Authors: Edwards Robert , Vega Alejandro , Norman Holly , Ohaeri Maria Cynthia , Levi Kyle , Dinsdale Elizabeth , Cinek Ondrej , Aziz Ramy , McNair Katelyn , Barr Jeremy , Bibby Kyle , Brouns Stan , Cazares Adrian , de Jonge Patrick A. , Desnues Christelle , Diaz-Munoz Samuel , Fineran Peter , Kurilshikov Alexander , Lavigne Rob , Mazankova Karla , McCarthy David , Nobrega Franklin , Reyes Alejandro , Tapia German , Trefault Nicole , Tyakht Alexander , Vinuesa Pablo , Wagemans Jeroen , Zhernakova Alexandra , Aarestrup Frank , Ahmadov Gunduz , Alassaf Abeer , Anton Josefa , Asangba Abigail , Billings Emma , Cantu Adrian , Carlton Jane , Cazares Lopez Daniel , Cho Gyu-Sung , Condeff Tess , Cortes Pilar , Cranfield Micheal , Cuevas Daniel , De la Iglesia Rodrigo , Decewicz Przemyslaw , Doane Michael , Dominy Nathaniel , Dziewit Lukasz , Elmahi Bashir , Eren Murat , Franz Charles , Fu Jingyuan , Garcia-Aljaro Cristina , Ghedin Elodie , Gulino Kristen , Haggerty John , Head Steven , Hendriksen Rene S. , Hill Colin , Hyoty Heikki , Ilina Elena , Irwin Mitchell , Jeffries Thomas , Jofre Juan , Junge Randall , Kelley Scott , Kowalewski Martin , Kumaresan Deepak , Leigh Steven , Lisitsyna Eugenia , Llagostera Montserrat , Maritz Julia M. , Marr Linsey , McCann Angela , Khan Mirzaei Mohammadali , Molshanski-Mor Shahar , Monteiro Silvia , Moreira-Grez Benjamin , Morris Megan , Mugisha Lawrence , Muniesa Maite , Neve Horst , Nguyen Nam-phuong , Nigro Olivia , Nilsson Anders , O'Connell Taylor , Odeh Rasha , Oliver Andrew , Piuri Mariana , Prussin Aaron , Qimron Udi , Quan Zhe-Xue , Rainetova Petra , Ramirez-Rojas Adan , Raya Raul , Rice Gillian , Rossi Alessandro , Santos Ricardo , Shimashita John , Stachler Elyse , Stene Lars , Strain Ronan , Stumpf Rebecca , Torres Pedro , Twaddle Alan , Ibekwe Maryann Ugochi , Villagra Nicolas , Wandro Stephen , White Bryan , Whiteley Andrew , Whiteson Katrine , Wijmenga Cisca , Zambrano Maria Mercedes , Zschach Henrike , Dutilh Bas E.
Published: January 2019

Microbiomes are vast communities of microbes and viruses that populate all natural ecosystems. Viruses have been considered the most variable component of microbiomes, as supported by virome surveys and examples of high genomic mosaicism. However, recent evidence suggests that the human gut virome is remarkably stable compared to other environments. Here we investigate the origin, evolution, and epidemiology of crAssphage, a widespread human gut virus. Through a global collaboratory, we obtained DNA sequences of crAssphage from over one-third of the world's countries, and showed that its phylogeography is locally clustered within countries, cities, and individuals. We also found colinear crAssphage-like genomes in both Old-World and New-World primates, challenging genomic mosaicism and suggesting that the association of crAssphage with primates may be millions of years old. We conclude that crAssphage is a benign globetrotter virus that may have co-evolved with the human lineage and an integral part of the normal human gut virome.
Genome wide meta-analysis identifies genomic relationships, novel loci, and pleiotropic mechanisms across eight psychiatric disorders
Authors:   Cross-Disorder Group of the Psychiatric Genomics Consortium, Lee Phil H. , Anttila Verneri , Won Hyejung , Feng Yen-Chen A. , Rosenthal Jacob , Zhu Zhaozhong , Tucker-Drob Elliot M. , Nivard Michel G. , Grotzinger Andrew D. , Posthuma Danielle , Wang Meg M.-J. , Yu Dongmei , Stahl Eli , Walters Raymond K. , Anney Richard J.L. , Duncan Laramie E. , Belangero Sintia , Luykx Jurjen , Kranzler Henry , Keski-Rahkonen Anna , Cook Edwin H. , Kirov George , Coppola Giovanni , Kaprio Jaakko , Zai Clement C. , Hoekstra Pieter J. , Banaschewski Tobias , Rohde Luis A. ,   PGC Attention Deficit Hyperactivity Disorder Group,   PGC Autism Spectrum Disorder Group,   PGC Bipolar Disorder Group,   PGC Eating Disorders Group,   PGC Major Depressive Disorder Group,   PGC Obsessive Compulsive Disorder and Tourette Syndrome Group,   PGC Schizophrenia Group, Sullivan Patrick F. , Franke Barbara , Daly Mark J. , Bulik Cynthia M. , Lewis Cathryn M. , McIntosh Andrew M. , O’Donovan Michael C. , Zheutlin Amanda , Andreassen Ole A. , Borglum Anders D. , Breen Gerome , Edenberg Howard J. , Fanous Ayman H. , Faraone Stephen V. , Gelernter Joel , Mathews Carol A. , Mattheisen Manuel , Mitchell Karen , Neale Michael C. , Nurnberger John I. , Ripke Stephan , Santangelo Susan L. , Scharf Jeremiah M. , Stein Murray B. , Thornton Laura M. , Walters James T.R. , Wray Naomi R. , Geschwind Daniel H. , Neale Benjamin , Kendler Kenneth S. , Smoller Jordan W.
Published: January 2019

Genetic influences on psychiatric disorders transcend diagnostic boundaries, suggesting substantial pleiotropy of contributing loci. However, the nature and mechanisms of these pleiotropic effects remain unclear. We performed a meta-analysis of 232,964 cases and 494,162 controls from genome-wide studies of anorexia nervosa, attention-deficit/hyperactivity disorder, autism spectrum disorder, bipolar disorder, major depression, obsessive-compulsive disorder, schizophrenia, and Tourette syndrome. Genetic correlation analyses revealed a meaningful structure within the eight disorders identifying three groups of inter-related disorders. We detected 109 loci associated with at least two psychiatric disorders, including 23 loci with pleiotropic effects on four or more disorders and 11 loci with antagonistic effects on multiple disorders. The pleiotropic loci are located within genes that show heightened expression in the brain throughout the lifespan, beginning in the second trimester prenatally, and play prominent roles in a suite of neurodevelopmental processes. These findings have important implications for psychiatric nosology, drug development, and risk prediction.
The HIV-1 ribonucleoprotein dynamically regulates its condensate behavior and drives acceleration of protease activity through membraneless granular phase separation
Authors: Lyonnais Sébastien , Sadiq S. Kashif , Lorca-Oró Cristina , Dufau Laure , Nieto-Marquez Sara , Escriba Tuixent , Gabrielli Natalia , Tan Xiao , Ouizougun-Oubari Mohamed , Okoronkwo Josephine , Reboud-Ravaux Michèle , Gatell José Maria , Marquet Roland , Paillart Jean-Christophe , Meyerhans Andreas , Tisné Carine , Gorelick Robert J. , Mirambeau Gilles
Published: January 2019

A growing number of studies indicate that mRNAs and long ncRNAs can affect protein populations by assembling dynamic ribonucleoprotein (RNP) granules. These phase separated molecular ‘sponges’, stabilized by quinary (transient and weak) interactions, control proteins involved in numerous biological functions. Retroviruses such as HIV-1 form by self-assembly when their genomic RNA (gRNA) traps Gag and GagPol polyprotein precursors. Infectivity requires extracellular budding of the particle followed by maturation, an ordered processing of ~2400 Gag and ~120 GagPol by viral protease (PR). This leads to a condensed gRNA-NCp7 nucleocapsid and a CAp24-self-assembled capsid surrounding the RNP. The choreography by which all of these components dynamically interact during virus maturation is one of the missing milestones to fully depict the HIV life cycle. Here, we describe how HIV-1 has evolved a dynamic RNP granule with successive weak-strong-moderate quinary NC-gRNA networks during the sequential processing of the GagNC domain. We also reveal two palindromic RNA-binding triads on NC, KxxFxxQ and QxxFxxK, that provide quinary NC-gRNA interactions. Consequently, the nucleocapsid complex appears properly aggregated for capsid reassembly and reverse transcription, mandatory processes for viral infectivity. We show that PR is sequestered within this RNP and drives its maturation/condensation within minutes, this process being most effective at the end of budding. We anticipate such findings will stimulate further investigations of quinary interactions and emergent mechanisms in crowded environments throughout the wide and growing array of RNP granules.