bluuebunny/crossref_metadata_2025 huggingface dataset:
Facilitated temporal summation of pain correlates with clinical pain intensity after hip arthroplasty
Authors: Izumi Masashi , Petersen Kristian Kjær , Laursen Mogens Berg , Arendt-Nielsen Lars , Graven-Nielsen Thomas
Published: November 2016

Widespread hyperalgesia has been found in patients with painful hip osteoarthritis (OA) which can be normalized after total hip arthroplasty (THA) if patients have no residual postoperative pain. This study characterized the preoperative somatosensory profiles and provided possible interpretation of underlying pain mechanisms that might influence the development of postoperative pain. Forty hip OA patients with unilateral pain were assessed before and 6 weeks post-THA and compared with 40 asymptomatic control subjects. Hip pain intensity at rest and while walking was assessed on a visual analogue scale (VAS). Bilateral cuff algometry from the thighs was used to assess the cuff pressure pain thresholds, pressure values at VAS scores equal with 6 cm (PVAS6), cuff pressure tolerance, and temporal summation of pain (TSP) quantified by an increase in VAS scores to repeated phasic cuff stimulations. Correlations between hip pain VAS post-THA and preoperative quantitative sensory testing results were analyzed. Post-THA hip pain VAS scores decreased (P < 0.05) compared with pre-THA. The cuff pressure pain threshold, PVAS6, and cuff pressure tolerance were significantly lower bilaterally in both patients with pre-THA and post-THA compared with controls (P < 0.05). Temporal summation of pain was facilitated bilaterally in patients with pre-THA compared with controls and normalized after THA in postoperative pain-free patients (P < 0.05). Postoperative hip pain VAS scores correlated with preoperative ipsilateral TSP (r = 0.44, P < 0.05). Bilateral pressure pain hypersensitivity and facilitated TSP were demonstrated in patients with preoperative hip OA. Although persistent postoperative pain is known as multifactorial, greater preoperative TSP was associated with greater pain and less reduction in pain after THA.
Psychosocial factors predict opioid analgesia through endogenous opioid function
Authors: Burns John W. , Bruehl Stephen , France Christopher R. , Schuster Erik , Orlowska Daria , Buvanendran Asokumar , Chont Melissa , Gupta Rajnish K.
Published: November 2016

Use of opioid analgesics for management of chronic nonmalignant pain has become common, yet there are presently no well-validated predictors of optimal opioid analgesic efficacy. We examined whether psychosocial factors (eg, depressive symptoms) predicted changes in spontaneous low back pain after administration of opioid analgesics, and whether endogenous opioid (EO) function mediated these relationships. Participants with chronic low back pain but who were not chronic opioid users (N = 89) underwent assessment of low back pain intensity pre- and post-drug in 3 (counterbalanced) conditions: (1) placebo, (2) intravenous naloxone, and (3) intravenous morphine. Comparison of placebo condition changes in back pain intensity to those under naloxone and morphine provided indexes of EO function and opioid analgesic responses, respectively. Results showed that (1) most psychosocial variables were related significantly and positively to morphine analgesic responses for low back pain, (2) depressive symptoms, trait anxiety, pain catastrophizing, and pain disability were related negatively to EO function, and (3) EO function was related negatively to morphine analgesic responses for low back pain. Bootstrapped mediation analyses showed that links between morphine analgesic responses and depressive symptoms, trait anxiety, pain catastrophizing, and perceived disability were partially mediated by EO function. Results suggest that psychosocial factors predict elevated analgesic responses to opioid-based medications, and may serve as markers to identify individuals who benefit most from opioid therapy. Results also suggest that people with greater depressive symptoms, trait anxiety, pain catastrophizing, and perceived disability may have deficits in EO function, which may predict enhanced response to opioid analgesics.
Growth hormone regulates the sensitization of developing peripheral nociceptors during cutaneous inflammation
Authors: Liu Xiaohua , Green Kathryn J. , Ford Zachary K. , Queme Luis F. , Lu Peilin , Ross Jessica L. , Lee Frank B. , Shank Aaron T. , Hudgins Renita C. , Jankowski Michael P.
Published: November 2016

Cutaneous inflammation alters the function of primary afferents and gene expression in the affected dorsal root ganglia (DRG). However, specific mechanisms of injury-induced peripheral afferent sensitization and behavioral hypersensitivity during development are not fully understood. Recent studies in children suggest a potential role for growth hormone (GH) in pain modulation. Growth hormone modulates homeostasis and tissue repair after injury, but how GH affects nociception in neonates is not known. To determine whether GH played a role in modulating sensory neuron function and hyperresponsiveness during skin inflammation in young mice, we examined behavioral hypersensitivity and the response properties of cutaneous afferents using an ex vivo hairy skin-saphenous nerve-DRG-spinal cord preparation. Results show that inflammation of the hairy hind paw skin initiated at either postnatal day 7 (P7) or P14 reduced GH levels specifically in the affected skin. Furthermore, pretreatment of inflamed mice with exogenous GH reversed mechanical and thermal hypersensitivity in addition to altering nociceptor function. These effects may be mediated through an upregulation of insulin-like growth factor 1 receptor (IGFr1) as GH modulated the transcriptional output of IGFr1 in DRG neurons in vitro and in vivo. Afferent-selective knockdown of IGFr1 during inflammation also prevented the observed injury-induced alterations in cutaneous afferents and behavioral hypersensitivity similar to that after GH pretreatment. These results suggest that GH can block inflammation-induced nociceptor sensitization during postnatal development leading to reduced pain-like behaviors, possibly by suppressing the upregulation of IGFr1 within DRG.
Diagnosing acute respiratory distress syndrome in resource limited settings: the Kigali modification of the Berlin definition
Authors: Riviello Elisabeth D. , Buregeya Egide , Twagirumugabe Theogene
Published: November 2016

Purpose of review

The acute respiratory distress syndrome (ARDS) was re-defined by a panel of experts in Berlin in 2012. Although the Berlin criteria improved upon the validity and reliability of the definition, it did not make diagnosis of ARDS in resource limited settings possible. Mechanical ventilation, arterial blood gas measurements, and chest radiographs are not feasible in many regions of the world. In 2014, we proposed and applied the Kigali modification of the Berlin definition in a hospital in Rwanda. This review synthesizes literature from the last 18 months relevant to the Kigali modification.

Recent findings

In the last 18 months, the need for a universally applicable ARDS definition was reinforced by advances in supportive care that can be implemented in resource poor settings. Research demonstrating the variable impact of positive end expiratory pressure on hypoxemia, the validity of using pulse oximetry rather than arterial blood gas to categorize hypoxemia, and the accuracy of lung ultrasound support the use of the Kigali modification of the Berlin definition.

Studies directly comparing the Berlin definition to the Kigali modification are needed. Ongoing clinical research on ARDS needs to include low-income countries.
Extracorporeal membrane oxygenation: beyond rescue therapy for acute respiratory distress syndrome?
Authors: Combes Alain , Bréchot Nicolas , Luyt Charles-Edouard , Schmidt Matthieu
Published: November 2016

Purpose of review

This article summarizes the results of past and more recent series on venovenous extracorporeal membrane oxygenation (VV-ECMO) and discusses its potential indications beyond the rescue of patients with lung failure refractory to conventional mechanical ventilation.

Recent findings

Successful VV-ECMO treatment in patients with extremely severe influenza A(H1N1)-associated acute respiratory distress syndrome (ARDS) and positive results of the CESAR trial have led to an exponential use of the technology in recent years. Beyond its currently accepted indication as a salvage therapy in ARDS patients with refractory hypoxemia or unable to tolerate volume-limited strategies, VV-ECMO may improve the outcomes of less severe ARDS patients by facilitating lung-protective ventilation.

As initiation of VV-ECMO allows significant decrease in tidal volume, plateau and driving pressures, which has been associated with improved survival in ARDS patients, new trials should evaluate the impact of its early initiation in patients with severe but not refractory ARDS.
Should we use driving pressure to set tidal volume?
Authors: Grieco Domenico L. , Chen Lu , Dres Martin , Brochard Laurent
Published: November 2016

Purpose of review

Ventilator-induced lung injury (VILI) can occur despite use of tidal volume (V

t
) limited to 6 ml/kg of predicted body weight, especially in patients with a smaller aerated compartment (i.e. the baby lung) in which, indeed, tidal ventilation takes place. Because respiratory system static compliance (C
RS) is mostly affected by the volume of the baby lung, the ratio V
T/C
RS (i.e. the driving pressure, ΔP) may potentially help tailoring interventions on V
T setting.

Recent findings

Driving pressure is the ventilatory variable most strongly associated with changes in survival and has been shown to be the key mediator of the effects of mechanical ventilation on outcome in the acute respiratory distress syndrome. Observational data suggest an increased risk of death for patients with ΔP more than 14 cmH2O, but a well tolerated threshold for this parameter has yet to be identified. Prone position along with simple ventilatory adjustments to facilitate CO2 clearance may help reduce ΔP in isocapnic conditions. The safety and feasibility of low-flow extracorporeal CO2 removal in enhancing further reduction in V
T and ΔP are currently being investigated.

Driving pressure is a bedside available parameter that may help identify patients prone to develop VILI and at increased risk of death. No study had prospectively evaluated whether interventions on ΔP may provide a relevant clinical benefit, but it appears physiologically sound to try titrating V
T to minimize ΔP, especially when it is higher than 14 cmH2O and when it has minimal costs in terms of CO2 clearance.
Topiramate Blood Levels During Polytherapy for Epilepsy in Children
Authors: Toki Taira , Iwasaki Toshiyuki , Ishii Masahiro
Published: November 2016

Background:

The therapeutic range of topiramate (TPM) blood level is not set because the efficacy and safety are not considered to be related to the level. However, the therapeutic target without side effects is necessary, so the optimal range of TPM blood level was analyzed in this study.

Study Question:

This study was conducted to evaluate the efficacy of TPM over 2 years and the utility of measuring blood levels of TPM during the follow-up of epileptic patients.

Study Design:

Thirty patients (18 males, 12 females; age range, 6 months–15 years) were treated with TPM for epilepsy. The initial dosage of TPM was 1–3 mg·kg−1·d−1. If the effect proved insufficient after 2 weeks, the dosage was increased to 4–9 mg·kg−1·d−1.

Measures and Outcomes:

Blood levels of TPM were measured by liquid chromatography-tandem mass spectrometry at 1, 6, 12, and 24 months after levels reached steady state. The efficacy of TPM was evaluated by the reduction in epileptic seizure rate (RR) at the time of blood sampling. Statistical analysis was performed using the Mann–Whitney U test.

Results:

A positive correlation was seen between blood levels and maintenance dosages, but no correlation was observed between blood levels and RR. Any significant difference was not identified in TPM levels between the effective group (RR ≥50%) and the ineffective group (RR <50%; P = 0.159). In the subgroup of patients who did not use valproic acid, a significant difference in TPM levels was apparent between the effective and ineffective groups (P = 0.029). The optimal range of TPM was advocated 3.5–5.0 μg/mL. The optimal range was set, so that ranges did not overlap between the effective and ineffective groups. No patients experienced any side effects.

Conclusions:

Measuring blood levels of TPM based on the classification of concomitant drugs and adjusting the dosage to reach the optimal range were recommended.
Inter-visit Test-Retest Variability of OCT in Glaucoma
Authors: Pearce John Graham , Maddess Ted
Published: November 2016

Purpose

To determine the inter-visit test-retest variability (TRV) of a spectral domain optical coherence tomograph, the Topcon 3D OCT-2000, in the measurement of optic nerve head topography, peripapillary retinal nerve fiber layer (pRNFL), and macular ganglion cell complex (GCC) parameters in glaucoma patients. We also examine whether TRV with this instrument varies with the extent of glaucomatous damage.

Methods

Twenty-four subjects with varying degrees of glaucoma severity provided 41 eyes with usable results for the study. 3D Disc Retinal Nerve Fiber Layer Analysis and Macula V (GCC) scans were repeated 1 week apart, at the same time of day, to determine the inter-visit TRV. TRV was determined using Bland-Altman limits of agreement (LoA) and the resulting coefficients of repeatability (CR).

Results

The overall horizontal and vertical cup/disc ratio CRs were 0.05 and 0.07, respectively. The GCC CR was 2.9 μm. In contrast, average pRNFL TRV expanded with increasing damage, with the LoA being well fitted by ±(34.67 − 0.294(d)), where d is the pRNFL thickness. A more complex model, with constant LoA of ±5.61 μm at d >82 μm, and linearly expanding TRV below that, achieved marginal significance (P < .06).

Conclusions

The repeatability of GCC measurements with this instrument was excellent. The determination of statistically significant change in average pRNFL should take into account average pRNFL thickness.
Painless Acanthamoeba Keratitis with Normal Vision
Authors: Kwok Pui Wai Rachel , Kam Ka Wai , Jhanji Vishal , Young Alvin L.
Published: November 2016

Purpose

To report an atypical case of contact lens–related Acanthamoeba keratitis.

Case Report

A 15-year-old secondary school female student with a history of soft contact lens wear was referred to our hospital by a private general practitioner for management of right eye redness and discomfort for 2 weeks. Upon examination, the best-corrected visual acuity was 20/20 and 20/16 for her right and left eyes, respectively. There was diffuse radial keratoneuritis noted in the cornea of her right eye without any associated epithelial defect. Corneal scraping was performed to induce epithelial defect over the keratoneuritis area, and it was positive for Acanthamoeba trophozoites. She was treated with amoebicidal therapy consisting of propamidine isethionate 0.1% and polyhexamethylene biguanide 0.02%, for 6 months. The patient did not complain of any ocular pain in the entire course of her disease. She attained a final visual acuity of 20/13 in the affected eye with residual peripheral radial perineuritic scar.

Conclusions

Atypical presentation of Acanthamoeba infection is uncommon. This case should arouse the awareness of an indolent presentation of this potentially sight-threatening disease. Clinicians should have a high level of suspicion in contact lens users who present with corneal abnormalities despite an absence of pain. Microbiological work-up and prompt treatment led to a complete resolution of Acanthamoeba infection in our patient.
Minocycline-Induced Scleral and Dermal Hyperpigmentation
Authors: Haskes Cheryl , Shea Michael , Imondi David
Published: November 2016

Purpose

To present a case of minocycline-induced blue scleral pigmentation and discuss the pathophysiology and differential diagnoses. The uses, mechanisms, and other adverse effects of minocycline will also be highlighted.

Case Report

An elderly Caucasian male patient presented for routine ocular examination complaining of blue discoloration to the whites of his eyes. He was found to have bilateral blue scleral pigmentation and blue discoloration to various other dermal areas of his body. The blue pigmentation was also visible in the posterior segment within a scleral crescent around his right optic nerve. This pigmentation was determined to be caused by long-term use of oral minocycline.

Conclusions

Long-term minocycline use may induce scleral, dermal, and organ hyperpigmentation, typically blue or black in coloration. The pigmentation may reverse with discontinuation of the medication, but can also be permanent. The exact mechanism of pigment deposition remains uncertain, but several theories have been proposed. While the cosmetic appearance may be dramatic, this side effect is not known to cause any systemic or ocular morbidity.
Intussusception With Cecal Cyst as Lead Point in a Child
Authors: Lai Michelle , Coakley Brian A. , Webber Eric M. , Goldman Ran D.
Published: November 2016

Intussusception is a pediatric abdominal emergency in early childhood involving telescoping of 1 part of the bowel into another part. In most children, the condition is idiopathic with no identifiable lead point. Meckel diverticulum is the most common lead point, followed by polyps and duplication cysts. We describe a case of a boy with intussusception caused by a duplication cyst that was drawn retrograde through the ileocecal valve. The patient presented after a 3-month period of symptomatology and had been considered to have constipation before signs of intestinal obstruction developed. Only mild bowel ischemia was seen during the surgical reduction and resection of the cyst which may suggest an ongoing partial obstruction that eventually became more significant. In children with recurrent abdominal pain, surgeons should consider the possibility of intermittent intussusceptions caused by a duplication cyst.
Abdominal Pain Caused by a Potentially Fatal Attraction
Authors: Mercurio Danielle Claire , Scace Candace , Shah Bhairav , Weiner Evan , Prasad Rajeev
Published: November 2016

Abdominal pain is a challenging presentation in children. Examination findings and etiology vary greatly, spanning a vast spectrum from flatulence to frank peritonitis with septic shock. Here, we discuss a 10-year-old boy with 24 hours of progressively worsening lower abdominal pain, nausea, and subjective fevers. History and physical examination findings were consistent with appendicitis. However, physicians were surprised when the single-view abdominal radiograph showed an unanticipated, somewhat perplexing discovery.
Cohort Study to Assess the Impact of Breast Implants on Breastfeeding
Authors: Filiciani Sandra , Siemienczuk Guillermo F. , Nardín Juan M. , Cappio Bárbara , Albertengo Andrés C. , Nozzi Guillermo , Caggioli Matías
Published: November 2016

Background:

The objective of this study was to evaluate the impact of breast implant surgery and its approaches on lactation by comparing women with and without breast implants at the time of childbirth.

Methods:

Between April of 2013 and July of 2014, in Rosario (Sanatorio de la Mujer and Centro Quirúrgico Rosario), Argentina, a prospective cohort study of women with and without breast implants was performed. Of a total of 3950 births that occurred during this period, 200 patients with similar anthropometric characteristics (maternal and newborn) were selected. Breastfeeding (exclusive or mixed) was compared with artificial feeding at 24 and 48 hours and 30 days in both groups, and the type of incision was also compared.

Results:

Breastfeeding at 30 days showed a nonsignificant trend favoring the control group (OR, 7.39; 95 percent CI, 0.92 to 339.2). The percentage of women with implants who succeeded in establishing breastfeeding (exclusive or mixed) was very high (93 percent). In the control group, 99 percent of the women were breastfeeding at 30 days. In a comparison of the submammary and areola incision, breastfeeding showed odds ratios of 0.78 (95 percent CI, 0.33 to 1.87) at 24 hours, 1.10 (95 percent CI, 0.48 to 2.56) at 48 hours, and 0.18 (95 percent CI, 0.36 to 1.82) at 30 days.

Conclusions:

This study shows that most patients with breast implants were able to establish breastfeeding. However, there is a higher number of women without implants that established exclusive breastfeeding. No significant difference was found between the different surgical approaches.

CLINICAL QUESTION/LEVEL OF EVIDENCE:

Therapeutic, II.
Improving Outcomes in Tendon Repair: A Critical Look at the Evidence for Flexor Tendon Repair and Rehabilitation
Authors: Khor Wee S. , Langer Martin F. , Wong Richard , Zhou Rui , Peck Fiona , Wong Jason K. F.
Published: November 2016

Learning Objectives:

After reading this article, the participant should be able to: 1. Appreciate the variation and evolution of flexor tendon management 2. Know how to assess the patient who presents with a flexor tendon laceration. 3. Understand the biology of repairing flexor tendon lacerations. 4. Appreciate the technical challenges in flexor tendon repair relating to different zones. 5. Understand the rationale of postoperative hand therapy. 6. Have an overview of the types of secondary tendon surgery.

Background:

Flexor tendon injury constitutes a considerable trauma workload for hand surgeons, and a vast amount of research is dedicated toward improving outcomes in tendon repair. This Continuing Medical Education article aims to provide an up-to-date evidence-based outline of flexor tendon surgery in the hand.

Methods:

The authors reviewed the literature on flexor tendon repairs to include a balanced overview of the experimental and clinical research. For each section, the best levels of evidence were assessed in the context of past research to provide a comprehensive opinion on best management.

Results:

The review highlights current trends in flexor tendon surgery, clinical assessment, anesthetic technique, surgical approach, repair technique, and rehabilitation. Carefully selected illustrations, figures, tables, and video have been used to supplement the findings of the review.

Conclusions:

Early active mobilization remains the only long-term proven strategy to improve outcomes. Incorporating intraoperative mobilization using “wide-awake” surgery could emerge to further improve tendon outcomes. Good surgical approach, meticulous surgery, up-to-date physiotherapy regimens, and patient education remain the cornerstone of obtaining best outcomes.
Molecular Profiling Using Breast Cancer Subtype to Plan for Breast Reconstruction
Authors: Sandberg Lars Johan , Clemens Mark W. , Symmans W. F. , Valero Vicente , Caudle Abigail S. , Smith Benjamin , Kuerer Henry M. , Hsu Limin , Kronowitz Steven J.
Published: November 2016

Background:

Molecular profiling using breast cancer subtype has an increasing role in the multidisciplinary care of the breast cancer patient. The authors sought to determine the role of breast cancer subtyping in breast reconstruction and specifically whether breast cancer subtyping can determine the need for postmastectomy radiation therapy and predict recurrence-free survival to plan for the timing and technique of breast reconstruction.

Methods:

The authors reviewed prospectively collected data from 1931 reconstructed breasts in breast cancer patients who underwent mastectomy between November of 1999 and December of 2012. Reconstructed breasts were grouped by breast cancer subtype and examined for covariates predictive of recurrence-free survival and need for postmastectomy radiation therapy.

Results:

Of the reconstructed breasts, 753 (39 percent) were luminal A, 538 (27.9 percent) were luminal B, 224 (11.6 percent) were luminal HER2, 143 (7.4 percent) were HER2-enriched, and 267 (13.8 percent) were triple-negative breast cancer. Postmastectomy radiation therapy was delivered in 69 HER2-enriched patients (48.3 percent), 94 luminal HER2 patients (42 percent), 200 luminal B patients (37.2 percent), 99 triple-negative breast cancer patients (37.1 percent), and 222 luminal A patients (29.5 percent) (p < 0.0001). Luminal A cases had better recurrence-free survival than HER2-enriched cases, and triple-negative breast cancer cases had worse recurrence-free survival than HER2-enriched cases. Luminal B and luminal HER2 cases had recurrence-free survival similar to that for HER2-enriched cases. Luminal A subtype was associated with the best recurrence-free survival. Subtyping may have improved the breast surgery planning for 33.1 percent of delayed reconstructions that did not require postmastectomy radiation therapy and 37 percent of immediate reconstructions that did require postmastectomy radiation therapy.

Conclusion:

This study is the first publication in the literature to evaluate breast cancer subtype to stratify risk for decision making in breast reconstruction.

CLINICAL QUESTION/LEVEL OF EVIDENCE:

Risk, III.
Where next with preexposure prophylaxis?
Authors: Nugent Diarmuid , Gilson Richard
Published: November 2016

Purpose of review

Controlling the HIV epidemic remains a major public health challenge, and there is an urgent need for novel prevention strategies. Preexposure prophylaxis (PrEP) refers to the use of antiretrovirals in HIV-negative people at high risk to prevent infection and has the potential to be an important component in the global effort to end the HIV epidemic by 2030. We review the current evidence for the safety and efficacy of PrEP in its different forms and address emergent issues and concerns regarding its implementation.

Recent findings

Two further randomized control trials report high efficacy of both daily and intermittent PrEP in MSM leading to renewed calls for wider availability of PrEP for this group. Oral tenofovir disoproxil/emtricitabine has been licensed for PrEP in many countries and is well tolerated, safe and effective.

Oral PrEP is well tolerated and effective in reducing the incidence of HIV infection in individuals at high risk. Implementation in high-income countries is progressing slowly; demonstration projects and trials continue in low and middle-income countries.
The Reliability of Disease Activity Score in 28 Joints–C-Reactive Protein Might Be Overestimated in a Subgroup of Rheumatoid Arthritis Patients, When the Score Is Solely Based on Subjective Parameters
Authors: Jensen Hansen Inger Marie , Asmussen Andreasen Rikke , van Bui Hansen Mark Nam , Emamifar Amir
Published: November 2016

Background

Disease Activity Score in 28 Joints (DAS28) is a scoring system to evaluate disease activity and treatment response in rheumatoid arthritis (RA). A DAS28 score of greater than 3.2 is a well-described limit for treatment intensification; however, the reliability of DAS28 might be overestimated.

Objective

The aim of this study was to evaluate the reliability of DAS28 in RA, especially focusing on a subgroup of patients with a DAS28 score of greater than 3.2.

Methods

Data from RA patients registered in the local part of Danish DANBIO Registry were collected in May 2015. Patients were categorized into 2 groups: First, those with DAS28 >3.2 with at least one swollen joint (SJ) or elevated C-reactive protein (CRP) (“objective group”), and second, patients with a DAS28 >3.2 who had no SJ, and CRP values were within the reference range (“subjective group”). Disease Activity Score in 28 Joints, Clinical Disease Activity Index, and Health Assessment Questionnaire scores were calculated for each group. We defined new score, DAS28 subjective, to focus on subjective parameters.

Results

Two hundred thirty patients were included; 198 (86.1%) and 32 (13.9%) patients were in the objective and subjective groups, respectively. Patients in the subjective group had lower mean values of DAS28 (P < 0.001) and Evaluator Global Assessment (P < 0.001) with less common immunoglobulin M rheumatoid factor (P < 0.001) and anti–cyclic citrullinated peptide positivity (P = 0.02) and contrarily higher mean values of tender joints (P = 0.04) and DAS28 based on subjective parameters (P = 0.003) compared with the objective group.

Conclusions

Rheumatoid arthritis scoring systems should be used cautiously in patients who are considered for treatment intensification. Patients with central sensitization and psychological problems and those with false-positive diagnosis of RA are at high risk of overtreatment.
Scalable variational inference for super resolution microscopy
Authors: Sun Ruoxi , Archer Evan , Paninski Liam
Published: November 2016

Super-resolution microscopy methods (e.g. STORM or PALM imaging) have become essential tools in biology, opening up a variety of new questions that were previously inaccessible with standard light microscopy methods. In this paper we develop new Bayesian image processing methods that extend the reach of super-resolution microscopy even further. Our method couples variational inference techniques with a data summarization based on Laplace approximation to ensure computational scalability. Our formulation makes it straightforward to incorporate prior information about the underlying sample to further improve accuracy. The proposed method obtains dramatic resolution improvements over previous methods while retaining computational tractability.
Resting-state fMRI correlations: from link-wise unreliability to whole brain stability
Authors: Pannunzi Mario , Hindriks Rikkert , Bettinardi Ruggero G. , Wenger Elisabeth , Lisofsky Nina , Martensson Johan , Butler Oisin , Filevich Elisa , Becker Maxi , Lochstet Martyna , Lindenberger Ulman , Kühn Simone , Deco Gustavo
Published: November 2016

The functional architecture of spontaneous BOLD fluctuations has been characterized in detail by numerous studies, demonstrating its potential relevance as a biomarker. However, the systematic investigation of its consistency is still in its infancy. Here, we analyze both the within- and between-subject variability as well as the test-retest reliability of resting-state functional connectivity (FC) estimates in a unique data set comprising multiple fMRI scans (42) from 5 subjects, and 50 single scans from 50 subjects. To this aim we adopted a statistical framework enabling us to disentangle the contribution of different sources of variability and their dependence on scan duration, and showed that the low reliability of single links can be largely improved using multiple scans per subject. Moreover, we show that practically all observed inter-region variability (at the link-level) is not significant and due to the statistical uncertainty of the estimator itself rather than to genuine variability among areas. Finally, we use the proposed statistical framework to demonstrate that, despite the poor consistency of single links, the information carried by the whole-brain spontaneous correlation structure is indeed robust, and can in fact be used as a functional fingerprint.
Anterior cingulate is a source of valence-specific information about value and uncertainty
Authors: Monosov Ilya E.
Published: November 2016

Expectations of rewards and punishments can promote similar behavioral states, such as vigilance, as well as distinct behavioral states, such as approach or avoidance. However, the cortical circuits that underlie this behavioral diversity are poorly understood. In a Pavlovian procedure in which monkeys displayed a diverse repertoire of reward, punishment, and uncertainty related behaviors not mandated by the task, I show that many anterior-cingulate (ACC) neurons represent expected value and uncertainty in a valence-specific manner, for example about either rewards or punishments. This flexibility may facilitate the top-down control of many reward- and punishment-related actions and behavioral states.
Chromosome assembly of large and complex genomes using multiple references
Authors: Kolmogorov Mikhail , Armstrong Joel , Raney Brian J. , Streeter Ian , Dunn Matthew , Yang Fengtang , Odom Duncan , Flicek Paul , Keane Thomas , Thybert David , Paten Benedict , Pham Son
Published: November 2016

Despite the rapid development of sequencing technologies, assembly of mammalian-scale genomes into complete chromosomes remains one of the most challenging problems in bioinformatics. To help address this difficulty, we developed Ragout, a reference-assisted assembly tool that now works for large and complex genomes. Taking one or more target assemblies (generated from an NGS assembler) and one or multiple related reference genomes, Ragout infers the evolutionary relationships between the genomes and builds the final assemblies using a genome rearrangement approach. Using Ragout, we transformed NGS assemblies of 15 differentMus musculusand oneMus spretusgenomes into sets of complete chromosomes, leaving less than 5% of sequence unlocalized per set. Various benchmarks, including PCR testing and realigning of long PacBio reads, suggest only a small number of structural errors in the final assemblies, comparable with direct assembly approaches. Additionally, we applied Ragout toMus caroliandMus paharigenomes, which exhibit karyotype-scale variations compared to other genomes from theMuridaefamily. Chromosome color maps confirmed most large-scale rearrangements that Ragout detected.
A lumenal interrupted helix in human sperm tail microtubules
Authors: Zabeo Davide , Heumann John M. , Schwartz Cindi L. , Suzuki-Shinjo Azusa , Morgan Garry , Widlund Per O. , Höög Johanna L.
Published: November 2016

Eukaryotic flagella are complex cellular extensions involved in many human diseases gathered under the term ciliopathies. Currently, detailed insights on flagellar structure come from studies on protozoa. Here, cryo-electron tomography (cryo-ET) of intact human spermatozoon tails showed a variable number of microtubules in the singlet region. Inside their lumen, a novel left-handed interrupted helix which extends several micrometers at their plus ends was discovered. This structure was named Tail Axoneme Intra-Lumenal Spiral (TAILS) and binds directly to 11 protofilaments on the internal microtubule wall, coaxial with the surrounding microtubule lattice. It leaves a gap over the microtubule seam, which was directly visualized in both singlet and doublet microtubules. We suggest that TAILS may stabilize microtubules, enable rapid swimming or play a role in controlling the swimming direction of spermatozoa.
Conformational landscape of the p28-bound human proteasome regulatory particle
Authors: Lu Ying , Wu Jiayi , Chen Shuobing , Sun Shuangwu , Ma Yong-Bei , Ouyang Qi , Finley Daniel , Kirschner Marc W. , Mao Youdong
Published: November 2016

The proteasome holoenzyme is activated by its regulatory particle (RP) consisting of two subcomplexes, the lid and the base. A key event in base assembly is the formation of a heterohexameric ring of AAA-ATPases, which is guided by at least four RP assembly chaperones in mammals: PAAF1, p28/gankyrin, p27/PSMD9 and S5b. We determined a cryo-EM structure of the human RP in complex with its assembly chaperone p28 at 4.5-Å resolution. The Rpn1-p28-AAA subcomplex in the p28-bound RP is highly dynamic and was resolved to subnanometer resolution in seven states, which recapitulate the conformational landscape of the complex. Surprisingly, the p28-bound AAA ring does not form a channel in the free RP. Instead, it spontaneously samples multiple ‘open’ and ‘closed’ topologies. Our analysis suggests that p28 guides the proteolytic core particle to select certain conformation of the ATPase ring for RP engagement in the last step of the chaperone-mediated proteasome assembly.
Host Vesicle Fusion Proteins VAPB, Rab11b and Rab18 Contribute to HSV-1 Infectivity by Facilitating Egress through the Nuclear Membrane
Authors: Saiz-Ros Natalia , Czapiewski Rafal , Stevenson Andrew , Epifano Ilaria , Swanson Selene K. , McElwee Marion , Vijayakrishnan Swetha , Richardson Christine A. , Dixon Charles , Pytowski Lior , Goldberg Martin W. , Florens Laurence , Graham Sheila V. , Schirmer Eric C.
Published: November 2016

The herpesvirus process of primary envelopment and de-envelopment as viral particles exit the nucleus has been for many years one of the least understood steps in the virus life cycle. Though viral proteins such as pUL31, pUL34, pUS3 and others are clearly important, these are likely insufficient for efficient fusion with the nuclear membrane. We postulated that host nuclear membrane proteins involved in virus nuclear egress would move from the inner to outer nuclear membranes due to membrane fusion events in primary envelopment and de-envelopment and then diffuse into the endoplasmic reticulum. Membrane fractions were prepared enriched in the nuclear envelope or the endoplasmic reticulum with and without HSV-1 infection and analyzed by mass spectrometry, revealing several vesicle fusion proteins as candidates in the viral nuclear egress pathway. Knockdown of three of these, VAPB, Rab11b, and Rab18, significantly reduced titers of released virus while yielding nuclear accumulation of encapsidated particles. Antibody staining revealed that VAPB visually accumulates in the inner nuclear membrane during HSV-1 infection. VAPB also co-localizes at early time points with the viral pUL34 protein known to be involved in nuclear egress. Most strikingly, VAPB was also observed on HSV-1 virus particles by immunogold labelling electron microscopy. Thus, these data reveal several new host cell vesicle fusion proteins involved in viral nuclear egress.

Author Summary

Human herpesviruses are associated with common human diseases such as chicken pox, shingles and mononucleosis and infect a wide range of animals making them economically important pathogens for livestock. Herpes simplex virus 1 (HSV-1) is most commonly associated with cold sores, but is also the leading cause of blindness by infection in the Western world. All herpesviruses share many aspects of infection. As large nuclear replicating dsDNA viruses with capsid sizes too large to use the nuclear pores to exit the nucleus, they have evolved a complex mechanism for envelopment and de-envelopment of primary herpesvirus particles, but this critical step in the virus lifecycle remains poorly understood. We have identified several host cell vesicle fusion proteins, VAPB, Rab11b and Rab18 that appear to contribute to this step in the HSV-1 life cycle. VAPB accumulates at the nuclear envelope with the HSV-1 pUL34 protein important for viral nuclear egress. Knockdown of any of these vesicle fusion proteins reduces viral titers, further arguing that they are important for nuclear egress. As there appears to be a specific subset of vesicle fusion proteins involved in viral egress, they could possibly represent novel targets for therapeutic interventions.
UNCROSS: Filtering of high-frequency cross-talk in 16S amplicon reads
Authors: Edgar Robert C.
Published: November 2016

Next-generation amplicon sequencing is widely used for surveying biological diversity in applications such as microbial metagenomics, immune system repertoire analysis and targeted tumor sequencing of cancer-associated genes. In such studies, assignment of reads to incorrect samples (cross-talk) is a well-documented problem that is rarely considered in practice. By considering unexpected OTUs in artificial (mock) samples, I estimate that cross-talk occurred for ~2% of the reads in one Illumina GAIIx run and eleven Illumina MiSeq runs targeting 16S ribosomal RNA. I also describe UNCROSS, an algorithm for detecting and filtering cross-talk in OTU tables.
DIV-1/PolA2 Promotes GLP-1/Notch-Mediated Cellular Events inCaenorhabditis elegans
Authors: Yoon Dong Suk , Cha Dong Seok , Lee Myon-Hee
Published: November 2016

Notch signaling is a highly conserved cell signaling system in most multicellular organisms and plays a critical role in animal development. In various tumor cells, Notch signaling is elevated and has been considered as an important target in cancer treatments. InC. elegans, GLP-1 (one of twoC. elegansNotch receptors) activity is required for cell fate specification in germline and somatic tissues. In this study, we have identifieddiv-1gene as a positive regulator for GLP-1/Notch-mediated cellular events.C. elegans div-1encodes the B subunit of the DNA polymerase alpha-primase complex and is highly expressed in proliferative germ cells. Functional analyses demonstrated thati) DIV-1 is required for the robust proliferation typical of the germline,ii) loss of DIV-1 enhances and suppresses specific phenotypes that are associated with reduced and elevated GLP-1/Notch activity in germline and somatic tissues, andiii) DIV-1 works together with FBF/PUF proteins, downstream regulators of GLP-1/Notch signaling, to promote germline stem cell (GSC) maintenance and germline proliferation. To maintain GSCs and proliferative cell fate, GLP-1/Notch activity must remain above a threshold for proliferation/differentiation decision. Our results propose that DIV-1 may control the level of threshold for GLP-1/Notch-mediated germline proliferation. PolA2, a mammalian homolog of theC. elegansDIV-1, has been emerged as a therapeutic target for non-small cell lung cancer (NSCLC). Notably, Notch signaling is altered in approximately one third of NSCLCs. Therefore, the discovery of the DIV-1 effect on GLP-1/Notch-mediated cellular events has implications for our understanding of vertebrate PolA2 protein and its influence on stem cell maintenance and tumorigenesis.
Identifying Y-chromosome haplogroups in arbitrarily large samples of sequenced or genotyped men
Authors: Poznik G. David
Published: November 2016

We have developed an algorithm to rapidly and accurately identify the Y-chromosome haplogroup of each male in a sample of one to millions. The algorithm, implemented in the yHaplo*software package (yHaplo), does not rely on any particular genotyping modality or platform. Full sequences yield the most granular haplogroup classifications, but genotyping arrays can yield reliable calls, provided a reasonable number of phylogenetically informative variants has been assayed. The algorithm is robust to missing data, genotype errors, mutation recurrence, and other complications. We have tested the software on full sequences from phase 3 of the 1000 Genomes Project and on subsets thereof constructed by downsampling to SNPs present on each of four genotyping arrays. We have also run the software on array data from more than 600,000 males.
Chromatin accessibility dynamics reveal novel functional enhancers inC. elegans
Authors: Daugherty Aaron C. , Yeo Robin , Buenrostro Jason D. , Greenleaf William J. , Kundaje Anshul , Brunet Anne
Published: November 2016

Chromatin accessibility, a crucial component of genome regulation, has primarily been studied in homogeneous and simple systems, such as isolated cell populations or early-development models. Whether chromatin accessibility can be assessed in complex, dynamic systemsin vivowith high sensitivity remains largely unexplored. In this study, we use ATAC-seq to identify chromatin accessibility changes in a whole animal, the model organismC. elegans, from embryogenesis to adulthood. Chromatin accessibility changes between developmental stages are highly reproducible, recapitulate histone modification changes, and reveal key regulatory aspects of the epigenomic landscape throughout organismal development. We find that over 5,000 distal non-coding regions exhibit dynamic changes in chromatin accessibility between developmental stages, and could thereby represent putative enhancers. When testedin vivo, several of these putative enhancers indeed drive novel cell-type-and temporal-specific patterns of expression. Finally, by integrating transcription factor binding motifs in a machine learning framework, we identify EOR-1 as a unique transcription factor that may regulate chromatin dynamics during development. Our study provides a unique resource forC. elegans, a system in which the prevalence and importance of enhancers remains poorly characterized, and demonstrates the power of using whole organism chromatin accessibility to identify novel regulatory regions in complex systems.
Immunotropic aspect of theBacillus coagulansprobiotic action
Authors: Bomko T.V. , Nosalskaya T. N. , Kabluchko T. V. , Lisnyak Yu. V. , Martynov A. V.
Published: November 2016

Immunotropic aspect of theBacillus coagulansprobiotic action

Objective

Currently, probiotics are increasingly used as the alternative to antibiotics as well as the preventive measures in humans. In particular, probiotics occupy a key position in the treatment of antibiotics-associated intestinal dysbiosis. A spore-forming microorganism lactobacillusBacillus coagulansis one of the most promising probiotics. However, some of its pharmacological effects remain poorly understood.

Aim.

This study is aimed at investigation of the effect ofBacillus coagulans(Laktovit Forte) on the intestinal dysbiosis syndrome in mice caused by streptomycin against the background of cyclophosphamide-induced cellular immunodeficiency.

Methods.

Pharmacological method: mouse model in vivo with immunodeficiency caused by cyclophosphamide.

Key findings.

In mice with colitis caused by streptomycin treatment, the administration ofBacillus coagulans(Laktovit Forte medicinal product) resulted in an antidiarrheal effect, normalization of gastrointestinal motility, and prevention of the animals’ weight loss. Given the cyclophosphamide-induced immunosuppression and streptomycin-associated diarrhoea, the immunity was completely restored only under the action ofBacillus coagulans.

Conclusions.

According to all parameters,Bacillus coagulanshas been proved to be more effective as compared to the Linex Forte reference product containing lacto‐ and bifidobacteria.
Development of tools to automate quantitative analysis of radiation damage in SAXS experiments
Authors: Brooks-Bartlett Jonathan C. , Batters Rebecca A. , Bury Charles S. , Lowe Edward D. , Ginn Helen Mary , Round Adam , Garman Elspeth F.
Published: November 2016

Biological small-angle X-ray scattering (SAXS) is an increasingly popular technique used to obtain nanoscale structural information on macromolecules in solution. However, radiation damage to the samples limits the amount of useful data that can be collected from a single sample. In contrast to the extensive analytical resources available for macromolecular crystallography (MX), there are relatively few tools to quantitate radiation damage for SAXS, some of which require a significant level of manual characterization, with the potential of leading to conflicting results from different studies. Here, computational tools have been developed to automate and standardize radiation damage analysis for SAXS data. RADDOSE-3D, a dose calculation software utility originally written for MX experiments, has been extended to account for the cylindrical geometry of the capillary tube, the liquid composition of the sample and the attenuation of the beam by the capillary material to allow doses to be calculated for many SAXS experiments. Furthermore, a library has been written to visualize and explore the pairwise similarity of frames. The calculated dose for the frame at which three subsequent frames are determined to be dissimilar is defined as the radiation damage onset threshold (RDOT). Analysis of RDOTs has been used to compare the efficacy of radioprotectant compounds to extend the useful lifetime of SAXS samples. Comparison of the RDOTs shows that, for radioprotectant compounds at 5 and 10 mM concentration, glycerol is the most effective compound. However, at 1 and 2 mM concentrations, dithiothreitol (DTT) appears to be most effective. Our newly developed visualization library contains methods that highlight the unusual radiation damage results given by SAXS data collected using higher concentrations of DTT: these observations should pave the way to the development of more sophisticated frame merging strategies.