bluuebunny/crossref_metadata_2025 huggingface dataset:
High exposure to statins decrease the risk of new-onset dementia
Authors: Chang Chih-Feng , Liou Yi-Sheng , Lin Tsung-Kun , Ma Stacey , Hu Yu-Ru , Chen Hung-Yi , Jong Gwo-Ping
Published: August 2019

Several studies have shown that statin users have a lower risk of new-onset dementia (NOD) compared nonusers. However, other studies have shown opposite results. In this study, we investigated the association between the use of statins and the development of NOD.

This was a longitudinal cohort study using data from claim forms submitted to the Taiwanese Bureau of National Health Insurance. The study included patients with NOD and non-NOD subjects from January 2002 to December 2013. We estimated the hazard ratios (HRs) of NOD associated with statin use, whereas nonuser subjects were used as a reference group.

A total of 19,522 NOD cases were identified in 100,610 hyperlipidemic patients during the study period. The risk of NOD, after adjusting for sex, age, comorbidities, and concurrent medication, was lower among statin users than nonusers (HR 0.95, 95% CI [confidence interval] 0.94–0.96; P < .001). The adjusted HRs for NOD were 1.53 (95% CI, 1.45–1.62), 0.63 (95% CI, 0.57–0.71), and 0.34 (95% CI, 0.30–0.38) when the cumulative defined daily doses ranged from 28 to 365, 366 to 730, and more than 730 relative to nonusers, respectively.

We concluded that statin use is associated with a decreased NOD risk. The protective effect of statins for NOD seemed to be related to high exposure to statins. This study also highlights that high exposure to statins has a dose-response effect on lowering NOD risk.
Effectiveness of tenofovir and entecavir in nucleos(t)ide analogue-naive chronic hepatitis B
Authors: Chen Mao-bing , Wang Hua , Zheng Qi-han , Zheng Xu-wen , Fan Jin-nuo , Ding Yun-long , Yue Mao-xing
Published: August 2019

Background:

Chronic hepatitis b (CHB) is a serious problem worldwide. Tenofovir disoproxil fumarate (TDF) and entecavir (ETV) both are first-line drugs for CHB, but there is debate about which is more appropriate in nucleos(t)ide analogue-naive CHB.

Objective:

To systematically evaluate the effectiveness and safety of tenofovir and ETV in nucleos(t)ide analogue-naive CHB.

Methods:

The Web of Science, PubMed, The Cochrane Library, EMBASE, Clinical Trials, and China National Knowledge Infrastructure databases will be electronically searched to collect randomized controlled trials regarding the comparison between tenofovir and ETV in nucleos(t)ide analogue-naive CHB since the date of database inception to July 2019. Two researchers independently screened and evaluated the obtained studies and extracted the outcome indexes. RevMan 5.3 software will be used for the meta-analysis.

Result:

We will provide practical and targeted results assessing the effectiveness and safety of TDF and ETV for nucleos(t)ide analogue-naive CHB patients, try to compare the advantages of TDF and ETV.

Conclusion:

The stronger evidence about the effectiveness and safety of TDF and ETV for nucleos(t)ide analogue-naive CHB patients will be provided for clinicians.

Protocol registration number:

PROSPERO CRD42019134194.
Safety and efficacy of flecainide for patients with catecholaminergic polymorphic ventricular tachycardia
Authors: Wang Guangqiang , Zhao Na , Zhong Shu , Wang Yingrong , Li Jianping
Published: August 2019

Background:

Owing to reports of recurrent cardiac events in some catecholaminergic polymorphic ventricular tachycardia (CPVT) patients using β-blockers, safer alternatives are being investigated. Flecainide is an alternative adjunctive anti-arrhythmic agent known to provide incomplete protection to CPVT patients.

Methods:

To investigate the efficacy and tolerability of flecainide, we searched 4 databases for retrospective cohort studies (RCs) and randomized controlled trials (RCTs) investigating the efficacy and safety of flecainide for CPVT patients. Data were extracted and analyzed (risk ratio [RR] or mean difference [MD]) using RevMan software. Seven RCs and 1 RCT (333 CPVT patients; 152 patients treated with flecainide) were identified.

Results:

Flecainide monotherapy was superior to standard therapy in alleviating the risk of arrhythmic events (RR = 0.46, confidence interval [CI] = [0.38, 0.56], P < .00001) and exercise-induced arrhythmia scores (MD = −0.39, CI = [−0.74, −0.05], P = .03). Combination therapy of flecainide and β-blockers was superior to β-blocker monotherapy in reducing the risk of arrhythmic and symptomatic events (RR = 0.29, CI = [0.13, 0.69], P = .005; RR = 0.36, CI = [0.20, 0.62], P = .0003, respectively), peak heart rate (MD = −16.81, CI = [−28.21, −5.41], P = .004), and exercise-induced arrhythmia scores (MD = −1.87, CI = [−2.71, 1.04], P < .0001). Flecainide did not increase the risk of all side effects (RR = 0.76, CI = [0.42, 1.40], P = .38) compared to that with β-blockers alone. No deaths were reported among patients treated with flecainide.

Conclusions:

Flecainide is an effective and safe anti-arrhythmic agent, and its use as a monotherapy might be a good alternative for CPVT patients with β-blocker intolerance. Combination therapy was superior to β-blocker monotherapy. More randomized clinical trials are required to explore the long-term efficacy and safety of flecainide in these patients.
The effect of direct antiviral treatment on the depression, anxiety, fatigue and quality-of-life in chronic hepatitis C patients
Authors: Durcan Emre , Hatemi Ibrahim , Sonsuz Abdullah , Canbakan Billur , Ozdemir Sebati , Tuncer Murat
Published: August 2019

Objective

In this study, we aimed to investigate the effects of direct antiviral treatment on depression, anxiety, fatigue and quality of life in patients with chronic hepatitis C.

Methods

Subjects included in study were treatment experienced and treatment naive chronic hepatitis C patients admitted to the hepatology outpatient clinic between December 2016 and June 2017. Before and after the treatment, Beck depression, Beck anxiety, liver-specific quality of life and fatigue severity-impact scales were administered. Descriptive statistical methods, Kolmogorov-Smirnov distribution test Wilcoxon sign and kappa coefficient tests were used to evaluate the study data.

Results

Forty-four patients were included in the study; however, it was completed with 35 patients only, as some of the patients were excluded for various reasons. There was no significant difference between depression and anxiety scores of the patients before and after the treatment, but depression and anxiety were found to be recovered in 28.5% (4/14) and 23.5% (4/17) of the subjects, respectively. At the end of the treatment, fatigue severity-impact scales and liver-specific quality of life were not significantly different from those before the treatment.

Conclusion

In this study, we found that direct antivirals did not lead to depression, anxiety or fatigue and did not decrease liver-specific quality of life. In some cases, depression and anxiety decreased after the treatment.
Treatment of Hermansky-Pudlak syndrome Associated granulomatous colitis with anti-TNF agents: case series and review of literature
Authors: Demirtas Coskun Ozer , Alahdab Yesim Ozen , Kani Haluk Tarik , Atug Ozlen , Imeryuz Nese
Published: August 2019

Hermansky-Pudlak syndrome is a rare syndrome characterized by bleeding diathesis due to platelet dysfunction, oculocutaneous albinism and other systemic involvements. Granulomatous colitis may occur in the disease course and have similarities with Crohn’s disease. Herein, we present four cases with Hermansky-Pudlak syndrome associated colitis with the longest follow-up period having various responses to different anti-TNF agents. Four patients with Hermansky-Pudlak syndrome colitis were started on anti-TNF agents between 2008 and 2013. After a mean follow-up period of 7.5 years, two of four patients exhibited a significant improvement in symptoms, whereas the other two experienced undesirable disease course. Although having many similarities with Crohn’s disease; Hermansky-Pudlak syndrome colitis appears to have lower anti-TNF response rates. Pathophysiological differences need to be enlightened to find more appropriate therapeutic targets for Hermansky-Pudlak syndrome colitis.
Optimal duration of concomitant nonbismuth quadruple therapy as first-line therapy for Helicobacter pylori: a prospective, open-label, comparative study
Authors: Kapizioni Christina , Koutoufaris Georgios , Ntouli Vasiliki , Makris Konstantinos , Milioni Konstantia , Kourkoulis Panagiotis , Giannelis Panagiotis , Mellos Aristotelis , Michalopoulos Georgios , Vrakas Spyridon , Xourgias Vasileios
Published: August 2019

Background

Concomitant nonbismuth quadruple therapy is recommended as first-line treatment for Helicobacter pylori infection in high clarithromycin resistance areas, but the ideal duration of the regimen remains elusive. Aim of this study was to assess the efficacy and tolerability of 10- versus 14-day concomitant therapy for H. pylori eradication in an area of high clarithromycin and low dual clarithromycin/metronidazole resistance.

Methods

This was a prospective, open-label study including adult patients with H. pylori infection without previous treatment, from September 2014 to June 2017. Concomitant therapy consisting of pantoprazole 40 mg, amoxicillin 1g, clarithromycin 500 mg, and a nitroimidazole 500 mg was administered twice daily for 10 days in the first phase and for 14 days in the second phase of the study. Efficacy and side effects were compared between groups using chi-square and Fisher’s exact tests.

Results

In per protocol analysis, rates of eradication for the 10- and 14-day regimen were 91.9% (114/124) and 90.9% (110/121), respectively (P = 0.77). In intention to treat analysis, rates of eradication were lower than 90%. Specifically, rates were 86.3% (114/132) for the 10-day regimen and 85.2% (110/129) for the 14-day regimen (P = 0.8). Side effects, present in 31.3% of treated patients, were significantly more common in the 14-day group (P = 0.015). Four patients discontinued treatment, all in the 14-day group.

Conclusions

Ten day concomitant nonbismuth quadruple therapy for H. pylori is highly efficacious and better tolerated than the 14-day regimen. Thus, 10-day therapy may be preferred as first-line treatment in clinical practice.
Efficacy and safety of direct-acting antivirals in older patients with cirrhosis and high comorbidity index
Authors: Amoros-Reboredo Patricia , Sotoca Josep Miquel , Mariño Zoe , Rodríguez-Tajes Sergio , Pocurull Anna , Soy Dolors , Forns Xavier , Lens Sabela
Published: August 2019

Objective

There is scarce data with regard to the effectiveness and safety of direct-acting antivirals and possible drug–drug interactions between antiviral therapy and the multiple drugs frequently assumed by older patients. The aim is to evaluate the impact of comorbidities and drug–drug interactions on the efficacy and tolerability of direct-acting antivirals in this population.

Methods

Observational retrospective study of patients at least 65 years old receiving all-oral antiviral therapy between April 2015 and March 2016.

Results

Two hundred sixty-one patients were identified. Age distribution: 65–74 (73.9%), 75–79 (18.4%) and ≥80 (7.7%) years. Average age was 71 years, 38.7% were male, and 90% of patients took concomitant medication (43% patients taking ≥ 5 medicines). Predicted clinically significant drug–drug interactions were present in 72.8% of patients. The sustained viral response 12 weeks after end of treatment was 96.9%. Patients with serious adverse events received more concomitant drugs and all of them presented a clinical risk group ≥06/5.

Conclusions

Direct antiviral agents are highly effective also in older patients with advanced liver disease, comorbidities and concomitant medications. Serious adverse events increased with the number of concomitant medications and the severity of comorbidity. A clinical risk group score ≥06/5 may help to decide the indication of antiviral therapy in this difficult-to-treat population.
Process Mining for Quality Improvement: Propositions for Practice and Research
Authors: Dahlin Sara , Eriksson Henrik , Raharjo Hendry
Published: August 2019

Objective:

Process mining offers ways to discover patient flow, check how actual processes conform to a standard, and use data to enhance or improve processes. Process mining has been used in health care for about a decade, however, with limited focus on quality improvement. Hence, the aim of the article is to present how process mining can be used to support quality improvement, thereby bridging the gap between process mining and quality improvement.

Method:

We have analyzed current literature to perform a comparison between process mining and process mapping.

Result:

To better understand how process mining can be used for quality improvement we provide 2 examples. We have noted 4 limitations that must be overcome, which have been formulated as propositions for practice. We have also formulated 3 propositions for future research.

Conclusion:

In summary, although process mapping is still valuable in quality improvement, we suggest increased focus on process mining. Process mining adds to quality improvement by providing a better understanding of processes in terms of uncovering (un)wanted variations as to obtain better system results.
Sustainment of Lean Redesigns for Primary Care Teams
Authors: Hung Dorothy Y. , Gray Caroline P. , Truong Quan A. , Harrison Michael I.
Published: August 2019

Background:

Quality improvements are notoriously followed by “backsliding” or relapse to the status quo. This mixed-methods study examined the sustainment of Lean workflow redesigns for primary care teams several years after being implemented in a large, ambulatory care delivery system.

Methods:

We conducted qualitative interviews of 57 leaders and frontline providers, and fielded post-Lean implementation surveys to 1164 physicians and staff in 17 primary care clinics across the system. We analyzed interviews and conducted independent sample t tests to identify key factors that facilitated the sustainment of new workflows among primary care teams. All analyses were conducted after Lean redesigns were implemented and scaled across the system in 3 consecutive phases.

Results:

Adherence to Lean redesigns was highest in the pilot clinic, despite having the longest postdesign measurement period. Members of the pilot clinic reported greatest participation in designing workflows, were most highly engaged in quality improvement efforts, and held most favorable beliefs about Lean changes. Adherence to redesigns was lowest among clinic members in the second phase of implementation; these members also reported highest levels of burnout.

Conclusions:

Staff participation in Lean redesign is a key to facilitating buy-in and adherence to changes. Change ownership and continued availability of time for improvement activities are also critical to the long-term success of Lean implementation in primary care.
Can Nurse-Based Management Screening Ensure Adequate Outcomes in Patients With Gestational Diabetes? A Comparison of 2 Organizational Models
Authors: Nollino Laura , Marcon Maria Lisa , Kiwanuka Edward , Merlotto-Cazziola Michela , Sambataro Maria , Sambado Luisa , Trevisiol Enrica , Scantamburlo Antonella , Mauri Alessandra , Busato Enrico , Pirolo Roberta , Boaretto Massimo , Turolla Licia , Faronato Pietro Paolo , Cadamuro-Morgante Marco , Migot Roberta , Paccagnella Agostino
Published: August 2019

Background:

Gestational diabetes mellitus (GDM) is an impaired glucose tolerance with onset or first recognition during pregnancy. The purpose of this study is to evaluate the clinical outcomes of a blood glucose monitoring protocol implemented by nurses and dietitians in a diabetes team to the previously established protocol of direct monitoring of GDM patients by a diabetologist.

Methods:

Two groups of patients were formed: The first group was based on a traditional protocol (P1: 230 patients) with patients' blood glucose constantly checked by a diabetologist. In the second structured group (P2: 220 patients) patients were referred to a diabetologist only if they required insulin therapy.

Results:

The number of medical visits (P2: 1.28 ± 0.70 vs P1: 3.27 ± 1.44; P < .001) and the percentage of patients with hypoglycemia (P2: 6.8% vs P1: 15.2%; P < .006) were found to be lower in group P2 than in group P1. In both groups, a direct relationship was found between a parental history of diabetes and the risk of GDM (odds ratio [OR]: P1 = 2.2 [1.17-4.12]; P2 = 2.5 [1.26-5.12]). In group P1, it was observed that hyperweight gain in patients who were already overweight before becoming pregnant significantly increased the risk of macrosomia (OR: 3.11 [1.39-25.7]), whereas this was not detected in patients in group P2. In group P2, a correlation was found between macrosomia and insulin therapy (OR: 0.066 vs 0.34). In group P1 and group P2, a correlation was observed between insulin therapy and a family history of diabetes (OR: 2.20 vs 2.27), and a body mass index of greater than 30 kg/m2 in group P2 (OR: 3.0 vs 1.47).

Conclusions:

The data we collected show that creating a structured protocol for GDM management reduces the number of medical visits required by patients without increasing the risk of hypoglycemia, macrosomia, or hyperweight gain during pregnancy.
Hyperparathyroidism Due to Concurrent Parathyroid Carcinoma and Parathyroid Adenoma
Authors: Yang Jiqin , Li Yanmei , Li Juan , Yang Pengfei , Huang Lingyan
Published: August 2019

Parathyroid carcinoma is uncommon, and its coexistence with parathyroid adenoma is extremely rare. A 28-year-old woman with hyperparathyroidism underwent dual-phase 99mTc-sestamibi SPECT/CT scan for presurgical evaluation. The images showed intense activity inside the left side thyroid and mild activity inside the right side of the thyroid. The histopathologic findings showed intrathyroidal parathyroid carcinoma on the left side and intrathyroid parathyroid adenoma on the right side.
Immune gene regulation in the gut during metamorphosis in a holo- versus a hemimetabolous insect
Authors: Johnston Paul R. , Paris Véronique , Rolff Jens
Published: August 2019

During metamorphosis, holometabolous insects completely replace the larval gut and must control the microbiota to avoid septicaemia. Rapid induction of bactericidal activity in the insect gut at the onset of pupation has been described in numerous orders of the Holometabola and is best-studied in the Lepidoptera where it is under control of the 20-hydroxyecdysone (20E) moulting pathway. Here, using RNAseq, we compare the expression of immune effector genes in the gut during metamorphosis in a holometabolous (
Galleria mellonella
) and a hemimetabolous insect (
Gryllus bimaculatus
). We find that in
G. mellonella
, the expression of numerous immune effectors and the transcription factor GmEts are upregulated, with peak expression of three antimicrobial peptides (AMPs) and a lysozyme coinciding with delamination of the larval gut. By contrast, no such upregulation was detectable in the hemimetabolous
Gr. bimaculatus
. These findings support the idea that the upregulation of immune effectors at the onset of complete metamorphosis is an adaptive response, which controls the microbiota during gut replacement.

This article is part of the theme issue ‘The evolution of complete metamorphosis’.
Association of Single Nucleotide Polymorphisms with Dyslipidemia in Antiretroviral Exposed HIV Patients in a Ghanaian population
Authors: Obirikorang Christian , Acheampong Emmanuel , Quaye Lawrence , Yorke Joseph , Amos-Abanyie Ernestine Kubi , Akyaw Priscilla Abena , Anto Enoch Odame , Bani Simon Bannison , Asamoah Evans Adu , Batu Emmanuella Nsenbah
Published: August 2019

Dyslipidemia is a potential complication of long-term usage of antiretroviral therapy (ART) and also known to be associated with genetic factors. The host genetic variants associated with dyslipidemia in HIV patients on ART in Ghana have not been fully explored. The study constituted a total of 289 HIV-infected patients on stable ART for at least a year and 85 aged matched apparently healthy control subjects with no history of HIV and dyslipidemia. Fasting blood was collected into EDTA tube for lipids measurements. Lipid profiles were determined as a measure of dyslipidemia. HIV-infected patients were categorized into two groups; those with dyslipidemia(HIV-Dys+) (n=90; 31.1%) and without dyslipidemia (n=199; 68.9%) based on the NCEP-ATP III criteria. Four candidate single nucleotide polymorphisms (SNPs) genes (ABCA1-rs2066714, LDLR-rs6511720, APOA5-rs662799 and DSCAML1-rs10892151) were determined. Genotyping was performed on isolated genomic DNA of study participants using PCR followed by a multiplex Ligation Detection Reaction (LDR). The percentage of the population who had the rare homozygote alleles for rs6511720 (T/T), rs2066714 (G/G), and rs10892151 (T/T) and rs662799 (G/G) among HIV+Dys+subjects were 5.5%, 14.4%, 6.6% and 10.0%; 2.0% 9.1%, 6.5% and 4.0% among HIV+Dys-subjects while 3.5%, 4.7%, 4.7% and 2.4% were observed in HIV-Dys-subjects. Statistically significant difference in genotypic prevalence of APOA5 polymorphisms was observed among different groups (p=0.0196). Compared to the AA genotype of the APOA5 polymorphisms, individuals with the rare homozygote genotype [aOR =4.01, 95%CI(1.57-22.39), p=0.004] were significantly more likely to develop dyslipidemia after controlling for age, gender, treatment duration and CD4 counts among the HIV+Dys+subjects. There was also a significant associated between GG genotype of ABCA1 and dyslipidemia [aOR =3.29, 95% (1.08 −12.43); p=0.042]. Individuals with the rare homozygote variant (GG) of APOA5 (rs662799) were significantly associated with increased likelihood of developing dyslipidemia [OR =2.24, 95% CI (1.20 −6.83); p=0.0370] holding other variables constant in the HIV+Dys-subjects. Our data accentuate the presence of SNPs in four candidate genes and its association with dyslipidemia among HIV patients exposed to ART in the Ghanaian population especially variants in APOA5-rs662799 ABCA1-rs2066714 respectively. These findings provide baseline information that necessitates a pre-symptomatic strategy for monitoring dyslipidemia in ART-treated HIV patients. There is a need for longitudinal studies to validate a comprehensive number of SNPs and its association with dyslipidemia.
Impairment of dual-task gait dynamics in older adults with mild cognitive impairment: Relationships to neuropsychological status, fitness and brain morphology
Authors: Hawkins Tess C , Samuel Rebecca , Fiatarone Singh Maria A , Gates Nicola , Wilson Guy C , Jain Nidhi , Meiklejohn Jacinda , Brodaty Henry , Wen Wei , Singh Nalin , Baune Bernhard T , Suo Chao , Baker Michael K , Foroughi Nasim , Wang Yi , Sachdev Perminder S , Valenzuela Michael J , Hausdorff Jeffrey M , Mavros Yorgi
Published: August 2019

Background

Individuals with Mild Cognitive Impairment (MCI) have more gait variability under dual-task conditions than cognitively healthy adults. However, characteristics associated with this susceptibility of gait to dual-task stress are unknown.

Methods

Testing was performed at baseline in the Study of Mental And Resistance Training (SMART). Ninety-three adults with MCI (age 70±6.8 years; 66.6% female) performed a single- and dual-task walk (cognitive distractor=letter fluency), in random order. Linear and non-linear gait variability were measured using force-sensitive insoles. Cognitive performance during dual-tasking was assessed by the number of correct words vocalized. Cognitive function, brain Magnetic Resonance Imaging (MRI), muscle strength, aerobic capacity, body composition, physical and psychosocial function were also assessed as potential correlates of gait dynamics.

Results

Gait dynamics worsened during dual-tasking, with decrements in both stride time variability (p<0.001) and detrended fluctuation analysis (DFA) (p=0.001). Lower aerobic capacity and thinner posterior cingulate cortex were associated with greater decrements in DFA (p<0.05). Smaller hippocampal volume, worse psychological well-being and poorer static balance were associated with greater decrements in stride time variability (p<0.05). By contrast, cognitive performance did not change under dual-task conditions compared to seated testing (p=0.13).

Conclusions

Under dual-task conditions, participants with MCI preserved their cognitive performance at the expense of gait stability. Decrements in dual-tasking gait were associated with lower aerobic fitness, balance, psychological well-being, and brain volume in cognitively-relevant areas of the posterior cingulate and hippocampus, all potentially modifiable characteristics. Trials of targeted interventions are needed to determine the potential plasticity of gait variability in high-risk cohorts.
Efficient CRISPR/Cas9 genome editing in a salmonid fish cell line using a lentivirus delivery system
Authors: Gratacap Remi L. , Regan Tim , Dehler Carola E. , Martin Samuel A.M. , Boudinot Pierre , Collet Bertrand , Houston Ross D.
Published: August 2019

1

Genome editing is transforming bioscience research, but its application to non-model organisms, such as farmed animal species, requires optimisation. Salmonids are the most important aquaculture species by value, and improving genetic resistance to infectious disease is a major goal. However, use of genome editing to evaluate putative disease resistance genes in cell lines, and the use of genome-wide CRISPR screens is currently limited by a lack of available tools and techniques. In the current study, an optimised protocol using lentivirus transduction for efficient integration of constructs into the genome of a Chinook salmon (Oncorhynchus tshwaytcha) cell line (CHSE-214) was developed. As proof-of-principle, two target genes were edited with high efficiency in an EGFP-Cas9 stable CHSE cell line; specifically, the exogenous, integrated EGFP and the endogenous RIG-I locus. Finally, the effective use of antibiotic selection to enrich the successfully edited targeted population was demonstrated. The optimised lentiviral-mediated CRISPR method reported here increases possibilities for efficient genome editing in salmonid cells, in particular for future applications of genome-wide CRISPR screens for disease resistance.
Immunotherapy prevents long-term disability in relapsing multiple sclerosis over 15 years
Authors: Kalincik Tomas , Sharmin Sifat , Malpas Charles , Spelman Tim , Horakova Dana , Havrdova Eva Kubala , Trojano Maria , Izquierdo Guillermo , Lugaresi Alessandra , Prat Alexandre , Girard Marc , Duquette Pierre , Grammond Pierre , Jokubaitis Vilija , van der Walt Anneke , Grand’Maison Francois , Sola Patrizia , Ferraro Diana , Shaygannejad Vahid , Alroughani Raed , Hupperts Raymond , Terzi Murat , Boz Cavit , Lechner-Scott Jeannette , Pucci Eugenio , Van Pesch Vincent , Granella Franco , Bergamaschi Roberto , Spitaleri Daniele , Slee Mark , Vucic Steve , Ampapa Radek , McCombe Pamela , Ramo-Tello Cristina , Prevost Julie , Olascoaga Javier , Cristiano Edgardo , Barnett Michael , Saladino Maria Laura , Sanchez-Menoyo Jose Luis , Hodgkinson Suzanne , Rozsa Csilla , Hughes Stella , Moore Fraser , Shaw Cameron , Butler Ernest , Skibina Olga , Gray Orla , Kermode Allan , Csepany Tunde , Singhal Bhim , Shuey Neil , Piroska Imre , Taylor Bruce , Simo Magdolna , Sirbu Carmen-Adella , Sas Attila , Butzkueven Helmut ,   on behalf of the MSBase Study group
Published: August 2019

Objective

Whether immunotherapy improves long-term disability in multiple sclerosis has not been satisfactorily demonstrated. This study examined the effect of immunotherapy on long-term disability outcomes in relapsing-remitting multiple sclerosis.

Methods

We studied patients from MSBase followed for ≥1 year, with ≥3 visits, ≥1 visit per year and exposed to a multiple sclerosis therapy, and a subset of patients with ≥15-year follow-up. Marginal structural models were used to compare the hazard of 12-month confirmed increase and decrease in disability, EDSS step 6 and the incidence of relapses between treated and untreated periods. Marginal structural models were continuously re-adjusted for patient age, sex, pregnancy, date, disease course, time from first symptom, prior relapse history, disability and MRI activity.

Results

14,717 patients were studied. During the treated periods, patients were less likely to experience relapses (hazard ratio 0.60, 95% confidence interval 0.43–0.82, p=0.0016), worsening of disability (0.56, 0.38-0.82, p=0.0026) and progress to EDSS step 6 (0.33, 0.19-0.59, p=0.00019). Among 1085 patients with ≥15-year follow-up, the treated patients were less likely to experience relapses (0.59, 0.50–0.70, p=10-9) and worsening of disability (0.81, 0.67-0.99, p=0.043).

Conclusions

Continued treatment with multiple sclerosis immunotherapies reduces disability accrual (by 19-44%), the risk of need of a walking aid by 67% and the frequency of relapses (by 40-41%) over 15 years. A proof of long-term effect of immunomodulation on disability outcomes is the key to establishing its disease modifying properties.
Pupil diameter encodes the idiosyncratic, cognitive complexity of belief updating
Authors: Filipowicz Alexandre L.S. , Glaze Christopher M. , Kable Joseph W. , Gold Joshua I.
Published: August 2019

Pupils tend to dilate in response to surprising events, but it is not known whether these responses are primarily stimulus driven or instead reflect a more nuanced relationship between pupil-linked arousal systems and cognitive expectations. Using an auditory adaptive decision-making task, we show that evoked pupil diameter is more parsimoniously described as signaling violations of learned, top-down expectations than changes in low-level stimulus properties. We further show that both baseline and evoked pupil diameter is modulated by the degree to which individual subjects use these violations to update their subsequent expectations, as reflected in the complexity of their updating strategy. Together these results demonstrate a central role for idiosyncratic cognitive processing in how arousal systems respond to new inputs and, via our complexity-based analyses, provide a unified framework for understanding these effects in terms of both inference processes aimed to reduce belief uncertainty and more traditional notions of mental effort.
Genome sequence and comparative analysis of reindeer (Rangifer tarandus) in northern Eurasia
Authors: Weldenegodguad Melak , Pokharel Kisun , Ming Yao , Honkatukia Mervi , Peippo Jaana , Reilas Tiina , Røed Knut H. , Kantanen Juha
Published: August 2019

Reindeer are semi-domesticated ruminants that have adapted to the challenging northern Eurasian environment characterized by long winters and marked annual fluctuations in daylight. We explored the genetic makeup behind their unique characteristics by de novo sequencing the genome of a male reindeer and conducted gene family analyses with nine other mammalian species. We performed a population genomics study of 23 additional reindeer representing both domestic and wild populations and several ecotypes from various geographic locations. We assembled 2.66 Gb (N50 scaffold of 5 Mb) of the estimated 2.92 Gb reindeer genome, comprising 27,332 genes. The results from the demographic history analysis suggested marked changes in the effective population size of reindeer during the Pleistocene period. We detected 160 reindeer-specific and expanded genes, of which zinc finger proteins (n=42) and olfactory receptors (n=13) were the most abundant. Comparative genome analyses revealed several genes that may have promoted the adaptation of reindeer, such as those involved in recombination and speciation (PRDM9), vitamin D metabolism (TRPV5, TRPV6), retinal development (PRDM1, OPN4B), circadian rhythm (GRIA1), immunity (CXCR1, CXCR2, CXCR4, IFNW1), tolerance to cold-triggered pain (SCN11A) and antler development (SILT2). The majority of these characteristic reindeer genes have been reported for the first time here. Moreover, our population genomics analysis suggested at least two independent reindeer domestication events with genetic lineages originating from different refugial regions after the Last Glacial Maximum. Taken together, our study has provided new insights into the domestication, evolution and adaptation of reindeer and has promoted novel genomic research of reindeer.
Phase-amplitude markers of synchrony and noise: A resting-state and TMS-EEG study of schizophrenia
Authors: Freche D , Naim-Feil J , Hess S , Peled A , Grinshpoon A , Moses E , Levit-Binnun N
Published: August 2019

The electroencephalogram (EEG) of schizophrenia patients is known to exhibit a reduction of signal-to-noise ratio and of phase locking, as well as a facilitation of excitability, in response to a variety of external stimuli. Here we demonstrate these effects in transcranial magnetic stimulation (TMS)-evoked potentials and in the resting-state EEG. To ensure veracity we used three weekly sessions and analyzed both resting state and TMS-EEG data. For the TMS responses our analysis verifies known results. For the resting state we introduce the methodology of mean-normalized variation to the EEG analysis (quartile-based coefficient of variation), which allows for a comparison of narrow-band EEG amplitude fluctuations to narrow-band Gaussian noise. This reveals that amplitude fluctuations in the delta, alpha and beta bands of healthy controls are different from those in schizophrenia patients, on time scales of tens of seconds. We conclude that the EEG-measured cortical activity patterns of schizophrenia patients are more similar to noise, both in alpha and beta resting state and in TMS responses. Our results suggest that the ability of neuronal populations to form stable, locally and temporally correlated activity is reduced in schizophrenia, a conclusion that is in accord with previous experiments on TMS-EEG and on resting-state EEG.
Core Fermentation (CoFe) granules focus coordinated glycolytic mRNA localization and translation to fuel glucose fermentation
Authors: Morales-Polanco Fabian , Bates Christian , Lui Jennifer , Casson Joseph , Solari Clara A. , Pizzinga Mariavittoria , Forte Gabriela , Griffin Claire , Burt Harriet E. , Dixon Hannah L. , Hubbard Simon , Portela Paula , Ashe Mark P.
Published: August 2019

Glycolysis is a fundamental metabolic pathway for glucose catabolism across biology, and glycolytic enzymes are amongst the most abundant proteins in cells. Their expression at such levels provides a particular challenge. Here we demonstrate that the glycolytic mRNAs are localized to granules in yeast and human cells. Detailed live cell and smFISH studies in yeast show that the mRNAs are actively translated in granules, and this translation appears critical for the localization. Furthermore, this arrangement is likely to facilitate the higher level organisation and control of the glycolytic pathway. Indeed, the degree of fermentation required by cells is intrinsically connected to the extent of mRNA localization to granules. On this basis, we term these granules, Core Fermentation (CoFe) granules; they appear to represent translation factories allowing high-level co-ordinated enzyme synthesis for a critical metabolic pathway.
Investigating Confidence Judgments using Reviews in Human and Monkeys
Authors: Stoll Frederic M. , Procyk Emmanuel
Published: August 2019

Confidence judgments are self-assessments of the quality of one’s own performance, and are a crucial aspect of metacognitive abilities. The underlying neurobiological mechanisms are poorly understood. One approach to understanding these mechanisms would be to take advantage of putative metacognitive abilities in non-human models. However, many discrepancies exist between human and non-human studies on metacognition due to the mode of reporting judgements. We here present an attempt to directly compare human and non-human primates’ metacognitive abilities using a protocol assessing confidence judgments. After performing a categorization test, subjects could either validate their choice or review the test. We could assess whether subjects detected their errors and how they corrected them according to their confidence, and importantly did so in both human and non-human primates. 14 humans and 2 macaque monkeys were tested. Humans showed a well-adapted use of the review option by reviewing more after incorrect choices or difficult stimuli. Non-human primates did not demonstrate a convincing use of the review or validate opportunity. In both species, reviewing did not improve performance. This study shows that decisions to review under uncertainty are not naturally beneficial to performance and is rather perturbed by biases and alternative low-cognitive cost strategies.
Inflammation in Alzheimer’s disease: do sex and APOE matter?
Authors: Duarte-Guterman Paula , Albert Arianne Y. , Inkster Amy M. , Barha Cindy K. , Galea Liisa A.M. ,   on behalf of the Alzheimer’s Disease Neuroimaging Initiative
Published: August 2019

Alzheimer’s disease (AD) disproportionately affects females with steeper cognitive decline and more neuropathology compared to males, which is exacerbated in females carrying the APOEε4 allele. The risk of developing AD is also higher in female APOEε4 carriers in earlier age groups (aged 65-75), and the progression from cognitively normal to mild cognitive impairment (MCI) and to AD may be influenced by sex. Inflammation is observed in AD and is related to aging, stress, and neuroplasticity, and although studies are scarce, sex differences are noted in inflammation. The objective of this study was to investigate underlying physiological inflammatory mechanisms that may help explain why there are sex differences in AD and APOEε4 carriers. We investigated, using the ADNI database, the effect of sex and APOE genotype (non-carriers or carriers of 1 and 2 APOEε4 alleles) and sex and diagnosis (cognitively normal (CN), MCI, AD) on CSF (N= 279) and plasma (N= 527) markers of stress and inflammation. We found CSF IL-16 and IL-8 levels were significantly lower in female non-carriers of APOEε4 alleles compared to males, whereas levels were similar between the sexes among carriers of APOEε4 alleles. Furthermore, females had on average higher levels of plasma CRP and ICAM1 but lower levels of CSF ICAM1, IL-8, IL-16, and IgA than males. Carrying APOEε4 alleles and diagnosis (MCI and AD) decreased plasma CRP in both sexes. Sex differences in inflammatory biomarkers support that the underlying physiological changes during aging differ by sex and tissue origin.
Associations between Processing Speed and Psychopathology in a Transdiagnostic, Pediatric Sample
Authors: Kramer Eliza , Koo Bonhwang , Restrepo Anita , Koyama Maki , Neuhaus Rebecca , Pugh Kenneth , Andreotti Charissa , Milham Michael
Published: August 2019

Objective

The present study sought to examine the relationships between processing speed (PS), mental health disorders, and learning disorders. Prior work has tended to explore relationships between PS deficits and individual diagnoses (i.e., anxiety, autism, ADHD, depressive) in isolation of one another, often relying on relatively modest sample sizes. In contrast, the present work simultaneously investigated associations between PS deficits and these diagnoses, along with specific learning disabilities (i.e., reading, math), in a large-scale, transdiagnostic, community self-referred sample.

Method

A total of 843 children, ages 8-16 were included from the Healthy Brain Network (HBN) Biobank. Given the presence of four PS tasks in HBN, principal component analysis (PCA) was employed to create a composite measure that represented the shared variance of the four PS tasks, referred to as PC1. Intraclass correlation coefficient (ICC) between the four PS measures, as well as PC1, were calculated to assess reliability. We then used multiple linear regression models to assess specific relationships between PS deficits and psychiatric diagnoses.

Results

ICCs were moderate between WISC-V tasks (0.663), and relatively modest between NIH Toolbox Pattern Comparison and other PS scales (0.14-0.27). Regression analyses revealed specific significant relationships between PS and reading and math disabilities, ADHD-inattentive type (ADHD-I), and ADHD-combined type (ADHD-C). Secondary analyses accounting for inattention dimensionally diminished associations with ADHD-C, but not ADHD-I or specific learning disability subtypes. The present study did not find a significant relationship with Autism Spectrum Disorder after accounting for inattentive symptoms. Consistent with prior work, demographic variables, including sex, socioeconomic status, and motor control exhibited independent relationships with PC1 as well.

Discussion

This study provided a comprehensive examination of PS, mental health disorders, and learning disabilities through a transdiagnostic approach. Implications for understanding how PS interacts with a highly heterogeneous childhood sample, as well as the need for increased focus on detection of affected populations are discussed.
CD4+T follicular helper (Tfh) cells in human tonsil and blood are clonally convergent, but divergent from non-Tfh CD4+cells
Authors: Brenna Elena , Davydov Alexey N , Ladell Kristin , McLaren James E , Bonaiuti Paolo , Metsger Maria , Gilbert Sarah C , Lambe Teresa , Price David A , Campion Suzanne L , Chudakov Dmitriy M , Borrow Persephone , McMichael Andrew J
Published: August 2019

T follicular helper (Tfh) cells are fundamental for B cell selection and antibody maturation in germinal centers. Circulating Tfh (cTfh) cells constitute a minor proportion of the CD4+T cells in peripheral blood, but their clonotypic relationship to Tfh populations resident in lymph nodes and the extent to which they differ from non-Tfh CD4+cells has been unclear. Using donor-matched blood and tonsil samples we investigated T cell receptor (TCR) sharing between tonsillar Tfh cells and peripheral Tfh and non-Tfh cell populations. TCR transcript sequencing revealed considerable clonal overlap between peripheral and tonsillar Tfh cell subsets as well as a clear distinction between Tfh and non-Tfh cells. Furthermore, influenza-specific cTfh cell clones derived from blood could be found in the repertoire of tonsillar Tfh cells. Therefore, human blood samples can be used to gain insight into the specificity of Tfh responses occurring in lymphoid tissues, provided cTfh subsets are studied.
Hippocampal Remapping as Hidden State Inference
Authors: Sanders Honi , Wilson Matthew A. , Gershman Samuel J.
Published: August 2019

Cells in the hippocampus tuned to spatial location (place cells) typically change their tuning when an animal changes context, a phenomenon known as remapping. A fundamental challenge to understanding remapping is the fact that what counts as a “context change” has never been precisely defined. Furthermore, different remapping phenomena have been classified on the basis of how much the tuning changes after different types and degrees of context change, but the relationship between these variables is not clear. We address these ambiguities by formalizing remapping in terms of hidden state inference. According to this view, remapping does not directly reflect objective, observable properties of the environment, but rather subjective beliefs about the hidden state of the environment. We show how the hidden state framework can resolve a number of puzzles about the nature of remapping.
An uncertainty principle for neural coding: Conjugate representations of position and velocity are mapped onto firing rates and co-firing rates of neural spike trains
Authors: Grgurich Ryan , Blair Hugh T.
Published: August 2019

The hippocampal system contains neural populations that encode an animal’s position and velocity as it navigates through space. Here, we show that such populations can embed two codes within their spike trains: afiring rate code(R) conveyed by within-cell spike intervals, and aco-firing rate code(Ṙ) conveyed by between-cell spike intervals. These two codes behave asconjugatesof one another, obeying an analog of the uncertainty principle from physics: information conveyed inRcomes at the expense of information inṘ, and vice versa. An exception to this trade-off occurs when spike trains encode a pair of conjugate variables, such as position and velocity, which do not compete for capacity acrossRandṘ. To illustrate this, we describe two biologically inspired methods for decodingRandṘ, referred to assigmaandsigma-chidecoding, respectively. Simulations of head direction (HD) and grid cells show that if firing rates are tuned for position (but not velocity), then position is recovered by sigma decoding, whereas velocity is recovered by sigma-chi decoding. Conversely, simulations of oscillatory interference among theta-modulated “speed cells” show that if co-firing rates are tuned for position (but not velocity), then position is recovered by sigma-chi decoding, whereas velocity is recovered by sigma decoding. Between these two extremes, information about both variables can be distributed across both channels, and partially recovered by both decoders. These results suggest that neurons with different spatial and temporal tuning properties—such as speed versus grid cells—might not encode different information, but rather, distribute similar information about position and velocity in different ways acrossRandṘ. Such conjugate coding of position and velocity may influence how hippocampal populations are interconnected to form functional circuits, and how biological neurons integrate their inputs to decode information from firing rates and spike correlations.
Mapping effective connectivity between the frontal and contralateral primary motor cortex using dual-coil transcranial magnetic stimulation
Authors: Bunday Karen L. , Bonaiuto James , Betti Sonia , Orban Guy A. , Davare Marco
Published: August 2019

Cytoarchitectonic, anatomical and electrophysiological studies have divided the frontal cortex into distinct functional subdivisions. Many of these subdivisions are anatomically connected with the contralateral primary motor cortex (M1); however, effective neurophysiological connectivity between these regions is not well defined in humans. Therefore, we aimed to use dual-coil transcranial magnetic stimulation (TMS) to map, with high spatial resolution, the effective connectivity between different frontal regions of the right hemisphere and contralateral M1 (cM1). TMS was applied over the left M1 alone (test pulse) or after a conditioning pulse was applied to different grid points covering the right frontal cortex, while subjects were at rest, prepared an index finger abduction (Prep-ABD) or precision grip (Prep-PG). MEP motor maps were generated by creating synthetic fMRI volumes, including the normalised MEP values at vertices corresponding to the TMS grid locations. These maps were registered to a common atlas, and statistical parametric mapping was used to identify cortical clusters in which stimulation differentially modulated conditioned MEPs across conditions. We found five significant clusters in the frontal cortex. Three clusters in ventral premotor regions (areas 6v and 44) showed significant differential modulations of contralateral MEPs when rest was compared to Prep-ABD and Prep-PG. Two clusters in rostral dorsolateral prefrontal cortex (areas 8Av and 46) showed differential modulation in MEPs when Prep-ABD was compared to Prep-PG. Our findings demonstrate distinct regions that show task-related connectivity whereby interactions between ventral premotor regions and cM1 differentiate between rest and movement preparation and the dorsolateral prefrontal cortex differentiates primarily between preparation of different types of hand movements. These results thus demonstrate the utility of dual-coil TMS and MEP motor maps to define fine-grained sub-regions in the human frontal cortex, which are functional and causally involved in hand movements.

Highlights

Dual-coil TMS mapping allows defining of fine-grained frontal cortex subdivisions

Frontal cortex houses multiple areas with different neurophysiological properties

Interactions between premotor areas and M1 control rest vs movement

Interactions between prefrontal areas and M1 reflect movement selection