Miracle-dz/UniFAR-FTUs huggingface dataset:
Primary lateral sclerosis: a distinct entity or part of the ALS spectrum?

Abstract Primary lateral sclerosis (PLS) has been traditionally viewed as a distinct upper motor neuron condition (UMN) but is increasingly regarded as a sub-phenotype within the amyotrophic lateral sclerosis (ALS) spectrum. Despite established diagnostic criteria, formal diagnosis can be challenging and the protracted diagnostic journey and uncertainty about longer-term prognosis cause considerable distress to patients and caregivers. PLS patients are invariably excluded from ALS clinical trials, while PLS pharmacological trials are lacking. There remains an unmet need for diagnostic biomarkers for upper motor neuron predominant conditions and prognostic indicators regarding prognosis, survival, and risk of conversion to ALS. Validated biomarkers will not only have implications for individualized patient care but also serve as outcome measures in pharmaceutical trials. Given the paucity of post-mortem studies in PLS, novel pathological insights are generally inferred from state-of-the-art imaging studies. Computational neuroimaging has already contributed significantly to the characterization of PLS-associated pathology in vivo and has underscored the role of neuro-inflammation, the presence of extra-motor changes, and confirmed pathological patterns similar to ALS. This systematic review assesses the current state of PLS research across clinical, neuroimaging and neuropathological domains from a combined clinical and academic perspective. We discuss patterns of pathological overlap with other ALS phenotypes, examine if the biological processes of PLS warrant therapeutic strategies distinct from ALS, and evaluate the evidence that classes PLS as a distinct clinico-pathological entity.
Neuronal mechanisms of mutations in SCN8A causing epilepsy or intellectual disability

Ion channel mutations can cause distinct neuropsychiatric diseases. We first studied the biophysical and neurophysiological consequences of four mutations in the human Na+ channel gene SCN8A causing either mild (E1483K) or severe epilepsy (R1872W), or intellectual disability and autism without epilepsy (R1620L, A1622D). Only combined electrophysiological recordings of transfected wild-type or mutant channels in both neuroblastoma cells and primary cultured neurons revealed clear genotype-phenotype correlations. The E1483K mutation causing mild epilepsy showed no significant biophysical changes, whereas the R1872W mutation causing severe epilepsy induced clear gain-of-function biophysical changes in neuroblastoma cells. However, both mutations increased neuronal firing in primary neuronal cultures. In contrast, the R1620L mutation associated with intellectual disability and autism-but not epilepsy-reduced Na+ current density in neuroblastoma cells and expectedly decreased neuronal firing. Interestingly, for the fourth mutation, A1622D, causing severe intellectual disability and autism without epilepsy, we observed a dramatic slowing of fast inactivation in neuroblastoma cells, which induced a depolarization block in neurons with a reduction of neuronal firing. This latter finding was corroborated by computational modelling. In a second series of experiments, we recorded three more mutations (G1475R, M1760I, G964R, causing intermediate or severe epilepsy, or intellectual disability without epilepsy, respectively) that revealed similar results confirming clear genotype-phenotype relationships. We found intermediate or severe gain-of-function biophysical changes and increases in neuronal firing for the two epilepsy-causing mutations and decreased firing for the loss-of-function mutation causing intellectual disability. We conclude that studies in neurons are crucial to understand disease mechanisms, which here indicate that increased or decreased neuronal firing is responsible for distinct clinical phenotypes.
Is psychotherapy effective? Pretending everything is fine will not help the field forward

When we wrote our paper on the question whether psychotherapies are effective or not (Cuijpers et al., 2018), some colleagues said this paper was unnecessary. Our claims that waiting list control groups are problematic, that the quality of many papers is overall low and that many negative studies are not published are well-documented and well-known among researchers. So why describe them again? Our response was that many in the field of psychotherapy research are not aware of these fundamental problems, and are very much internally oriented with little knowledge about major developments in the methodologies in the broader biomedical field. Our paper was obviously meant to stimulate discussion and awareness about these problems in the field. Unfortunately, Munder and colleagues, in their re-analysis of our study (Munder et al., 2018), just choose to ignore the main message of our paper. Instead of admitting major problems in the field, the authors choose to do as if nothing is wrong and that both psychotherapies effects and psychotherapy research are fine.
Early alterations in hippocampal perisomatic GABAergic synapses and network oscillations in a mouse model of Alzheimer’s disease amyloidosis

Several lines of evidence imply changes in inhibitory interneuron connectivity and subsequent alterations in oscillatory network activities in the pathogenesis of Alzheimer’s Disease (AD). Recently, we provided evidence for an increased immunoreactivity of both the postsynaptic scaffold protein gephyrin and the GABAA receptor γ2-subunit in the hippocampus of young (1 and 3 months of age), APPPS1 mice. These mice represent a well-established model of cerebral amyloidosis, which is a hallmark of human AD. In this study, we demonstrate a robust increase of parvalbumin immunoreactivity and accentuated projections of parvalbumin positive (PV+) interneurons, which target perisomatic regions of pyramidal cells within the hippocampal subregions CA1 and CA3 of 3-month-old APPPS1 mice. Colocalisation studies confirmed a significant increase in the density of PV+ projections labeled with antibodies against a presynaptic (vesicular GABA transporter) and a postsynaptic marker (gephyrin) of inhibitory synapses within the pyramidal cell layer of CA1 and CA3. As perisomatic inhibition by PV+-interneurons is crucial for the generation of hippocampal network oscillations involved in spatial processing, learning and memory formation we investigated the impact of the putative enhanced perisomatic inhibition on two types of fast neuronal network oscillations in acute hippocampal slices: 1. spontaneously occurring sharp wave-ripple complexes (SPW-R), and 2. cholinergic γ-oscillations. Interestingly, both network patterns were generally preserved in APPPS1 mice similar to WT mice. However, the comparison of simultaneous CA3 and CA1 recordings revealed that the incidence and amplitude of SPW-Rs were significantly lower in CA1 vs CA3 in APPPS1 slices, whereas the power of γ-oscillations was significantly higher in CA3 vs CA1 in WT-slices indicating an impaired communication between the CA3 and CA1 network activities in APPPS1 mice. Taken together, our data demonstrate an increased GABAergic synaptic output of PV+ interneurons impinging on pyramidal cells of CA1 and CA3, which might limit the coordinated cross-talk between these two hippocampal areas in young APPPS1 mice and mediate long-term changes in synaptic inhibition during progression of amyloidosis.
Sour grapes and sweet victories: How actions shape preferences

Classical decision theory postulates that choices proceed from subjective values assigned to the probable outcomes of alternative actions. Some authors have argued that opposite causality should also be envisaged, with choices influencing subsequent values expressed in desirability ratings. The idea is that agents may increase their ratings of items that they have chosen in the first place, which has been typically explained by the need to reduce cognitive dissonance. However, evidence in favor of this reverse causality has been the topic of intense debates that have not reached consensus so far. Here, we take a novel approach using Bayesian techniques to compare models in which choices arise from stable (but noisy) underlying values (one-way causality) versus models in which values are in turn influenced by choices (two-way causality). Moreover, we examined whether in addition to choices, other components of previous actions, such as the effort invested and the eventual action outcome (success or failure), could also impact subsequent values. Finally, we assessed whether the putative changes in values were only expressed in explicit ratings, or whether they would also affect other value-related behaviors such as subsequent choices. Behavioral data were obtained from healthy participants in a rating-choice-rating-choice-rating paradigm, where the choice task involves deciding whether or not to exert a given physical effort to obtain a particular food item. Bayesian selection favored two-way causality models, where changes in value due to previous actions affected subsequent ratings, choices and action outcomes. Altogether, these findings may help explain how values and actions drift when several decisions are made successively, hence highlighting some shortcomings of classical decision theory.
A Literature Review of Proton Beam Therapy for Prostate Cancer in Japan

Aim: Patients of proton beam therapy (PBT) for prostate cancer had been continuously growing in number due to its promising characteristics of high dose distribution in the tumor target and a sharp distal fall-off. Considering the large number of proton beam facilities in Japan, the further increase of patients undergoing this treatment is due to the emendations by Japanese National Health Insurance (NHI) and the development of medical equipment and technology, it is necessary to know what kind of research and advancements has been done on proton therapy for prostate cancer in the country. For these reasons, this literature review was conducted. The aim of this review is to identify and discuss research studies of proton beam therapy for prostate cancer in Japan. These include observational, interventional, and secondary data analysis of published articles. Method: A literature review on published works related to proton beam therapy for prostate cancer in Japan was conducted using articles that were gathered in the PubMed database of June 2018. We went through abstracts and manuscripts written in English with the keywords ‘proton beam therapy’, ‘prostate cancer’, and ‘Japan’. Results: A total of 23 articles were included. Fourteen articles were observational studies, most of which focused on the adverse effects of Proton Beam Therapy (PBT). Seven articles were interventional studies related on treatment planning, equipment parts, as well as target positioning. Two were secondary data analysis. The included studies were published in 13 different journals by different institutions using various equipment. Conclusion: Despite the favorable results of proton beam therapy, future research should include more patients and longer follow-up schedules to clarify the definitive role of PBT, yet, up to recent retrospective studies, included in this paper, concluded that PBT can be a suitable treatment option for localized prostate cancer. In addition, interventional studies were conducted by several institutions to further embellish proton therapy.
D-hole breakage of 2 angular stable locking plates for medial opening-wedge high tibial osteotomy

Abstract An adequate stable fixation implant should be used for medial opening-wedge high tibial osteotomy (MOWHTO) to promote rapid bone healing without complications. To date, the highest fixation stability has been observed for angular stable locking plates. However, there is still little medical literature regarding breakage of these plates. The purpose of the present study was to report the results of plate breakage around D-hole with the use of both types of locking plate fixation for MOWHTO. Medical records of 12 patients who experienced plate breakage after MOWHTO with either a TomoFix or OhtoFix plate between August 2013 and August 2016 were retrospectively reviewed. A total of 12 patients (7 males and 5 females) who experienced plate breakage at the screw hole just above the osteotomy were evaluated (age, 63 ± 8 years; body mass index (BMI), 28 ± 2 kg/m2; opening gap height, 12 ± 2 mm). There were 9 patients (75%) with plate breakage and loss of correction necessitating revision surgery, and 11 patients (92%) had lateral cortical hinge fractures postoperatively. Of the 9 patients with loss of correction necessitating revision surgery, 4 had a TomoFix plate and 5 had an OhtoFix plate. The only statistically significant association with broken plates lost reduction was the presence of lateral cortical hinge fractures (P = .003), but there was no significant association with age, gender, BMI, diabetes, smoking, plate type, opening gap height, and material used to fill the wedge. In addition, mean knee society score in the 12 patients was significantly higher postoperatively than preoperatively (P < .001). Since the amount of plate breakage was just over 1% and with only 12 in total, no true conclusion can be made with certainty. However, in the face of no lateral hinge or cortical disruption, there is a 99% success rate with the plate described. If the lateral hinge is disrupted, a restriction of activity or weight bearing may be needed.
Neurocognitive and psychiatric comorbidities of posttraumatic stress disorder among older veterans: A systematic review

Posttraumatic stress disorder (PTSD) is associated with neurocognitive and psychiatric comorbidities, and older adults experience comorbid illnesses disproportionately. Little is known about the comorbidities of PTSD among older veterans. This systematic review examines the prevalence, incidence, and patterns of neurocognitive and psychiatric comorbidities of PTSD among older veterans and explores the factors associated with these comorbidities.
Decreased Colorectal Adenoma Risk After Helicobacter pylori Eradication: A Retrospective Cohort Study.

BACKGROUND Helicobacter pylori infection is associated with colorectal adenoma and confers a 1.3- to 2.26-fold increased risk. We evaluated the association between H. pylori and the progression of colorectal adenoma. METHODS This retrospective cohort study included 615 adults with no history of colorectal adenoma or cancer at baseline who participated in a repeated, regular health screening examination, which included a bidirectional gastrointestinal endoscopy, between July 2006 and June 2015. A gastric biopsy specimen from each subject was tested for H. pylori. RESULTS During follow-up, the incidence rates of colorectal adenoma progression in participants with persistent H. pylori infections (persistent group) and those whose infections had previously been successfully eradicated (eradication group) were 160.52 and 51.60 per 1000 person-years, respectively (P = .0003). After adjustment for confounding factors, the persistent group exhibited a higher risk of colorectal adenoma than the eradication group (hazard ratio = 3.04, 95% CI 1.899, 5.864). The colorectal adenoma ratio of patients uninfected with H. pylori was similar to that of the eradication group (23.93% vs 20.12%, P = .328). CONCLUSIONS Persistent H. pylori infection was associated significantly with the independent development of colorectal adenoma. H. pylori infection may have a pathophysiological role in colorectal adenoma development and, after successful eradication of H. pylori, the colorectal adenoma ratio might decrease.
Altered Uncinate Fasciculus Microstructure in Childhood Anxiety Disorders in Boys But Not Girls.

OBJECTIVE: Anxiety disorders are common, can result in lifelong suffering, and frequently begin before adolescence. Evidence from adults suggests that altered prefrontal-limbic connectivity is a pathophysiological feature of anxiety disorders. More specifically, in adults with anxiety disorders, decreased fractional anisotropy (FA), a measure of white matter integrity, has been observed in the uncinate fasciculus, the major tract that connects limbic and prefrontal regions. Because of the early onset of anxiety disorders and the increased incidence in anxiety disorders in females during their reproductive years, it is important to understand whether the reduction in uncinate fasciculus FA exists in children with anxiety disorders and the extent to which this alteration is sex related. To address these issues, the authors assessed FA in the uncinate fasciculus in unmedicated boys and girls with anxiety disorders. METHODS: FA measures were derived from diffusion tensor images that were acquired from 98 unmedicated children (ages 8-12); 52 met criteria for generalized anxiety disorder, separation anxiety disorder, social anxiety disorder, or anxiety disorder not otherwise specified, and 46 were matched control subjects. RESULTS: Tract-based results demonstrated that children with anxiety disorders have significant reductions in uncinate fasciculus FA. A significant sex-by-group interaction and post hoc testing revealed that this effect was evident only in boys. No other main effects or sex-by-group interactions were found for other white matter tracts. CONCLUSIONS: These findings provide evidence of uncinate fasciculus white matter alterations in boys with anxiety disorders. The data demonstrate that anxiety disorder-related alterations in prefrontal-limbic structural connectivity are present early in life, are not related to psychotropic medication exposure, and are sex specific. Building on these findings, future research has the potential to provide insights into the genesis and sexual dimorphism of the pathophysiology that leads to anxiety disorders, as well as to identify sex-specific early-life treatment targets.
The interplay between childhood trauma, cognitive biases, psychotic-like experiences and depression and their additive impact on predicting lifetime suicidal behavior in young adults

Abstract Background Childhood trauma, psychosis risk, cognition, and depression have been identified as important risk markers for suicidal behaviors. However, little is known about the interplay between these distal and proximal markers in influencing the risk of suicide. We aim to investigate the interplay between childhood trauma, cognitive biases, psychotic-like experiences (PLEs) and depression in predicting suicidal behaviors in a non-clinical sample of young adults. Methods In total, 3495 young adults were recruited to an online computer-assisted web interview. We used the Prodromal Questionnaire to assess PLEs. Childhood trauma was assessed with the Traumatic Experience Checklist (three items) and Childhood Experience of Care and Abuse Questionnaire (CECA.Q, three items). Cognitive biases were assessed with a short version of the Davos Assessment of Cognitive Biases Scale. Suicidality, psychiatric diagnoses, and substance use were screened with a self-report questionnaire. Results Childhood trauma, as well as PLEs, was associated with an approximately five-fold increased risk of suicidal thoughts and plans as well as suicide attempts. Participants with depression were six times more likely to endorse suicidal behaviors. Path analysis revealed that PLEs, depression and cognitive biases are significant mediators of the relationship between trauma and suicidal behaviors. The model explained 44.6% of the variance in lifetime suicidality. Conclusions Cognitive biases, PLEs, and depression partially mediate the relationship between childhood trauma and suicidal behaviors. The interplay between distal and proximal markers should be recognized and become part of clinical screening and therapeutic strategies for preventing risk of suicidality.
RACCOON ( PROCYON LOTOR) RESPONSE TO ONTARIO RABIES VACCINE BAITS (ONRAB) IN ST. LAWRENCE COUNTY, NEW YORK, USA.

Oral rabies vaccination (ORV) campaigns have been conducted annually in the US over the past two decades to prevent raccoon ( Procyon lotor) rabies, which is enzootic along the eastern region of the country from southeastern Canada to Alabama. Because raccoon rabies has been eliminated from neighboring Canadian provinces, continued detection of the variant in the US is of concern due to the potential for infected raccoons to cross the border via the St. Lawrence River. Ontario Rabies Vaccine Baits (ONRAB) containing a live, recombinant human adenovirus expressing the rabies virus glycoprotein have been under experimental use in the US since 2011. We distributed ONRAB in St. Lawrence County, New York, from 2013 to 2015 as part of field trials to evaluate serologic responses in raccoons. Prior to ONRAB distribution, rabies virus neutralizing antibody (RVNA) seroprevalence in raccoons was 45.2% (183 of 405) and increased to 57.7% (165 of 286) after 3 yr of ONRAB baiting. Postbait RVNA seroprevalence increased each year, with a lower response observed in juvenile compared with adult raccoons. The pre-ONRAB seroprevalence detected in 2013 was relatively high and was likely impacted both by elevated rabies activity in the county and the use of ORV with a different vaccine bait for 14 consecutive years prior to our study. Tetracycline biomarker prevalence increased from 1.4% prior to ONRAB baiting to 51.3% from 2013 to 2015, demonstrating bait palatability to raccoons. These data complemented related field trials conducted in West Virginia and the northeastern US.
Assessing the fitness consequences of mitonuclear interactions in natural populations

Metazoans exist only with a continuous and rich supply of chemical energy from oxidative phosphorylation in mitochondria. The oxidative phosphorylation machinery that mediates energy conservation is encoded by both mitochondrial and nuclear genes, and hence the products of these two genomes must interact closely to achieve coordinated function of core respiratory processes. It follows that selection for efficient respiration will lead to selection for compatible combinations of mitochondrial and nuclear genotypes, and this should facilitate coadaptation between mitochondrial and nuclear genomes (mitonuclear coadaptation). Herein, we outline the modes by which mitochondrial and nuclear genomes may coevolve within natural populations, and we discuss the implications of mitonuclear coadaptation for diverse fields of study in the biological sciences. We identify five themes in the study of mitonuclear interactions that provide a roadmap for both ecological and biomedical studies seeking to measure the contribution of intergenomic coadaptation to the evolution of natural populations. We also explore the wider implications of the fitness consequences of mitonuclear interactions, focusing on central debates within the fields of ecology and biomedicine.