bluuebunny/crossref_metadata_2025 huggingface dataset:
Accelerated Trajectories of Walking Capacity Across the Adult Life Span in Persons With Multiple Sclerosis: An Underrecognized Challenge
Authors: Hvid Lars G. , Feys Peter , Baert Ilse , Kalron Alon , Dalgas Ulrik
Published: March 2020

Background. In the general population, trajectories of walking capacity is accelerated and nonlinear with advanced age. Whether this is more pronounced in persons with multiple sclerosis (pwMS), along with the prevalence of dismobility (ie, slow gait speed), are currently unknown. Our objective was to investigate trajectories of walking capacity and prevalence of dismobility across the adult life span in pwMS versus healthy controls (HC). Methods. Data on maximal timed 25-foot walk test (T25FWT), 2-minute walk test (2MWT), and 6-minute walk test (6MWT) along with prevalence of dismobility were assembled from 2 RIMS multicenter studies (n = 502 pwMS; age range 21-77 years, 6 age groups: 20-29, 30-39, 40-49, 50-59, 60-69, and 70-79 years). HC data were extracted from studies containing normative reference values (n = 1070-3780 HC). Results. Age trajectories of walking capacity was nonlinear and accelerated in pwMS versus HC. While measures of walking capacity in pwMS were suppressed already early in life, the gap between pwMS and HC significantly widened across the 6 age groups (pwMS performed 64%, 70%, 57%, 59%, 51%, and 37% of HC, respectively). This coincided with high prevalences of dismobility in pwMS across the 6 age groups when using usual gait speed cut-point values <1.0 m/s (corresponding to 33%, 32%, 51%, 59%, 75%, and 100%) and <0.6 m/s (corresponding to 19%, 12%, 26%, 23%, 33%, and 43%), markedly exceeding that observed in HC. Conclusion. The present data on walking capacity provide evidence for an accelerated deterioration in pwMS with advanced age, coinciding with high prevalences of dismobility (ie, slow gait speed).
Positive Psychology and Hope as Lifestyle Medicine Modalities in the Therapeutic Encounter: A Narrative Review
Authors: Duncan Ashten R. , Jaini Paresh A. , Hellman Chan M.
Published: March 2020

The majority of deaths in the United States are attributable to lifestyle-associated chronic diseases. Therapeutic encounters must now routinely address lifestyle-related behavior changes and promote patients’ active involvement in self-care and chronic disease management. Positive psychology has been recognized in the realm of lifestyle medicine for its potential applications in effecting patient behavior change. One notable framework within positive psychology that is well suited for facilitating specific behavior changes is hope theory, which can be used to elicit change talk and build agency among patients with chronic diseases. This review explores key literature in positive psychology and hope theory and its practical applications to direct patient care, which includes an illustrative case study. There are still many unexplored intersections of health-related variables and hope. The cognitive framework of hope theory lends itself well to a broad range of situations, including brief ambulatory encounters. Clinicians will be instrumental in increasing our understanding of how hope theory can be applied to the therapeutic encounter. There are simple and efficient ways to innovate in this area. Having information about a patient’s hope has the potential to make empathic connections easier and create opportunities to ask specific questions to help patients overcome barriers.
On the time it takes to judge grammaticality
Authors: Mirault Jonathan , Grainger Jonathan
Published: March 2020

The presentation duration of five-word sequences was varied and participants were asked to judge their grammaticality. The five-word sequences were presented for a variable duration randomly selected between 50 and 500 ms with 50-ms steps and were immediately followed by a masking stimulus. Half of the sequences were correct sentences which were randomly intermixed with ungrammatical sequences formed of the same words in scrambled order. We measured the proportion of correct responses for each presentation duration in the grammatical and ungrammatical conditions, and calculated sensitivity and bias from these measures. Both the sensitivity measure ( d′) and the probability correct responses to grammatical and ungrammatical sequences increased as the stimulus duration increased, with a d′ of 2 and an average percent correct close to 87% for the grammatical sequences already attained at 300 ms. The rate of increase in performance diminished beyond 300 ms. Grammatical decision times were faster and more accurate for the grammatically correct sequences, thus indicating that participants were not responding by detecting illegal word combinations in the ungrammatical sequences. On the basis of these findings, we provide an upper estimate of 300 ms as the time it takes to access reliable syntactic information from five-word sequences in French, and we discuss the implications of this constraint for models of reading.
High incidence of FLT3 mutations in follicular thyroid cancer: potential therapeutic target in patients with advanced disease stage
Authors: Borowczyk Martyna , Szczepanek-Parulska Ewelina , Dębicki Szymon , Budny Bartłomiej , Janicka-Jedyńska Małgorzata , Gil Lidia , Verburg Frederik A. , Filipowicz Dorota , Wrotkowska Elżbieta , Majchrzycka Blanka , Marszałek Andrzej , Ziemnicka Katarzyna , Ruchała Marek
Published: March 2020

Background:

Conventional treatments for follicular thyroid cancer (FTC) can be ineffective, leading to poor prognosis. The aim of this study was to identify mutations associated with FTC that would serve as novel molecular markers of the disease and its outcome and could potentially identify new therapeutic targets.

Methods:

FLT3 mutations were first detected in a 29-year-old White female diagnosed with metastasized, treatment-refractory FTC. Analyses of FLT3 mutational status through next-generation sequencing of formalin-fixed, paraffin-embedded FTC specimens were subsequently performed in 35 randomly selected patients diagnosed with FTC.

Results:

FLT3 mutations were found in 69% of patients. FLT3 mutation-positive patients were significantly older than those that were FLT3 mutation-negative [median age at diagnosis 54 (36–82) versus 45 (27–58) ( p = 0.023)]. Patients over 60 years were 23 times more likely to be FLT3 mutation-positive ( p = 0.006). However, the number of FLT3 mutations did not correlate with age ( r-Pearson: –0.244, p-value: 0.25). A total of 26 mutations were identified in the FLT3 gene with 2–16 FLT3 mutations in each FLT3 mutation-positive patient (mean: 5.6 mutations/patient). Tyrosine kinase domain (TKD) mutations in the FLT3 gene were detected in 58% of FLT3 mutation-positive patients. All FLT3 mutation-positive patients with a disease stage of pT2N1 or worse harbored at least one mutation in the TKD of FLT3.

Conclusions:

There is a wide spectrum and high frequency of FLT3 mutations in FTC. The precise role of FLT3 mutations in the genesis of FTC, as well as its potential role as a therapeutic target, requires further investigation.
A Retrospective Comparison of 3-Factor Prothrombin Complex Concentrate Products for Warfarin Reversal
Authors: Jones G. Morgan , Cave Brandon , Cook Ryan
Published: March 2020

Background and Purpose:

Current guidelines suggest that 3-factor prothrombin complex concentrate is a possible alternative to 4-factor products for the emergent reversal of bleeding secondary to warfarin. While multiple observational studies have evaluated various forms of 3-factor prothrombin complex concentrate individually, no study has compared the efficacy of the 2 products. The purpose of this study is to compare the efficacy and safety of Bebulin™ and Profilnine™ for the emergent reversal of warfarin-associated major bleeding.

Methods:

We conducted a retrospective cohort study of patients receiving both Bebulin™ and Profilnine™ at an urban, academic medical center with comprehensive stroke center designation and a neurosurgical center of excellence. All patients were treated at a single center that utilized a fixed, weight-based dosing protocol. The primary outcome was the percentage of patients in each group achieving a goal international normalization ratio of 1.4 or less.

Results:

There was a significant difference in goal international normalization ratio achieved favoring Bebulin™ (85.5% vs 27.3%; P < .001) over Profilnine™. Median dose per kilogram of actual body weight was the same between the groups. When we assessed results by baseline™ international normalization ratio subgroup, more patients in the Bebulin™ group achieved goal when baseline values were 6 or less. No thrombotic events were documented in either group.

Conclusions:

We found that patients treated with Bebulin™ experienced significantly higher rates of successful international normalization ratio reversal when compared to those who received Profilnine™. Further research is needed to determine the comparative efficacy between the 2 agents.
Factors associated with plasma antigen carbohydrate 125 and amino-terminal pro-B-type natriuretic peptide concentrations in acute heart failure
Authors: Miñana Gema , de la Espriella Rafael , Mollar Anna , Santas Enrique , Núñez Eduardo , Valero Ernesto , Bodí Vicent , Chorro Francisco J , Fernández-Cisnal Agustin , Martí-Cervera Jorge , Sanchis Juan , Bayés-Genís Antoni , Núñez Julio
Published: March 2020

Background:

Plasma amino-terminal pro-B-type natriuretic peptide and antigen carbohydrate 125 levels are positively associated with a higher risk of adverse clinical outcomes in acute heart failure. As a proxy of congestion, antigen carbohydrate 125 has also been proposed as a right-sided heart failure marker. Thus, we aimed to determine in this population the main factors – including echocardiographic right-sided heart failure parameters – associated with antigen carbohydrate 125 and amino-terminal pro-B-type natriuretic peptide.

Methods and results:

We prospectively included 2949 patients admitted with acute heart failure. Amino-terminal pro-B-type natriuretic peptide and antigen carbohydrate 125 were used as dependent variables in a multivariable linear regression analysis. The mean age of the sample was 73.9±11.1 years; 48.9% were female, 35.8% showed ischaemic aetiology, and 51.6% exhibited heart failure with preserved ejection fraction. The median (interquartile range) for amino-terminal pro-B-type natriuretic peptide and antigen carbohydrate 125 were 4840 (2111–9204) pg/ml and 58 (26–129) U/ml, respectively. In a multivariable setting, and ranked in order of importance (R2), estimated glomerular filtration rate (43.7%), left ventricle ejection fraction (15.1%), age (12.4%) and high-sensitivity troponin T (10.9%) emerged as the most important factors associated with amino-terminal pro-B-type natriuretic peptide. The five main factors associated with antigen carbohydrate 125 were, in order of importance: the presence of pleural effusion (36.8%), tricuspid regurgitation severity (25.1%), age (11.9%), amino-terminal pro-B-type natriuretic peptide (6.5%) and peripheral oedema (4.3%).

Conclusion:

In patients with acute heart failure the main factors associated with amino-terminal pro-B-type natriuretic peptide were renal dysfunction, left ventricle ejection fraction and age. For antigen carbohydrate 125, clinical parameters of congestion and the severity of tricuspid regurgitation were the most important predictors. These results endorse the value of antigen carbohydrate 125 as a useful marker of right-sided heart failure.
Alveolar soft part sarcoma presenting as a uterine polyp: A case report
Authors: Gomez Mariangela , Whiting Kerry , Naous Rana
Published: March 2020

Alveolar soft part sarcoma is a rare malignant soft tissue tumor, mainly localized in the extremities and occurring principally in adolescents and young adults. Alveolar soft part sarcoma are uncommon in the female genital tract. We here report a case of alveolar soft part sarcoma in a 20-year-old nullipara, presenting with vaginal bleeding and profound anemia requiring blood transfusions. Ultrasonographic examination revealed a polyp in the lower uterine segment. Surgical resection of the polyp was performed, and pathological evaluation showed typical histological, immunohistochemical, and molecular features consistent with alveolar soft part sarcoma. Patient underwent for total hysterectomy. Currently, she follows up with her surgeon and has no new complains. Given the infrequency of alveolar soft part sarcoma, this case report raises the awareness of alveolar soft part sarcoma as one of the entities to consider when confronted with a uterine polyp in a young patient.
Comparing the Impact of Primary Care Practice Design in Two Inner City UK Homelessness Services
Authors: Zeitler Martina , Williamson Andrea E. , Budd John , Spencer Ruth , Queen Anton , Lowrie Richard
Published: March 2020

Background: Specialist homeless primary health care services in the United Kingdom have arisen from the need for bespoke approaches to providing health care for people experiencing homelessness but descriptions of the design characteristics of homeless health services together with associated long-term condition (LTC) prevalence, health care utilization, and prescribing remain unexplored, thereby limiting our understanding of potential impact of service configuration on outcomes. Aim: Description of specialist homeless general practitioner services in Glasgow and Edinburgh, in terms of practice design (staff, skill mix, practice systems of registration, and follow-up); and exploration of the potential impact of differences on LTC prevalence, health care utilization, and prescribing. Method: Patient data were collected from computerized general practitioner records in Glasgow (2015, n = 133) and Edinburgh (2016, n = 150). Homeless health service configuration and anonymized patient data, including demographics, LTCs service utilization, and prescribing were summarized and compared. Results: Marked differences in infrastructure emerged between 2 practices, including the patient registration process, segmentation versus integration of services, recording systems, and the availability of staff expertise. Patient characteristics differed in terms of LTC diagnoses, health care utilization and prescribing. Higher rates of recorded mental health and addiction problems were found in Edinburgh, as well as higher rates of physical LTCs, for example, cardiovascular and respiratory conditions. There were significantly higher rates of consultations with nurses and other staff in Edinburgh, although more patients had consultations with pharmacists in Glasgow. Medication adherence was low in both cohorts, and attendance at referral appointments was particularly poor in Glasgow. Conclusion: Service design and professional skill mix influence recording of LTCs, service uptake, and identification and management of health conditions. Service configuration, professional skill mix, and resources may profoundly affect diagnoses, utilization of health care, and prescribing. Attention to homeless service design is important when providing care to this disadvantaged patient group.
Performance on the Multisource Interference Task Moderates the Relationship Between Trauma Exposure and Posttraumatic Stress Symptoms
Authors: Darnell Benjamin C. , Valentiner David P.
Published: March 2020

We examined performance on the Multisource Interference Task (MSIT) as a moderator of the relationship between traumatic experience and posttraumatic stress symptom (PTSS) severity. A college sample ( N = 108) completed the MSIT, the Wisconsin Card Sorting Task (WCST), and self-report questionnaires. Both MSIT and WCST performance were examined in moderation models to demonstrate the specificity of MSIT performance as a moderator. Absolute processing speed during the MSIT significantly moderated the relationship between number of traumatic experiences and PTSS severity. Moderation was not demonstrated for WCST performance, relative processing speed during the MSIT, or absolute or relative MSIT error rates. Implications for research and practical applications are discussed.
Pathological Personality Traits and the Experience of Daily Situations
Authors: Hong Ryan Y. , Chan Wing Yan , Lim Jacqueline Y. R.
Published: March 2020

We examined the associations between personality pathology and daily situational experiences. College student participants ( N = 180) were assessed on pathological personality traits along with six assessments of everyday situation experiences. Independent raters judged situation descriptions provided by the participants to estimate the normative and consensually shared aspect of situations. Participants’ subjective situational construals were obtained by partialing the consensual aspect out of their in situ situation ratings. Substantive and meaningful relations between personality pathology and situations were found, and they were predominantly underpinned by subjective construal of situational characteristics. By using comprehensive taxonomies of personality pathology and situations, we advanced current understanding on the day-to-day situational dynamics and experiences of individuals with pathological personality tendencies.
Distanced Self-Talk Enhances Goal Pursuit to Eat Healthier
Authors: Furman Celina R. , Kross Ethan , Gearhardt Ashley N.
Published: March 2020

Attempts to make healthier food choices often fail, particularly for people who are actively trying to diet. Distanced self-talk—using one’s name and non-first-person-singular pronouns (vs. first-person pronouns) to reflect on the self—provides a relatively effortless self-control tool that enhances goal pursuit. We investigated whether distanced (vs. immersed) self-talk would enhance goal pursuit to eat healthier using a novel experimental design ( N = 244). Findings indicated that dieters benefited the most from the combined use of distanced self-talk and a health prime. Nondieters made healthier choices when using distanced self-talk regardless of whether they were primed with a health goal or not. These findings suggest that distanced self-talk may constitute a self-control strategy that encourages healthier eating and highlight the need for future research to examine its translational potential.
One-year follow-up of efficacy and cost of repeated doses versus single larger dose of intra-articular hyaluronic acid for knee osteoarthritis
Authors: Suppan Vijaya Kumar L , Tew Mei Mei , Wong Bor Chern , Chan Huan Keat , Chew Yu Wei , Tan Chin Siong , Nanta Kumar Vijay Kumar , Shafie Asrul Akmal , Sadashiva Rao Ashutosh
Published: March 2020

Purpose:

A recent 3-month randomized, open-label controlled trial found that the intra-articular hyaluronic acid injection (GO-ON®) given as a single dose of 5 mL is as effective and safe as three repeated doses of 2.5 mL in patients with knee osteoarthritis. However, the information on the long-term efficacy and economic implications of the single-dose regimen is still limited. Hence, this follow-up study was designed to compare the effectiveness and costs of the two regimens 12 months following the treatment.

Methods:

All the 127 patients, who received either three repeated doses ( n = 64) or a single dose ( n = 63) of GO-ON in the previous trial, were followed up in month 12 following the treatment. The effectiveness of both the regimens was assessed using the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), and the mean WOMAC scores were compared with those recorded at the baseline and in month 3. Additionally, the total treatment costs of the two regimens, taking account of both direct and indirect costs, were computed and compared.

Results:

A total of 125 patients (98.4%) completed the assessment. Despite the reduction of the overall mean WOMAC score from 39.24 to 19.93 ( p < 0.001) in the first 3 months following the treatment with GO-ON, no further changes were observed up to month 12 ( p > 0.95). In the meantime, the two regimens did not differ in the mean WOMAC scores ( p = 0.749) and in the subscale scores for pain ( p = 0.970), stiffness ( p = 0.526), and physical functioning ( p = 0.667) in month 12. The cost for single-dose injection was found to be approximately 30% lower compared to the repeated doses.

Conclusion:

These findings indicate that the single larger dose of GO-ON is as effective as the repeated doses over 12 months, and yet the total treatment cost is lowered.
Achillon versus modified minimally invasive repair treatment in acute Achilles tendon rupture
Authors: Liu Jun-Yi , Duan Wei-Feng , Shen Sheng , Ye Ye , Sun Yong-Qiang , He Wei
Published: March 2020

Purpose:

To date, the best treatment of acute Achilles tendon rupture (AATR) is still inconclusive. Achillon seems to be a promising approach with satisfactory function and low complication rate. We hypothesize a modified minimally invasive repair (MMIR), which provides direct visualization of proximal tendon stump without specialized equipment that could provide comparable results. This trial is aimed to evaluate the functional and surgical outcomes of MMIR comparing with Achillon.

Methods:

From February 2013 to February 2017, 114 patients with AATR were enrolled in this trial, underwent an alternative operation (Achillon or MMIR), and accelerated rehabilitation protocol. Forty-four patients took the Achillon and the other 70 patients took the MMIR at their subjective choice. One hundred eleven full follow-up data were obtained including Achilles tendon total rupture score (ATRS), time back to work, rerupture rate, overall complication rate, and operation time.

Results:

There was no significant difference between groups in demographic characters. There was no statistical difference between both groups regarding to time return to work and ATRS at 3rd, 6th, 12th, and 24th month, respectively. Five reruptures and two Achilles tendons tethering to skins were found in the Achillon group, and two reruptures and one sural nerve injury in the MMIR group. No wound infection and dehiscence occurred. Overall complication rate in the Achillon group is higher (16.3% vs. 4.4%, p = 0.044). The operation time of Achillon is less than MMIR (34.84 vs. 39.71, p < 0.001).

Conclusion:

Both techniques combining with accelerated rehabilitation showed to be reliable and effective. MMIR is safer and more economical, and Achillon is faster.
Partners’ Educational Pairings and Fertility Intentions in the United States: Evidence from 2015–2017 National Survey of Family Growth
Authors: Morales Danielle Xiaodan
Published: March 2020

In light of the ongoing educational shift from favoring men to favoring women, this study contributes to the literature on fertility by investigating the relationship between educational pairings and fertility intentions. To test two competing hypotheses, nationally representative data from the latest wave (2015–2017) of the National Survey of Family Growth were used, and four generalized estimating equation models were estimated. Results indicate that women’s intentions for additional children were influenced by educational pairings. Specifically, when highly educated women had a highly educated partner, their fertility intentions were higher than lower-educated women, but this difference disappeared if those women were in hypogamous relationships; when lower-educated women had lower- or medium-educated partners, their intentions for additional children were significantly lower than highly educated women, but the difference disappeared when she had a highly educated partner. Findings from this study provide new insights into fertility intentions by taking into account both partners’ education.
Deus ex mitigata: Denaturalizing the discursive power of Solar India
Authors: Stock Ryan
Published: March 2020

Post-Paris Agreement, India is swiftly transitioning to low-carbon electricity generation through solar park development. Despite exceeding emissions reduction targets, many social development claims remain unrealized. This paper addresses the following questions: (1) What discourses do state institutions utilize to justify solar park development in rural spaces? (2) What sociopolitical effects do these discourses have at the local scale? I conducted a critical discourse analysis of technical and policy documents focusing on knowledge production to influence social power and the political economy. I also draw on eight months of fieldwork, including semi-structured interviews of residents, bureaucrats, and solar employees in Gujarat, Andhra Pradesh, and New Delhi. This paper argues that solar parks are rationalized via discursive formations of the climate crisis, economic development, and ecological modernization. These discursive formations are stitched together into story-lines and circulated by public and private institutions (Solar India), comprising a “deus ex mitigata,” a deus ex machina set of discursive formations that rationalize greener capital accumulation in neoliberal India that does not address asymmetric power relations. The modalities by which this is accomplished dispossess peasants of land and livelihoods. As such, low-carbon electricity generation does not positively “transform the lives” of residents, a raison d’être for solar park development.
Factor VIII exhibits chaperone-dependent and glucose-regulated reversible amyloid formation in the endoplasmic reticulum
Authors: Poothong Juthakorn , Pottekat Anita , Siirin Marina , Campos Alexandre Rosa , Paton Adrienne W. , Paton James C. , Lagunas-Acosta Jacqueline , Chen Zhouji , Swift Mark , Volkmann Niels , Hanein Dorit , Yong Jing , Kaufman Randal J.
Published: March 2020

Hemophilia A, an X-linked bleeding disorder caused by deficiency of factor VIII (FVIII), is treated by protein replacement. Unfortunately, this regimen is costly due to the expense of producing recombinant FVIII as a consequence of its low-level secretion from mammalian host cells. FVIII expression activates the endoplasmic reticulum (ER) stress response, causes oxidative stress, and induces apoptosis. Importantly, little is known about the factors that cause protein misfolding and aggregation in metazoans. Here, we identified intrinsic and extrinsic factors that cause FVIII to form aggregates. We show that FVIII forms amyloid-like fibrils within the ER lumen upon increased FVIII synthesis or inhibition of glucose metabolism. Significantly, FVIII amyloids can be dissolved upon restoration of glucose metabolism to produce functional secreted FVIII. Two ER chaperone families and their cochaperones, immunoglobulin binding protein (BiP) and calnexin/calreticulin, promote FVIII solubility in the ER, where the former is also required for disaggregation. A short aggregation motif in the FVIII A1 domain (termed Aggron) is necessary and sufficient to seed β-sheet polymerization, and BiP binding to this Aggron prevents amyloidogenesis. Our findings provide novel insight into mechanisms that limit FVIII secretion and ER protein aggregation in general and have implication for ongoing hemophilia A gene-therapy clinical trials.
Progression of AITL-like tumors in mice is driven by Tfh signature proteins and T-B cross talk
Authors: Witalis Mariko , Chang Jinsam , Zhong Ming-Chao , Bouklouch Yasser , Panneton Vincent , Li Joanna , Buch Thorsten , Kim Seok Jin , Kim Won Seog , Ko Young Hyeh , Veillette André , Suh Woong-Kyung
Published: March 2020

Angioimmunoblastic T-cell lymphoma (AITL) is an aggressive peripheral T-cell lymphoma driven by a pool of neoplastic cells originating from T follicular helper (Tfh) cells and concomitant expansion of B cells. Conventional chemotherapies for AITL have shown limited efficacy, and as such, there is a need for improved therapeutic options. Because AITL originates from Tfh cells, we hypothesized that AITL tumors continue to rely on essential Tfh components and intimate T-cell–B-cell (T-B) interactions. Using a spontaneous AITL mouse model (Roquinsan/+ mice), we found that acute loss of Bcl6 activity in growing tumors drastically reduced tumor size, demonstrating that AITL-like tumors critically depend on the Tfh lineage–defining transcription factor Bcl6. Because Bcl6 can upregulate expression of signaling lymphocytic activation molecule–associated protein (SAP), which is known to promote T-B conjugation, we next targeted the SAP-encoding Sh2d1a gene. We observed that Sh2d1a deletion from CD4+ T cells in fully developed tumors also led to tumor regression. Further, we provide evidence that tumor progression depends on T-B cross talk facilitated by SAP and high-affinity LFA-1. In our study, AITL-like tumors relied heavily on molecular pathways that support Tfh cell identity and T-B collaboration, revealing potential therapeutic targets for AITL.
Insight into unique somitogenesis of yak (Bos grunniens) with one additional thoracic vertebra
Authors: Wang Yu , Cai Haoyang , Luo Xiaolin , Ai Yi , Jiang Mingfeng , Wen Yongli
Published: March 2020

Background

The yak is a species of livestock which is crucial for local communities of the Qinghai-Tibet Plateau and adjacent regions and naturally owns one more thoracic vertebra than cattle. Recently, a sub-population of yak termed as the Jinchuan yak has been identified with over half its members own a thoracolumbar vertebral formula of T15L5 instead of the natural T14L5 arrangement. The novel T15L5 positioning is a preferred genetic trait leading to enhanced meat and milk production. Selective breeding of this trait would have great agricultural value and exploration of the molecular mechanisms underlying this trait would both accelerate this process and provide us insight into the development and regulation of somitogenesis.

Results

Here we investigated the genetic background of the Jinchuan yak through resequencing fifteen individuals, comprising five T15L5 individuals and ten T14L5 individuals with an average sequencing depth of > 10X, whose thoracolumbar vertebral formulae were confirmed by anatomical observation. Principal component analysis, linkage disequilibrium analysis, phylogenetic analysis, and selective sweep analysis were carried out to explore Jinchuan yak’s genetic background. Three hundred and thirty candidate markers were identified as associated with the additional thoracic vertebrae and target sequencing was used to validate seven carefully selected markers in an additional 51 Jinchuan yaks. The accuracies of predicting 15 thoracic vertebrae and 20 thoracolumbar vertebrae with these 7 markers were 100.00 and 33.33% despite they both could only represent 20% of all possible genetic diversity. Two genes, PPP2R2B and TBLR1, were found to harbour the most candidate markers associated with the trait and likely contribute to the unique somitic number and identity according to their reported roles in the mechanism of somitogenesis.

Conclusions

Our findings provide a clear depiction of the Jinchuan yak’s genetic background and a solid foundation for marker-assistant selection. Further exploitation of this unique population and trait could be promoted with the aid of our genomic resource.
Novel pathogenic VPS13A mutation in Moroccan family with Choreoacanthocytosis: a case report
Authors: Ouchkat Fatima , Regragui Wafaa , Smaili Imane , Naciri Darai Hajar , Bouslam Naima , Rahmani Mounia , Melhaoui Adyl , Arkha Yasser , El Fahime Elmostafa , Bouhouche Ahmed
Published: March 2020

Background

Choreoacanthocytosis (ChAc), is a rare neurodegenerative disease, characterized by movement disorders and acanthocytosis in the peripheral blood smears, and various neurological, neuropsychiatric and neuromuscular signs. It is caused by mutations in VPS13A gene with autosomal recessive pattern of inheritance.

Case presentation

Here we report two patients belonging to a consanguineous Moroccan family who present with movement disorder pathology. They were suspected to have choreoacanthocytosis according to biological, clinical and radiological finding. Thus, whole-exome sequencing was performed for precise diagnosis and identified a homozygous novel nonsense mutation c.337C > T (p.Gln113*) in exon 5 of VPS13A in the two affected siblings.

Conclusion

Here, we report a novel nonsense p.Gln113* mutation in VPS13A identified by whole-exome sequencing, which caused ChAc in a Moroccan family. This is the first description of ChAc in Morocco with genetic confirmation, that expands the mutation diversity of VPS13A and provide clinical, neuroimaging and deep brain stimulation findings.
Influence of Casein kinase II inhibitor CX-4945 on BCL6-mediated apoptotic signaling in B-ALL in vitro and in vivo
Authors: Richter Anna , Sender Sina , Lenz Annemarie , Schwarz Rico , Hinz Burkhard , Knuebel Gudrun , Sekora Anett , Murua Escobar Hugo , Junghanss Christian , Roolf Catrin
Published: March 2020

Background

Casein kinase II (CK2) is involved in multiple tumor-relevant signaling pathways affecting proliferation and apoptosis. CK2 is frequently upregulated in acute B-lymphoblastic leukemia (B-ALL) and can be targeted by the ATP-competitive CK2 inhibitor CX-4945. While reduced proliferation of tumor entities including B-ALL after CX-4945 incubation has been shown in vitro and in vivo, the detailed way of action is unknown. Here, we investigated the influence on the PI3K/AKT and apoptosis cascades in vivo and in vitro for further clarification.

Methods

A B-ALL xenograft model in NSG mice was used to perform in vivo longitudinal bioluminescence imaging during six day CX-4945 treatment. CX-4945 serum levels were determined at various time points. Flow cytometry of bone marrow and spleen cells was performed to analyze CX-4945-induced effects on tumor cell proliferation and distribution in B-ALL engrafted mice. ALL cells were enriched and characterized by targeted RNA sequencing. In vitro, B-ALL cell lines SEM, RS4;11 and NALM-6 were incubated with CX-4945 and gene expression of apoptosis regulators BCL6 and BACH2 was determined.

Results

In B-ALL-engrafted mice, overall tumor cell proliferation and distribution was not significantly influenced by CK2 inhibition. CX-4945 was detectable in serum during therapy and serum levels declined rapidly after cessation of CX-4945. While overall proliferation was not affected, early bone marrow and spleen blast frequencies seemed reduced after CK2 inhibition. Gene expression analyses revealed reduced expression of anti-apoptotic oncogene BCL6 in bone marrow blasts of CX-4945-treated animals. Further, BCL6 protein expression decreased in B-ALL cell lines exposed to CX-4945 in vitro. Surprisingly, levels of BCL6 opponent and tumor suppressor BACH2 also declined after prolonged incubation. Simultaneously, increased phosphorylation of direct CK2 target and tumor initiator AKT was detected at respective time points, even in initially pAKT-negative cell line NALM-6.

Conclusions

The CK2 inhibitor CX-4945 has limited clinical effects in an in vivo B-ALL xenograft model when applied as a single drug over a six day period. However, gene expression in B-ALL cells was altered and suggested effects on apoptosis via downregulation of BCL6. Unexpectedly, the BCL6 opponent BACH2 was also reduced. Interactions and regulation loops have to be further evaluated.
Germline BRCA, chemotherapy response scores, and survival in the neoadjuvant treatment of ovarian cancer
Authors: Lee Yong Jae , Kim Hyun-Soo , Rim John Hoon , Lee Jung-Yun , Nam Eun Ji , Kim Sang Wun , Kim Sunghoon , Kim Young Tae
Published: March 2020

Background

To analyze the effects of BRCA1/2 mutations on chemotherapy response scores (CRS) and survival in a cohort of patients with advanced-stage ovarian cancer who were treated with neoadjuvant chemotherapy (NAC) followed by interval debulking surgery (IDS).

Methods

We retrospectively reviewed the medical records of 169 high-grade serous ovarian cancer patients who underwent a germline BRCA1/2 test and received three cycles of NAC at the Yonsei Cancer Center from 2006 to 2018. Chemotherapy response scores were compared in patients with and without BRCA1/2 mutations. The effects of BRCA1/2 mutations and CRS on survival were evaluated.

Results

BRCA1/2 mutations were detected in 47 (28.1%) of the 169 patients. Overall, 16 (34.0%) patients with BRCA1/2 mutations had a CRS 3 to chemotherapy compared to scores of 43 in patients (35.2%) without a mutation. Response scores of 3 in patients with BRCA1/2 mutations were not significantly associated with either improved progression-free survival (PFS) (P = 0.949) or overall survival (OS) (P = 0.168). However, CRS 3 in patients without BRCA mutations was significantly associated with both improved PFS (P = 0.030) and OS (P = 0.039). In patients with CRS1/2, carriers of BRCA1/2 mutations had better PFS (P = 0.0344) and OS (P = 0.043) than wild-type BRCA genotype patients.

Conclusion

In ovarian cancer patients treated with NAC, CRS did not predict survival for BRCA 1/2 mutation carriers but did for BRCA wild-type patients.
Newborn feeding recommendations and practices increase the risk of development of overweight and obesity
Authors: Watchmaker Brittany , Boyd Bridget , Dugas Lara R.
Published: March 2020

Background

The prevalence of obesity among infants less than 2 years of age has increased by more than 60% over the last three decades. Obese infants and toddlers are at an increased risk for staying overweight into adolescence and adulthood. Metabolic programming has been demonstrated in animal models whereby early life feeding habits result in life-long changes in hormone balance and metabolism. Our study explores if newborn over-nutrition on the first day of life (DOL1) is associated with risk for future overweight and obesity in childhood.

Methods

Retrospective chart data was collected for full term formula-fed infants born between January 2008 and December 2012 who continued care at the same institution. Data included the volume of formula (ml) consumed on DOL1 as well, as subsequent yearly BMI measures from well child checkups (WCC). Overfeeding was categorized as any feed greater than or equal to 30 ml on any of the first seven feeds while controlling for birth weight.

Results

The final data set included 1106 infants (547 male; 559 female). 1023 of the 1106 newborns (93%) were overfed at least once during DOL1, while 789 of 1106 (71%) were overfed 3 or more times during their first 7 feeds. After adjusting for birth weight, infants who were overfed 5 of the first 7 feeds were 5 times as likely to be overweight or obese at their 4th year well child check-up (p < 0.05) compared to children not overfed. Infants who were overfed on all 7 of their first 7 feeds were 7 times more likely to be overweight or obese at their 4th year WCC (p = 0.017).

Conclusions

Infants overfed on DOL1 were significantly more likely to be overweight or obese at their 4th year WCC, compared to infants not overfed on their first day of life. Newborn families may benefit from counseling regarding age-appropriate volumes of formula during this critical time period. Future studies will aim to look at effect of implementation of smaller feeding bottle size on reducing overfeeding practices and future risk of overweight and obesity.
How well do elderly patients with major depressive disorder respond to antidepressants: a systematic review and single-group meta-analysis
Authors: Gutsmiedl Katharina , Krause Marc , Bighelli Irene , Schneider-Thoma Johannes , Leucht Stefan
Published: March 2020

Background

Depression is one of the leading causes of the global burden of disease, and it has particularly negative consequences for elderly patients. Antidepressants are the most frequently used treatment. We present the first single-group meta-analysis examining: 1) the response rates of elderly patients to antidepressants, and 2) the determinants of antidepressants response in this population.

Methods

We searched multiple databases for randomized controlled trials on antidepressants in the elderly with major depressive disorder above 65 years (last search: December 2017). Response was defined as 50% improvement on validated rating scales. We extracted response rates from studies and imputed the missing ones with a validated method. Data were pooled in a single-group meta-analysis. Additionally, several potential moderators of response to antidepressants were examined by subgroup and meta-regression analyses.

Results

We included 44 studies with a total of 6373 participants receiving antidepressants. On average, 50.7% of the patients reached a reduction of at least 50% on the Hamilton Depression Scale (HAMD). Subgroup and meta-regression analyses revealed a better response to treatment for patients in antidepressant-controlled trials compared to placebo-controlled trials. Mean age, study duration, percentage of woman, severity of illness at baseline, dose of antidepressants in fluoxetine equivalents, year of publication, setting (in- or out-patients), antidepressant groups (SSRI, TCA, SSNRI, α2-antagonist, SNRI, MAO-inhibitor), ITT (intention-to-treat) analysis vs completer analysis, sponsorship and overall risk of bias were not significant moderators of response.

Conclusions

Our findings suggest an improvement in symptoms can be found in about 50% of the elderly with major depressive disorder treated with antidepressants.
Perinatal complications and executive dysfunction in early-onset schizophrenia
Authors: Teigset Charlotte M. , Mohn Christine , Rund Bjørn Rishovd
Published: March 2020

Background

The present study examined the association between perinatal obstetric complications and executive dysfunction in early-onset schizophrenia (EOS), compared to healthy controls. Higher incidences of obstetric complications and more severe executive dysfunctions characterize EOS. Research shows extensive brain maturation in newborns, suggesting them to be particularly vulnerable for perinatal insults. Executive function is mainly mediated by the prefrontal cortex, an area that matures last during pregnancy. Thus, exposure to perinatal complications may influence executive dysfunction in EOS.

Methods

The participants were 19 EOS patients and 54 healthy controls. Executive function was assessed with the D-KEFS Color Word Interference Test and the Wisconsin Card Sorting Test. Information on perinatal obstetric complications and Apgar 5-min scores were obtained from the Norwegian Medical Birth Registry. Associations between perinatal conditions and executive function were studied using stepwise regression analyses.

Results

Perinatal complications, and especially shorter gestational lengths, were significantly associated with significant executive dysfunctions in EOS. Perinatal complications did not affect executive function among healthy controls. A significant relationship between lower Apgar 5-min scores and executive dysfunction was found among both EOS patients and healthy controls.

Conclusions

Exposure to perinatal complications, and particularly a shorter gestational length, was associated with increased executive dysfunction in EOS. Exposed healthy controls did not exhibit similar executive difficulties, suggesting that the EOS patients seemed especially vulnerable for executive deficits due to perinatal insults. The findings indicate that EOS youths learn more slowly and experience more difficulty with problem-solving, which carry important implications for clinical practice. Lower Apgar 5-min scores were associated with executive dysfunction in both groups. Low Apgar score at 5 min may therefore be an important early indicator of executive difficulties among adolescents, independent of diagnosis.
Conversations about alcohol in healthcare – cross-sectional surveys in the Netherlands and Sweden
Authors: Abidi Latifa , Nilsen Per , Karlsson Nadine , Skagerström Janna , O’Donnell Amy
Published: March 2020

Background

This study evaluated and compared the extent, duration, contents, experiences and effects of alcohol conversations in healthcare in the Netherlands and Sweden in 2017.

Methods

Survey data in the Netherlands and Sweden were collected through an online web panel. Subjects were 2996 participants (response rate: 50.8%) in Sweden and 2173 (response rate: 82.2%) in the Netherlands. Data was collected on socio-demographics, alcohol consumption, healthcare visits in the past 12 months, number of alcohol conversations, and characteristics of alcohol conversations (duration, contents, experience, effects).

Results

Results showed that Swedish respondents were more likely to have had alcohol conversations (OR = 1.99; 95%CI = 1.64–2.41; p = < 0.001) compared to Dutch respondents. In Sweden, alcohol conversations were more often perceived as routine (p = < 0.001), were longer (p = < 0.001), and more often contained verbal information about alcohol’s health effects (p = 0.007) or written information (p = 0.001) than in the Netherlands. In Sweden, 40+ year-olds were less likely to report a positive effect compared to the youngest respondents. In the Netherlands, men, sick-listed respondents, and risky drinkers, and in Sweden those that reported “other” occupational status such as parental leave, were more likely to have had alcohol conversations.

Conclusions

The results suggest that alcohol conversations are more common in healthcare practice in Sweden than in the Netherlands. However, positive effects of alcohol conversations were less likely to be reported among older respondents in Sweden. Our results indicate that alcohol preventative work should be improved in both countries, with more focus on risky drinkers and the content of the conversations in Sweden, and expanding alcohol screening in the Netherlands.
Socio-economic inequalities in the multiple dimensions of access to healthcare: the case of South Africa
Authors: Gordon Tanja , Booysen Frederik , Mbonigaba Josue
Published: March 2020

Background

The National Development Plan (NDP) strives that South Africa, by 2030, in pursuit of Universal Health Coverage (UHC) achieve a significant shift in the equity of health services provision. This paper provides a diagnosis of the extent of socio-economic inequalities in health and healthcare using an integrated conceptual framework.

Method

The 2012 South African National Health and Nutrition Examination Survey (SANHANES-1), a nationally representative study, collected data on a variety of questions related to health and healthcare. A range of concentration indices were calculated for health and healthcare outcomes that fit the various dimensions on the pathway of access. A decomposition analysis was employed to determine how downstream need and access barriers contribute to upstream inequality in healthcare utilisation.

Results

In terms of healthcare need, good and ill health are concentrated among the socio-economically advantaged and disadvantaged, respectively. The relatively wealthy perceived a greater desire for care than the relatively poor. However, postponement of care seeking and unmet need is concentrated among the socio-economically disadvantaged, as are difficulties with the affordability of healthcare. The socio-economic divide in the utilisation of public and private healthcare services remains stark. Those who are economically disadvantaged are less satisfied with healthcare services. Affordability and ability to pay are the main drivers of inequalities in healthcare utilisation.

Conclusion

In the South African health system, the socio-economically disadvantaged are discriminated against across the continuum of access. NHI offers a means to enhance ability to pay and to address affordability, while disparities between actual and perceived need warrants investment in health literacy outreach programmes.