bluuebunny/crossref_metadata_2025 huggingface dataset:
Health service costs and their association with functional impairment among adults receiving integrated mental health care in five low- and middle-income countries: the PRIME cohort study
Authors: Chisholm Dan , Garman Emily , Breuer Erica , Fekadu Abebaw , Hanlon Charlotte , Jordans Mark , Kathree Tasneem , Kigozi Fred , Luitel Nagendra , Medhin Girmay , Murhar Vaibhav , Petersen Inge , Rathod Sujit D , Shidhaye Rahul , Ssebunnya Joshua , Patel Vikram , Lund Crick
Published: February 2020

This study examines the level and distribution of service costs—and their association with functional impairment at baseline and over time—for persons with mental disorder receiving integrated primary mental health care. The study was conducted over a 12-month follow-up period in five low- and middle-income countries participating in the Programme for Improving Mental health carE study (Ethiopia, India, Nepal, South Africa and Uganda). Data were drawn from a multi-country intervention cohort study, made up of adults identified by primary care providers as having alcohol use disorders, depression, psychosis and, in the three low-income countries, epilepsy. Health service, travel and time costs, including any out-of-pocket (OOP) expenditures by households, were calculated (in US dollars for the year 2015) and assessed at baseline as well as prospectively using linear regression for their association with functional impairment. Cohort samples were characterized by low levels of educational attainment (Ethiopia and Uganda) and/or high levels of unemployment (Nepal, South Africa and Uganda). Total health service costs per case for the 3 months preceding baseline assessment averaged more than US$20 in South Africa, $10 in Nepal and US$3–7 in Ethiopia, India and Uganda; OOP expenditures ranged from $2 per case in India to $16 in Ethiopia. Higher service costs and OOP expenditure were found to be associated with greater functional impairment in all five sites, but differences only reached statistical significance in Ethiopia and India for service costs and India and Uganda for OOP expenditure. At the 12-month assessment, following initiation of treatment, service costs and OOP expenditure were found to be lower in Ethiopia, South Africa and Uganda, but higher in India and Nepal. There was a pattern of greater reduction in service costs and OOP spending for those whose functional status had improved in all five sites, but this was only statistically significant in Nepal.
The changing contribution of childhood social characteristics to mortality: a comparison of Finnish cohorts born in 1936–50 and 1961–75
Authors: Martikainen Pekka , Elo Irma , Tarkiainen Lasse , Mikkonen Janne , Myrskylä Mikko , Moustgaard Heta
Published: February 2020

Background

Life course epidemiology suggests that early life circumstances affect adult mortality, but most of the evidence is based on cohorts born in the beginning of the 20th century. It remains unclear whether and how the influences of early life circumstances on mortality have changed in later birth cohorts.

Methods

Analyses rely on 10% register-based samples of households drawn from the 1950 and the 1975 Finnish censuses, with consistent follow-up of socioeconomic and housing-related characteristics and early mid-life mortality (at ages 30–55 years). We estimate survival models for the associations between childhood circumstances and all-cause, internal and external mortality for cohorts born in 1936–50 and 1961–75 adjusting for attained social characteristics. We estimate sibling intraclass correlations as summary measures of all early life and familial influences.

Results

Adverse childhood social circumstances were typically associated with about 10–30% excess cause-specific mortality. These associations were almost fully attenuated by adjustment for achieved later life social characteristics. Early life influences have grown over time for mortality from external causes, particularly as related to home ownership and family type. Differentials have remained stable for internal causes. The intraclass correlations further confirmed the increasing association of early life circumstances on external-cause mortality.

Conclusions

Our analyses show that the associations between childhood characteristics and mid-life mortality are substantial and almost fully mediated by achieved adult social characteristics. The increase in the contribution of childhood circumstances to mid-life mortality is driven by ever stronger associations with external causes of death.
Optimization of a Low-Cost, Sensitive PNA Clamping PCR Method for JAK2 V617F Variant Detection
Authors: Di Francia Raffaele , Crisci Stefania , Muto Tommaso , Giancola Concetta , Petriccone Luigi , Catapano Oriana , Cummarro Annunziata , Pinto Antonio , Frigeri Ferdinando
Published: February 2020

Background

The JAK2 V617F variant is diagnostic for myeloproliferative neoplasms, a group of clonal disorders of hematopoietic stem and progenitor cells. Although several approaches have been developed to detect the variant, a gold standard diagnostic method has not yet been defined. We describe a simple, fast, and cost-effective PCR-based approach that enhances test specificity and sensitivity by blocking the amplification of the large excess of wild-type DNA.

Methods

The method involves using an oligo peptide nucleic acid (PNA) perfectly matching its corresponding DNA sequence. The PCR protocol was optimized by collecting a detailed thermodynamic data set on PNA-DNA wild-type duplexes by circular dichroism melting experiments. The specificity and sensitivity of PNA clamping PCR were assessed by genotyping 50 patients with myeloproliferative neoplasm who carried the JAK2 V617F variant and 50 healthy donors.

Results

The optimized protocol enabled selective amplification of the variant alleles, achieving maximum sensitivity (100%) and specificity (100%). Analytical sensitivity was 0.05% of variant alleles as assessed by serial dilutions of DNA from the HEL cell line (which carries the JAK2 V617F variant) mixed to wild-type DNA from healthy donors. The JAK2 V617F variant test performed according to this method has better diagnostic performance than its 2 main PCR-based competitors, at much lower cost.

Conclusions

High sensitivity and specificity and cost-effectiveness make PNA clamping PCR a useful testing platform for the detection of minor allele variants in small-scale diagnostic laboratories. It promises to improve patient care while enabling significant healthcare savings.
724 Factors Influencing Healing Time After Enzymatic Debridement
Authors: Sander Frank , Haller Herbert , Hartmann Bernd
Published: March 2020

Introduction

Enzymatic debridement (ED) as a noninvasive method is widely used and has been researched in several studies. The influence of key components of the trauma and overall treatment on healing time are often underrepresented. This paper describes the results from 56 wounds treated in a burn unit to evaluate factors influencing the healing time.

Methods

From all patients admitted to our unit from the year 2014 to 2016, 56 were treated with ED. Preclinical data and clinical data were compared in a retrospective review. Patients were divided into two groups with a separator of healing time of 30 days.

Results

ED was provided in 56 wounds in 52 patients on average to 7.0% ± 6.0 %, median 4.8% of patient’s body surface area. Comparing the group with a healing time of more than 30 days and less than 30 days. Statistically significant differences with a p< 0.05 were found in the rate of preclinical intubations, inhalation injuries, the application of fluids before admission, the type of dressing used and the BAUX index. Highly significant differences with a p< 0.01 were found in the ratio of pseudoeschars which had to be operated on and in the modified BAUX index (MBI). Mostly used dressings were a polylactic membrane (PLM) and silicone dressings. In the silicone group, MBI was significantly higher than in the polylactic group and healing time was significantly faster in the PLM group. Comparing groups with a higher than average MBI of 67.5 the PLM and the silicone group had a comparable MBI (p=0.337), but the PLM group had a five days shorter healing time of 43 days (p=0.2768). In a logistic regression formula over all PLM and Silicone patients (Days for healing after ED = 1.53 + 8.9 * dressing (PLM=1, silicone=2) + 0.35*MBI - 5.15483*incomplete debridement (Yes=1, No=0) + 7.96*pseudoeschar to be operated on (Yes=1, No=0) the influence of dressings could be demonstrated. No statistical differences (p >0.05) could be found in age, etiology of burn (fire scald, electric current injury or electrical arch with a p=0.4), location of accident out- or inside a building, cold water therapy applied or not, in TBSA, percentage of partial deep burns and full-thickness burns or the percentage of patients taken to ICU as inpatients and the timing of ED as well as the completeness of ED and in ABSI.

Conclusions

Healing time was dependent on parameters such as preclinical intubations, inhalation injuries, dressings used, and the severity calculated by MBI. Dressings are one of the few settings which can be changed proactively to achieve better outcomes. PLM over all clinical conditions have a shorter healing time (31 days) compared to silicon dressings (49 days)

Applicability of Research to Practice

Immediate.
731 The Wound Rounds Survey: Measuring Burn Wound Reading Skills
Authors: Lee Christina , Ketner Abigail , Rabbitts Angela , Gallagher James
Published: March 2020

Introduction

The assessment of burn depth and the prediction of spontaneous wound healing potential is one of the most important roles of any provider assessing burn wounds. In an attempt to determine whether burn wound reading by physical exam to determine best clinical treatment is a skill that can be measured, this article describes a method developed and employed at this urban burn center for assessment of burn wounds.

Methods

This study was conducted from August 8, 2019 to September 19, 2019. Study participants were attending physicians, fellows, residents and physician assistants. Cases were anonymized by the removal of personal identifiers, and participants were sent an SMS via mobile phone of a link to a Google Forms survey. After in person examination of the burn wounds, participants voted on each patient seen. Survey answer choices were 1 (healing without need for surgery), 2 (unsure), and 3 (need for surgical excision). Wound evaluations with unanimous responses were felt not to demonstrate the skill of burn wound assessment, as some wounds were obviously in need of surgery or were going to heal to even the most inexperienced examiner. The participants were grouped into expert, intermediate and novice groups, and the responses were classified as correct or incorrect based on the final outcome of the patient. Mean percentage of correct responses were calculated for each group, and statistical analysis of the means was performed using a one-way weighted ANOVA test.

Results

During the study period a total of 56 voting events were recorded, 26 of which were excluded based on exclusion criteria. The percentage of correct responses was 58.5 ±8.2% in the expert group (n=94), 50.8 ±11.7% in the intermediate group (n=65), and 41.7 ±16.8% in the novice group (n=72). ANOVA analysis showed that these were statistically significant differences (p < 0.01).

Conclusions

This pilot study shows that the current survey method of assessing burn wounds resulted in higher scores in experts when compared to intermediate and novice level practitioners, suggesting that burn wound reading is a skill that can be measured. Further development of a formative assessment could aid in the development of an educational module to improve wound reading skills.

Applicability of Research to Practice

Utilizing a daily survey as an instrument of formative assessment on burn wound reading.
797 Estimated Blood Loss in Burns: A Quality Metric That Defies Measurement?
Authors: Pasch Stuart , Joolukuntla Adithya , Hauck Ellen , Rae Lisa
Published: March 2020

Introduction

There are a handful of publications over the past 3 decades evaluating single institution blood loss during excision and grafting procedures (E/G) for thermal injuries. The average estimated blood loss (EBL) reported ranges from 0.75ml/cm2 excised to 9.2% total blood volume/1% E/G, with disparate standard deviations. EBL should be benchmarked and evaluated for improvement in quality metrics.

Methods

We performed a retrospective evaluation of 66 burn E/G cases. They were analyzed for blood loss at 24 and 72 hours post procedure, accounting for any intra-operative or immediate post-operative transfusions using the Mercuriali formula. Each unit of transfused blood was estimated to increase hemoglobin 1g/dL.

Results

Means and standard deviations for calculated EBL, taking into account transfused blood and ongoing donor site bleeding up to 72 hours is depicted in Table 1. EBL in < 20% TBSA and >20% TBSA cases were compared as well as those with and without tourniquet use. Means and standard deviations for calculated EBL, taking into account transfused blood and ongoing donor site bleeding up to 72 hours is depicted in Table 1. EBL in < 20% TBSA and >20% TBSA cases were compared as well as those with and without tourniquet use.

Conclusions

Benchmark quality measures for burn should include EBL. These preliminary data suggest that results could guide intraoperative transfusion decisions if enough cases are analyzed (data collection is ongoing). Evaluation of EBL may also provide insight for transfusion ratios for coagulopathy of burn.

Applicability of Research to Practice

Evaluation of blood loss during surgical treatment of thermal injuries is an important benchmark and its study may lead to improvements in care.
Introducing design for selective laser melting in aerospace industry☆
Authors: Stolt Roland , Elgh Fredrik
Published: February 2020

The selective laser melting (SLM) process has created new possibilities for the manufacture of new lightweight jet engine components with lattice structures replacing solid sections. Hopes are to reduce the density of the component and thereby saving weight. To introduce the new manufacturing process, the components need to be redesigned and verified to comply with an array of requirements concerning, for example, strength, aerodynamics, and manufacturing. To find out how a capability of designing and evaluating components for the SLM process can be built into an organization, an interview investigation has been conducted at an aerospace company finding the state of practice in technology and product development. The impact of introducing SLM is thereafter estimated. The result is that introducing a novel manufacturing process will primarily influence the methods used to predict product lifecycle performance. An important finding is that it is currently difficult to include a topology optimization step in the multiobjective design evaluation environment used at the company due to which the complexity would increase significantly.
Adherence Barriers for Adolescent and Young Adult Transplant Recipients: Relations to Personality
Authors: Quast Lauren F , Gutiérrez-Colina Ana M , Cushman Grace K , Rea Kelly E , Eaton Cyd K , Lee Jennifer L , George Roshan P , Blount Ronald L
Published: February 2020

Objective

Much of the extant literature on adherence barriers has focused on modifiable factors (e.g., knowledge, social support); however, less is known about how barriers may be associated with relatively stable constructs, such as personality traits. The current study examines associations between personality (i.e., agreeableness, conscientiousness, neuroticism) and adherence barriers in a group of adolescent and young adult (AYA) solid organ transplant recipients. Demonstrating associations between barriers and personality may help in understanding why barriers are stable over time. Additionally, different personality traits may relate to different types of barriers.

Methods

The sample included 90 AYAs (Mage = 17.31; SD = 2.05; 58% male) who received a kidney (n = 36), liver (n = 29), or heart (n = 25) transplant at least 1 year prior to study enrollment. AYAs completed the Agreeableness, Conscientiousness, and Neuroticism scales from the NEO Five-Factor Inventory and the Adolescent Medication Barriers Scale (AMBS).

Results

Lower levels of agreeableness and conscientiousness and higher levels of neuroticism were related to higher self-reported barrier scores (AMBS; r’s = .31– .53, p’s < .001). The relations differed by personality factor and barrier type.

Conclusion

Adherence barriers showed medium to large associations with personality traits that are known to be relatively stable. Our findings indicate that the temporal stability of barriers to adherence may be due in part to their association with relatively enduring personality characteristics.
Quantification by Ultrafiltration and Immunofixation Electrophoresis Testing for Monoclonal Serum Free Light Chains
Authors: Singh Gurmukh , Bollag Roni
Published: February 2020

Objective

Measurement of monoclonal immunoglobulins is a reliable estimate of the plasma cell tumor mass. About 15% of plasma cell myelomas secrete light chains only. The concentration of serum free light chains is insufficient evidence of the monoclonal light chain burden. A sensitive quantitative estimate of serum free monoclonal light chains could be useful for monitoring patients with light chain myeloma. We describe such an assay that does not require mass-spectrometry equipment or expertise.

Methods

Serum specimens from patients with known light chain myelomas and controls were subjected to ultrafiltration through a membrane with pore size of 50 kDa. The filtrate was concentrated and tested by immunofixation electrophoresis. The relative area under the monoclonal peak, compared to that of the total involved light chain composition, was estimated by densitometric scanning of immunofixation gels. The proportion of the area occupied by the monoclonal peak in representative densitometric scans was used to arrive at the total serum concentration of the monoclonal serum free light chains.

Results

Using an ultracentrifugation and concentration process, monoclonal serum free light chains were detectable, along with polyclonal light chains, in all 10 patients with active light chain myelomas. Monoclonal light chains were identified in serum specimens that did not reveal monoclonal light chains by conventional immunofixation electrophoresis. The limit of detection by this method was 1.0 mg/L of monoclonal serum free light chains.

Conclusion

The method described here is simple enough to be implemented in academic medical center clinical laboratories and does not require special reagents, equipment, or expertise. Even though urine examination is the preferred method for the diagnosis of light chain plasma cell myelomas, measurement of the concentration of serum free light chains provides a convenient, albeit inadequate, way to monitor the course of disease. The method described here allows effective electrophoretic differentiation of monoclonal serum free light chain from polyclonal serum free light chains and provides a quantitation of the monoclonal serum free light chains in monitoring light chain monoclonal gammopathies.
Responsiveness and the Role of Rights in Medical Law: Lessons from Montgomery†
Authors: Arvind T T , McMahon Aisling M
Published: February 2020

Over time, medical law has moved away from paternalism in favour of an approach grounded in patients’ rights. Using Montgomery v Lanarkshire Health Board (2015) as a case study, we offer a deeper analysis of this emerging approach. We argue that patients’ rights should be evaluated in terms of their contribution to making medical law more socially responsive, by developing it to give effect to social needs and aspirations pertaining to health care. Although rights can play an important role in achieving social responsiveness, they also carry the risk of entrenching approaches unrepresentative of patients’ actual needs and empirical realities. This is evident in Montgomery, where the law, despite being derived from General Medical Council (GMC) guidance, has effects that differ significantly from the GMC’s goals. Drawing on socio-legal literature, we outline a new approach for guiding the use of rights in medical law focused on the functional consequences of rights in facilitating patients’ aspirations, and the capacity of rights to respond to social and institutional contexts in which medical interaction occurs. We conclude by showing how this approach, applied to informed consent, would produce a different and arguably a superior duty, providing a sounder basis for responding to patient needs.
NP213 (Novexatin®): A unique therapy candidate for onychomycosis with a differentiated safety and efficacy profile
Authors: Mercer Derry K , Robertson Jennifer C , Miller Lorna , Stewart Colin S , O'Neil Deborah A
Published: February 2020

NP213 (Novexatin®) is a novel antifungal peptide specifically designed for the topical treatment of onychomycosis. NP213 was designed using host defense peptides (HDP), essential components of the innate immune response to infection, as a template. NP213 is a water-soluble cyclic fungicidal peptide that effectively penetrates human nail. NP213 demonstrated a promising preclinical and clinical safety profile, with no evidence of systemic exposure following topical application to the skin and nails. NP213 was efficacious in two phase IIa human trials with 43.3% of patients having no fungi detectable by culture of fragments from NP213-treated nails after 180 days in the first study and likewise 56.5% of patients were culture negative for dermatophytes after 360 days in the second phase IIa study. In both trials, NP213 was applied daily for only 28 days in marked contrast to other topical onychomycosis treatments that require application for up to 52 weeks. Patient reported outcomes from the phase IIa studies were positive with participants recording an improved appearance of their nails after only 14 days of application. All fungi identified in these studies were Trichophyton spp. NP213 (Novexatin®) is a promising, highly differentiated peptide-based candidate for the topical treatment of onychomycosis, addressing the infectious cause and cosmetic issues of this very common condition.
Prospects for γ-ray observations of narrow-line Seyfert 1 galaxies with the Cherenkov Telescope Array – II. γ–γ absorption in the broad-line region radiation fields
Authors: Romano P , Böttcher M , Foschini L , Boisson C , Vercellone S , Landoni M
Published: February 2020

Gamma-ray emitting narrow-line Seyfert 1 (γ-NLS1) galaxies possibly harbour relatively low-mass black holes (106–108 M⊙) accreting close to the Eddington limit, and share many characteristics with their sibling sources, flat-spectrum radio quasars. Although they have been detected in the MeV–GeV band with Fermi–LAT, they have never been seen in the very high energy band with current imaging atmospheric Cherenkov telescopes (IACTs). Thus, they are key targets for the next-generation IACT, the Cherenkov Telescope Array (CTA). In a previous work we selected, by means of extensive simulations, the best candidates for a prospective CTA detection (SBS 0846+513, PMN J0948+0022, and PKS 1502+036) taking into account the effects of both the intrinsic absorption (approximated with a cut-off at 30 GeV), and the extragalactic background light on the propagation of γ-rays. In this work, we simulate the spectra of these three sources by adopting more realistic broad-line region (BLR) absorption models. In particular, we consider the detailed treatment of γ–γ absorption in the radiation fields of the BLR as a function of the location of the γ-ray emission region with parameters inferred from observational constraints. We find that, due to the energy range extent and its sensitivity, CTA is particularly well suited to locate the γ-ray emitting region in γ-NLS1. In particular CTA will be able not only to distinguish whether the γ-ray emitting region is located inside or outside the BLR, but also where inside the BLR it may be.
Spinal Arteriovenous Fistula: 2-Dimensional Operative Video
Authors: Hendricks Benjamin K , Spetzler Robert F
Published: February 2020

Spinal dural arteriovenous fistulas (AVFs) have been categorized on the basis of the Anson and Spetzler classification into 4 types. Type I is the most common type and describes an abnormal connection between a radicular artery at the nerve root sleeve and an intradural draining vein. This communication results in progressive dilatation and mass effect from the draining vein experiencing arterial pressures without intervening arterioles. In this patient, preoperative angiography showed a type I dural AVF. A laminoplasty was performed to provide dural exposure, and a midline durotomy was performed. Indocyanine green (ICG) angiography was used to visualize flow within the fistula. This dorsal dural AVF demonstrated the characteristic slow venous flow. Pressure recordings were obtained and confirmed the elevated venous pressure observed in these lesions. Bipolar coagulation of the fistulous point was performed, and the vessel was removed at the site of the root entry zone to permit pathologic confirmation of the arteriovenous interface. Intraoperative ICG angiography findings confirmed disconnection. The patient gave informed consent for surgery and video recording. Institutional review board approval was deemed unnecessary. Used with permission from Barrow Neurological Institute, Phoenix, Arizona.
Contrasting Old and Young Volcanism from Aitutaki, Cook Islands: Implications for the Origins of the Cook–Austral Volcanic Chain
Authors: Jackson M G , Halldórsson S A , Price A , Kurz M D , Konter J G , Koppers A A P , Day J M D
Published: February 2020

The Cook–Austral volcanic lineament is thought to be the product of three overlapping South Pacific hotspot tracks: Macdonald, Arago, and Rarotonga. However, the entire Rarotonga hotspot track consists of volcanism on just two islands, Rarotonga and Aitutaki, making it difficult to evaluate a hotspot origin for the young volcanism on these islands. We present new Sr–Nd–Hf–Pb–He isotopic and major and trace element data on Aitutaki—which has two periods of volcanism, older (9·39 Ma) and younger (1·382–1·941 Ma)—and Atiu in the Cook Islands to evaluate a hotspot origin. Like Atiu, the ‘older volcanic series’ at Aitutaki was tentatively linked with the Arago hotspot based on its age, but this link has never been tested with geochemistry. New geochemical data on the older Aitutaki volcanic series show clear affinities to the Arago hotspot volcano Atiu. In contrast, the younger Aitutaki volcanic series, erupted on a near-atoll, exhibits evidence for a rejuvenated, non-plume volcanic origin. If Rarotonga (1·157–1·697 Ma) and the young series at Aitutaki share a common heritage and mechanism for formation as previously proposed—they erupted only 260 km apart over an overlapping time period and exhibit overlapping radiogenic isotopic compositions—then Rarotonga lavas may also represent a subaerial rejuvenated volcanic stage capping an older volcano related to a different hotspot, consistent with no direct involvement from a mantle plume in the origin of subaerial lavas at Rarotonga. Rarotonga, Aitutaki, and Atiu exhibit some of the most extreme enriched mantle (EM) signatures in the Cook–Austral volcanic lineament. There are three geographically separated geochemical domains along the Cook–Austral volcanic lineament—a northern geochemical domain with EM geochemical signatures is separated from a southern EM domain by a 1000 km long central HIMU (‘high μ’, or high 238U/204Pb) domain—and Rarotonga, Aitutaki, and Atiu are part of the northernmost geochemical domain. There is a possible role for lithospheric thickness in controlling geochemical compositions of melt extracted from the mantle along the Cook–Austral volcanic lineament, particularly across the Austral Fracture Zone. However, this is complicated by the lineament’s juxtaposition with the South Pacific Superswell, which may modify lithospheric behavior and complicate a simple lithospheric thickness model describing variable hotspot volcano compositions in the region.
The (Null) Effects of Clickbait Headlines on Polarization, Trust, and Learning
Authors: Munger Kevin , Luca Mario , Nagler Jonathan , Tucker Joshua
Published: February 2020

“Clickbait” headlines designed to entice people to click are frequently used by both legitimate and less-than-legitimate news sources. Contemporary clickbait headlines tend to use emotional partisan appeals, raising concerns about their impact on consumers of online news. This article reports the results of a pair of experiments with different sets of subject pools: one conducted using Facebook ads that explicitly target people with a high preference for clickbait, the other using a sample recruited from Amazon’s Mechanical Turk. We estimate subjects’ individual-level preference for clickbait, and randomly assign sets of subjects to read either clickbait or traditional headlines. Findings show that older people and non-Democrats have a higher “preference for clickbait,” but reading clickbait headlines does not drive affective polarization, information retention, or trust in media.
Circulating plasma metabolites and risk of rheumatoid arthritis in the Nurses’ Health Study
Authors: Chu Su H , Cui Jing , Sparks Jeffrey A , Lu Bing , Tedeschi Sara K , Speyer Cameron B , Moss LauraKay , Feser Marie L , Kelmenson Lindsay B , Mewshaw Elizabeth A , Edison Jess D , Deane Kevin D , Clish Clary , Lasky-Su Jessica , Karlson Elizabeth W , Costenbader Karen H
Published: February 2020

Objectives

RA develops slowly over years. We tested for metabolic changes prior to RA onset using a large non-targeted metabolomics platform to identify novel pathways and advance understanding of RA development.

Methods

Two hundred and fifty-four incident RA cases with plasma samples drawn pre-RA onset in the Nurses’ Health Study (NHS) cohorts were matched 1:2 to 501 controls on age, race, menopause/post-menopausal hormone use and blood collection features. Relative abundances of 360 unique, known metabolites were measured. Conditional logistic regression analyses assessed associations between metabolites and incidence of RA, adjusted for age, smoking and BMI, accounting for multiple comparisons. Subgroup analyses investigated seropositive (sero+) RA and RA within 5 years of sample collection. Significant metabolites were then tested in a female military pre-RA case–control study (n = 290).

Results

In the NHS, metabolites associated with RA and sero+RA in multivariable models included 4-acetamidobutanoate (odds ratio (OR) = 0.80/S.d., 95% CI: 0.66, 0.95), N-acetylputrescine (OR = 0.82, 95% CI: 0.69, 0.96), C5 carnitine (OR = 0.84, 95% CI: 0.71, 0.99) and C5:1 carnitine (OR = 0.81, 95% CI: 0.68, 0.95). These were involved primarily in polyamine and leucine, isoleucine and valine metabolism. Several metabolites associated with sero+RA within 5 years of diagnosis were replicated in the independent military cohort: C5 carnitine (OR = 0.55, 95% CI: 0.33, 0.92), C5:1 carnitine (OR = 0.62, 95% CI: 0.39, 0.99) and C3 carnitine (OR = 0.57, 95% CI: 0.36, 0.91).

Conclusion

Several metabolites were inversely associated with incidence of RA among women. Three short-chain acylcarnitines replicated in a smaller dataset and may reflect inflammation in the 5-year period prior to sero+RA diagnosis.
Safety and efficacy of rituximab biosimilar (CT-P10) in systemic sclerosis: an Italian multicentre study
Authors: Campochiaro Corrado , De Luca Giacomo , Lazzaroni Maria Grazia , Zanatta Elisabetta , Bosello Silvia Laura , De Santis Maria , Cariddi Adriana , Bruni Cosimo , Selmi Carlo , Gremese Elisa , Matucci-Cerinic Marco , Doria Andrea , Airò Paolo , Dagna Lorenzo
Published: February 2020

Objectives

Recent data have shown a significant efficacy of rituximab (RTX) in SSc. An RTX biosimilar (RTX-B) is a more affordable option. We assessed the safety and efficacy of an RTX-B (CT-P10) in SSc.

Methods

SSc patients treated with RTX-B with at least 6 months of follow-up were retrospectively identified from six Italian referral centres. SSc patients naïve to RTX-B (RTX-Bn) or already treated with RTX originator and switched to an RTX-B (RTX-Bs) were evaluated. A comprehensive assessment of disease characteristics and organ involvement at baseline and after 6 months was obtained.

Results

Thirty-three SSc patients were selected: 29 (87.9%) females, mean age 51.6 years (s.d. 14.2), mean disease duration 9.8 years (s.d. 8.1); 21 (64.5%) with dcSSc, 20 (60.1%) anti-topoisomerase I, 7 (21.2%) anti-RNA polymerase III and 6 (18.2%) anti-centromere positive. Seventeen (51.5%) were RTX-Bn and 16 were on RTX-Bs (48.5%). RTX was introduced because of skin progression in 18 patients (54.5%), interstitial lung disease (ILD) worsening in 11 (33.3%) and arthritis in 12 (36.4%). All patients were previously treated with immunosuppressants. At RTX-B introduction, 21 (63.6%) patients were on concomitant immunosuppressants: 15 (71.4%) on MMF and 6 (28.6%) on MTX. Twenty-three (69.7%) were on low-dose steroids. After 6 months, a significant reduction of the modified Rodnan skin score (mRSS), 28-joint DAS and CRP was observed (P = 0.002, 0.005 and 0.008, respectively); the mRSS significantly improved both in RTX-Bn (P < 0.024) and RTX-Bs patients (P < 0.031). No significant changes were observed for lung function tests, either in the entire cohort or in the subgroup of ILD patients. Only one RTX-Bs patient experienced transient neutropenia.

Conclusion

Our data suggest that RTX-B can represent a cheaper option in SSc patients, as it is effective in improving skin and joint involvement and in stabilizing lung function.
Predictors of turnover intention among Norwegian nurses
Authors: Søbstad Jenni Hellesøv , Pallesen Ståle , Bjorvatn Bjørn , Costa Giovanni , Hystad Sigurd William
Published: February 2020

Background

Shortage of nurses and instability in the nursing workforce due to turnover have become a global concern.

Purpose

The aim of this study was to investigate whether symptoms of psychological distress mediated the impact of age, gender, workplace bullying, job satisfaction, and hardiness on turnover intention when controlling for living with children, marital status, percentage of full-time equivalent, and number of night shifts last year and whether the same variables (except full-time equivalent and number of night shifts last year) could predict real turnover.

Methods

In all, 1,246 nurses took part in a survey in 2008/2009 (T1) assessing symptoms of insomnia, sleepiness, anxiety, depression, fatigue, alcohol consumption, age, gender, workplace bullying, job satisfaction, and hardiness. Three years (T2) later they completed a survey assessing turnover intention, living with children, marital status, percentage of full-time equivalent, and number of night shift last year. A total of 99 nurses had left the nursing profession during this period.

Results

Workplace bulling was positively related to turnover intention, whereas job satisfaction and hardiness were negatively related to turnover intention. The impact of all three predictors was partly mediated by symptoms of insomnia and anxiety. Age was negatively whereas male gender was positively associated with turnover intention. These effects were partly mediated by harmful alcohol use. Nurses who were living with a partner at T2 and nurses with high scores on fatigue at T1 were more prone to leave the nursing profession during the study period compared to their counterparts.

Conclusion

Symptoms like insomnia, anxiety, and alcohol consumption may mediate the impact of working conditions and personality traits associated with turnover intention in nurses.

Practice Implications

Interventions aiming at counteracting bullying, improving job satisfaction, and alleviating fatigue may reduce turnover intention/turnover.
Incidental Detection of Hypothyroidism on 68Ga-PSMA-HBED-CC PET/CT Imaging
Authors: Sood Apurva , Vadi Shelvin Kumar , Kumar Rajender , Singh Harmandeep , Mittal Bhagwant Rai
Published: February 2020

68Ga-labeled prostate-specific membrane antigen (PSMA) ligand PET/CT is a rapidly evolving imaging modality for prostate cancer. However, with the widespread use of 68Ga-PSMA PET/CT, various reports of nonprostatic uptake of 68Ga-PSMA in both benign and malignant lesions have also appeared. We report a recently diagnosed case of prostate cancer demonstrating diffuse 68Ga-PSMA expression in both the lobes of thyroid gland, which on further clinical and biochemical investigations was established as hypothyroidism.
The Prevalence and Correlates of Prehospital Delay and Health Belief in Chinese Patients With Colorectal Cancer
Authors: Wu Xiao-Dan , Zeng Ying-Yu , Wu Xiao-Jun , Qin Hui-Ying
Published: February 2020

The objective of this study was to describe prehospital delay and health beliefs in Chinese patients with colorectal cancer. A total of 756 adult Chinese patients with a first-time diagnosis of colorectal cancer were recruited during 2016 in Guangzhou, China. All patients completed the Chinese-language version of a questionnaire developed specifically for this study as well as the Chinese-language version of the Champion Health Belief Model Scale. The results of this study showed that the median length of the prehospital delay was 12 weeks and that the average delay was 18.29 (SD = 14.66) weeks. The rate of prehospital delay was 47.35%. The score of health beliefs among these patients was 115.56 (SD = 9.00) and the average score of the entries was 3.21 (SD = 0.25). Health beliefs about colorectal cancer were negatively correlated with prehospital delay. A multiple logistic regression showed that the level of health beliefs, frequency of physical examinations, occupation, and the site of the cancer were the major factors influencing prehospital delay (p < .05). The patients had a low rate of physical examination (41.40%), and colorectal cancer screening was not routine prior to their physical examination. This study showed that the incidence of prehospital delay among Chinese patients with colorectal cancer was 47.35%. Multiple factors influenced prehospital delay among Chinese patients with colorectal cancer.
LSP1-myosin1e bi-molecular complex regulates focal adhesion dynamics and cell migration
Authors: Schäringer Katja , Maxeiner Sebastian , Schalla Carmen , Rütten Stephan , Zenke Martin , Sechi Antonio
Published: February 2020

Several cytoskeleton-associated proteins and signalling pathways work in concert to regulate actin cytoskeleton remodelling, cell adhesion and migration. We have recently demonstrated that the bi-molecular complex between the leukocyte-specific protein 1 (LSP1) and myosin1e controls actin cytoskeleton remodelling during phagocytosis. In this study, we show that LSP1 down regulation severely impairs cell migration, lamellipodia formation and focal adhesion dynamics in macrophages. Inhibition of the interaction between LSP1 and myosin1e also impairs these processes resulting in poorly motile cells, which are characterised by few and small lamellipodia. Furthermore, cells in which LSP1-myosin1e interaction is inhibited are typically associated with inefficient focal adhesion turnover. Collectively, our findings show that the LSP1-myosin1e bimolecular complex plays a pivotal role in the regulation of actin cytoskeleton remodelling and focal adhesion dynamics required for cell migration.
Deep neural networks identify context-specific determinants of transcription factor binding affinity
Authors: Zheng An , Lamkin Michael , Wu Cynthia , Su Hao , Gymrek Melissa
Published: February 2020

Transcription factors (TFs) bind DNA by recognizing highly specific DNA sequence motifs, typically of length 6-12bp. A TF motif can occur tens of thousands of times in the human genome, but only a small fraction of those sites are actually bound. Despite the availability of genome-wide TF binding maps for hundreds of TFs, predicting whether a given motif occurrence is bound and identifying the influential context features remain challenging. Here we present a machine learning framework leveraging existing convolutional neural network architectures and state of the art model interpretation techniques to identify, visualize, and interpret context features most important for determining binding activity for a particular TF. We apply our framework to predict binding at motifs for 38 TFs in a lymphoblastoid cell line and achieve superior classification performance compared to existing frameworks. We compute importance scores for context regions at single base pair resolution and uncover known and novel determinants of TF binding. Finally, we demonstrate that important context bases are under increased purifying selection compared to nearby bases and are enriched in disease-associated variants identified by genome-wide association studies.
Genomic and transcriptomic analyses reveal a tandem amplification unit of 11 genes and mutations of mismatch repair genes in methotrexate-resistant HT-29 cells
Authors: Kim Ahreum , Shin Jong-Yeon , Seo Jeong-Sun
Published: February 2020

DHFRgene amplification is present in methotrexate (MTX)-resistant colon cancer cells and acute lymphoblastic leukemia. However, little is known aboutDHFRgene amplification due to difficulties in quantifying amplification size and recognizing the repetitive rearrangements involved in the process. In this study, we have proposed an integrative framework to characterize the amplified region by using a combination of single-molecule real time sequencing, next-generation optical mapping, and chromosome conformation capture (Hi-C). Amplification of theDHFRgene was optimized to generate homogenously amplified patterns. The amplification units of 11 genes, from theDHFRgene to theATP6AP1Lgene position on chromosome 5 (~2.2Mbp), and a twenty-fold tandemly amplified region were verified using long-range genome and RNA sequencing data. In doing so, a novel inversion at the start and end positions of the amplified region as well as frameshift insertions in most of theMSHandMLHgenes were detected. These might stimulate chromosomal breakage and cause the dysregulation of mismatch repair pathways. Using Hi-C technology, high adjusted interaction frequencies were detected on the amplified unit and unsuspected position on 5q, which could have a complex network of spatial contacts to harbor gene amplification. Characterizing the tandem gene-amplified unit and genomic variants as well as chromosomal interactions on intra-chromosome 5 can be critical in identifying the mechanisms behind genomic rearrangements. These findings may give new insight into the mechanisms underlying the amplification process and evolution of drug resistance.
Localized prediction of glutamate from whole-brain functional connectivity of the pregenual anterior cingulate cortex
Authors: Martens Louise , Kroemer Nils B. , Teckentrup Vanessa , Colic Lejla , Palomero-Gallagher Nicola , Li Meng , Walter Martin
Published: February 2020

Local measures of neurotransmitters provide crucial insights into neurobiological changes underlying altered functional connectivity in psychiatric disorders. However, non-invasive neuroimaging techniques such as magnetic resonance spectroscopy (MRS) may cover anatomically and functionally distinct areas, such asp32andp24of the pregenual anterior cingulate cortex (pgACC). Here, we aimed to overcome this low spatial specificity of MRS by predicting local glutamate and GABA based on functional characteristics and neuroanatomy, using complementary machine learning approaches. Functional connectivity profiles of pgACC areap32predicted pgACC glutamate better than chance (R2= .324) and explained more variance compared to areap24using both elastic net and partial least squares regression. In contrast, GABA could not be robustly predicted. To summarize, machine learning helps exploit the high resolution of fMRI to improve the interpretation of local neurometabolism. Our augmented multimodal imaging analysis can deliver novel insights into neurobiology by using complementary information.
Gut Microbiome Pattern Reflects Healthy Aging and Predicts Extended Survival in Humans
Authors: Wilmanski Tomasz , Diener Christian , Rappaport Noa , Patwardhan Sushmita , Wiedrick Jack , Lapidus Jodi , Earls John C. , Zimmer Anat , Glusman Gustavo , Robinson Max , Yurkovich James T. , Kado Deborah M. , Cauley Jane A. , Zmuda Joseph , Lane Nancy E. , Magis Andrew T. , Lovejoy Jennifer C. , Hood Leroy , Gibbons Sean M. , Orwoll Eric S. , Price Nathan
Published: February 2020

The gut microbiome has important effects on human health, yet its importance in human aging remains unclear. Using two independent cohorts comprising 4582 individuals across the adult lifespan we demonstrate that, starting in mid-to-late adulthood, gut microbiomes become increasingly unique with age. This uniqueness pattern is strongly associated with gut microbial amino acid derivatives circulating within the bloodstream, many of which have been previously identified as longevity biomarkers. At the latest stages of human life, two distinct patterns emerge wherein individuals in good health show continued microbial drift toward a unique compositional state, while the same drift is absent in individuals who perform worse on a number of validated health measures. The identified healthy aging pattern is characterized by an overall depletion of core genera found across most humans - primarily a depletion in the nearly ubiquitous genusBacteroides. Consistently, retaining a highBacteroidesdominance into extreme age, or, equivalently, having a low gut microbiome uniqueness score, predicts decreased survival in a four-year follow-up. Our comprehensive analysis identifies the gut microbiome as a novel component of healthy aging, with important implications for the world’s growing older population.
Crosstalk between invadopodia and the extracellular matrix
Authors: Iizuka Shinji , Leon Ronald P. , Gribbin Kyle P. , Zhang Ying , Navarro Jose , Smith Rebecca , Devlin Kaylyn , Wang Lei G. , Gibbs Summer L. , Korkola James , Nan Xiaolin , Courtneidge Sara A.
Published: February 2020

The scaffold protein Tks5α is required for invadopodia-mediated cancer invasion bothin vitroandin vivo. We have previously also revealed a role for Tks5 in tumor cell growth using three-dimensional (3D) culture model systems and mouse transplantation experiments. Here we use both 3D and high-density fibrillar collagen (HDFC) culture to demonstrate that native type I collagen, but not a form lacking the telopeptides, stimulated Tks5-dependent growth, which was dependent on the DDR collagen receptors. We used microenvironmental microarray (MEMA) technology to determine that laminin, collagen I, fibronectin and tropoelastin also stimulated invadopodia formation. A Tks5α-specific monoclonal antibody revealed its expression both on microtubules and at invadopodia. High- and super-resolution microscopy of cells in and on collagen was then used to place Tks5α at the base of invadopodia, separated from much of the actin and cortactin, but coincident with both matrix metalloprotease and cathepsin proteolytic activity. Inhibition of the Src family kinases, cathepsins or metalloproteases all reduced invadopodia length but each had distinct effects on Tks5α localization. These studies highlight the crosstalk between invadopodia and extracellular matrix components, and reveal the invadopodium to be a spatially complex structure.