bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of caste on health, independent of economic disparity: evidence from school children of two rural districts of India
Authors: Dutta Ambarish , Mohapatra Mrinal Kar , Rath Mrunalini , Rout Sarit Kumar , Kadam Shridhar , Nallalla Srinivas , Balagopalan Kavitha , Tiwari Divya , Yunus Shariqua , Behera Binod Kumar , Patro Binod Kumar , Mangaraj Manaswini , Sahu Suchanda , Paithankar Pradnya
Published: May 2020

Caste, a stratifying axis of the Indian society, is associated with wealth and health. However, to what extent caste‐based health inequality is explained by wealth disparities, is not clear. Therefore, we aimed to examine the caste‐based differences in anaemia (haemoglobin < 11 gm/dl) and self‐reported sickness absenteeism in schoolchildren and the mediating role of economic disparity. Students (n = 1764) were surveyed from 54 government schools of Dhenkanal and Angul, Odisha state. Socioeconomic data, anaemia and absenteeism were recorded. The relative risks of anaemia among Scheduled Tribe (least advantaged) and Scheduled Caste (second least advantaged) students were 1.19 (95% CI: 1.08, 1.26) and 1.13 (1.03, 1.20), respectively, as compared to students of the most advantaged caste and that for sickness absenteeism were 2.78 (2.03, 3.82) and 2.84 (2.13, 3.78); p < 0.05, with marginal attenuation when controlled for inter‐caste economic disparities. Caste had an independent effect on anaemia and sickness absenteeism in school children, unexplained by inter‐caste economic disparities.
Rethinking Integrated Care: A Systematic Hermeneutic Review of the Literature on Integrated Care Strategies and Concepts
Authors: HUGHES GEMMA , SHAW SARA E. , GREENHALGH TRISHA
Published: May 2020

Policy Points

Integrated care is best understood as an emergent set of practices intrinsically shaped by contextual factors, and not as a single intervention to achieve predetermined outcomes.

Policies to integrate care that facilitate person‐centered, relationship‐based care can potentially contribute to (but not determine) improved patient experiences.

There can be an association between improved patient experiences and system benefits, but these outcomes of integrated care are of different orders and do not necessarily align.

Policymakers should critically evaluate integrated care programs to identify and manage conflicts and tensions between a program's aims and the context in which it is being introduced.

Context

Integrated care is a broad concept, used to describe a connected set of clinical, organizational, and policy changes aimed at improving service efficiency, patient experience, and outcomes. Despite examples of successful integrated care systems, evidence for consistent and reproducible benefits remains elusive. We sought to inform policy and practice by conducting a systematic hermeneutic review of literature covering integrated care strategies and concepts.

Methods

We used an emergent search strategy to identify 71 sources that considered what integrated care means and/or tested models of integrated care. Our analysis entailed (1) comparison of strategies and concepts of integrated care, (2) tracing common story lines across multiple sources, (3) developing a taxonomy of literature, and (4) generating a novel interpretation of the heterogeneous strategies and concepts of integrated care.

Findings

We identified four perspectives on integrated care: patients’ perspectives, organizational strategies and policies, conceptual models, and theoretical and critical analysis. We subdivided the strategies into four framings of how integrated care manifests and is understood to effect change. Common across empirical and conceptual work was a concern with unity in the face of fragmentation as well as the development and application of similar methods to achieve this unity. However, integrated care programs did not necessarily lead to the changes intended in experiences and outcomes. We attribute this gap between expectations and results, in part, to significant misalignment between the aspiration for unity underpinning conceptual models on the one hand and the multiplicity of practical application of strategies to integrate care on the other.

Conclusions

Those looking for universal answers to narrow questions about whether integrated care “works” are likely to remain disappointed. Models of integrated care need to be valued for their heuristic rather than predictive powers, and integration understood as emerging from particular as well as common contexts.
Effect of hysterectomy on pain in women with endometriosis: a population‐based registry study
Authors: Sandström A , Bixo M , Johansson M , Bäckström T , Turkmen S
Published: May 2020

Objective

To assess pain symptoms before and after hysterectomy in women with endometriosis.

Design

A population‐based registry study.

Setting

Sweden.

Population

Women aged 18–45 years who underwent hysterectomy for endometriosis between 2010 and 2015.

Methods

Pain symptoms before hysterectomy and 12 months after surgery were collected from the Swedish National Quality Register for Gynaecological Surgery (GynOp). Pain symptoms were also assessed by follow‐up surveys after a median follow‐up period of 63 months.

Main outcome measures

Pelvic or lower abdominal pain after hysterectomy.

Results

The study included 137 women. The proportion of women experiencing pain of any severity decreased by 28% after hysterectomy (P < 0.001). The proportion of women with severe pain symptoms decreased by 76% after hysterectomy (P < 0.001). The majority of women (84%) were satisfied with the surgical result. Presence of severe pain symptoms after the hysterectomy was associated with less satisfaction (P < 0.001). Pain symptoms after surgery, patient satisfaction and the patient's perceived improvement were not significantly different between women whose ovarian tissue was preserved and women who underwent bilateral oophorectomy.

Conclusions

We observed a significant, long‐lasting reduction in pain symptoms after hysterectomy among women with endometriosis. Hysterectomy, with the possibility of ovarian preservation, may be a valuable option for women with endometriosis who suffer from severe pain symptoms.

Tweetable abstract

Hysterectomy is a valuable option for women with endometriosis and severe pain symptoms.
Early impact of the implementation of Medicaid episode‐based payment reforms in Arkansas
Authors: Toth Matt , Moore Paul , Tant Elizabeth , Rutledge Regina , Beil Heather , Arbes Sam , West Nathan , West Suzanne L.
Published: May 2020

Objective

To evaluate episode‐based payments for upper respiratory tract infections (URI) and perinatal care in Arkansas's Medicaid population.

Study Setting

Upper respiratory infection and perinatal episodes among Medicaid‐covered individuals in Arkansas and comparison states from fiscal year (FY) 2011 to 2014.

Study Design

Cross‐sectional observational analysis using a difference‐in‐difference design to examine outcomes associated with URI and perinatal episodes of care (EOC) from 2011 to 2014. Key dependent variables include antibiotic use, emergency department visits, physician visits, hospitalizations, readmission, and preventive screenings.

Data Collection

Claims data from the Medicaid Analytic Extract for Arkansas, Mississippi, and Missouri from 2010 to 2014 with supplemental county‐level data from the Area Health Resource File (AHRF).

Principal Findings

The URI EOC reduced the probability of antibiotic use (marginal effect [ME] = −1.8, 90% CI: −2.2, −1.4), physician visits (ME = 0.6, 90% CI: −0.8, −0.4), improved the probability of strep tests for children diagnosed with pharyngitis (ME = 9.4, 90% CI: 8.5, 10.3), but also increased the probability of an emergency department (ED) visit (ME = 0.1, 90% CI: 0.1, 0.2), relative to the comparison group. For perinatal EOCs, we found a reduced probability of an ED visit during pregnancy (ME = 0.1, 90% CI: −0.2, −0.0), an increased probability of screening for HIV (ME = 6.2, 90% CI: 4.0, 8.5), chlamydia (ME = 9.5, 90% CI: 7.2, 11.8), and group B strep‐test (ME = 2.6, 90% CI: 0.5, 4.6), relative to the comparison group. Predelivery and postpartum hospitalizations also increased (ME = 1.2, 90% CI: 0.4, 2.0; ME = 0.4, 90% CI: 0.0, 0.8, respectively), relative to the comparison group.

Conclusion

Upper respiratory infection and perinatal EOCs for Arkansas Medicaid beneficiaries produced mixed results. Aligning shared savings with quality metrics and cost‐thresholds may help achieve quality targets and disincentivize over utilization within the EOC, but may also have unintended consequences.
The impact of managerial discretion on fair value information in the Australian agricultural sector
Authors: He Liyu , Wright Sue , Evans Elaine
Published: May 2020

This study examines the application of fair value measurement for biological assets and how managers exercise their discretion over fair value measurement to achieve desired earnings outcomes. Using Australian data, we find that managers report larger agricultural gains when the earnings target is not met. This phenomenon is more prominent when managers are provided with higher levels of discretion. Boards of directors appear to understand this strategy and distinguish unrealised agricultural earnings from other earnings when compensating managers. However, boards do not appear to intervene in managers’ choices of fair value estimates.
Environmental Kuznets curve bibliographic map: a systematic literature review
Authors: Pincheira Roxana , Zuniga Felipe
Published: May 2020

This paper reviews the environmental Kuznets curve (EKC) literature, which postulates an inverted‐U association between pollutants and economic output, suggesting that economic growth initially leads to greater environmental deterioration at low levels of income, but that factors may eventually cause an improvement in environmental quality with further economic development. A systematic review was conducted using the bibliographic map method to identify the main research streams and to identify possible gaps and areas for future research. Six research streams were identified: testing the basic EKC equation, critique of EKC, determinants of EKC, review of EKC, a nexus of income–energy consumption and new environmental indicators.
Effect of structural stability on endolysosomal degradation and T‐cell reactivity of major shrimp allergen tropomyosin
Authors: Kamath Sandip D. , Scheiblhofer Sandra , Johnson Christopher M. , Machado Yoan , McLean Thomas , Taki Aya C. , Ramsland Paul A. , Iyer Swati , Joubert Isabella , Hofer Heidi , Wallner Michael , Thalhamer Josef , Rolland Jennifer , O’Hehir Robyn , Briza Peter , Ferreira Fatima , Weiss Richard , Lopata Andreas L.
Published: May 2020

Background

Tropomyosins are highly conserved proteins, an attribute that forms the molecular basis for their IgE antibody cross‐reactivity. Despite sequence similarities, their allergenicity varies greatly between ingested and inhaled invertebrate sources. In this study, we investigated the relationship between the structural stability of different tropomyosins, their endolysosomal degradation patterns, and T‐cell reactivity.

Methods

We investigated the differences between four tropomyosins—the major shrimp allergen Pen m 1 and the minor allergens Der p 10 (dust mite), Bla g 7 (cockroach), and Ani s 3 (fish parasite)—in terms of IgE binding, structural stability, endolysosomal degradation and subsequent peptide generation, and T‐cell cross‐reactivity in a BALB/c murine model.

Results

Tropomyosins displayed different melting temperatures, which did not correlate with amino acid sequence similarities. Endolysosomal degradation experiments demonstrated differential proteolytic digestion, as a function of thermal stability, generating different peptide repertoires. Pen m 1 (Tm 42°C) and Der p 10 (Tm 44°C) elicited similar patterns of endolysosomal degradation, but not Bla g 7 (Tm 63°C) or Ani s 3 (Tm 33°C). Pen m 1–specific T‐cell clones, with specificity for regions highly conserved in all four tropomyosins, proliferated weakly to Der p 10, but did not proliferate to Bla g 7 and Ani s 3, indicating lack of T‐cell epitope cross‐reactivity.

Conclusions

Tropomyosin T‐cell cross‐reactivity, unlike IgE cross‐reactivity, is dependent on structural stability rather than amino acid sequence similarity. These findings contribute to our understanding of cross‐sensitization among different invertebrates and design of suitable T‐cell peptide‐based immunotherapies for shrimp and related allergies.
Low testosterone levels predict clinical adverse outcomes in SARS‐CoV‐2 pneumonia patients
Authors: Rastrelli Giulia , Di Stasi Vincenza , Inglese Francesco , Beccaria Massimiliano , Garuti Martina , Di Costanzo Domenica , Spreafico Fabio , Greco Graziana Francesca , Cervi Giulia , Pecoriello Antonietta , Magini Angela , Todisco Tommaso , Cipriani Sarah , Maseroli Elisa , Corona Giovanni , Salonia Andrea , Lenzi Andrea , Maggi Mario , De Donno Giuseppe , Vignozzi Linda
Published: May 2020

Background

The pandemic of new severe acute respiratory syndrome (SARS) due to coronavirus (CoV) 2 (SARS‐CoV‐2) has stressed the importance of effective diagnostic and prognostic biomarkers of clinical worsening and mortality. Epidemiological data showing a differential impact of SARS‐CoV‐2 infection on women and men have suggested a potential role for testosterone (T) in determining gender disparity in the SARS‐CoV‐2 clinical outcomes.

Objectives

To estimate the association between T level and SARS‐CoV‐2 clinical outcomes (defined as conditions requiring transfer to higher or lower intensity of care or death) in a cohort of patients admitted in the respiratory intensive care unit (RICU).

Materials and methods

A consecutive series of 31 male patients affected by SARS‐CoV‐2 pneumonia and recovered in the respiratory intensive care unit (RICU) of the “Carlo Poma” Hospital in Mantua were analyzed. Several biochemical risk factors (ie, blood count and leukocyte formula, C‐reactive protein (CRP), procalcitonin (PCT), lactate dehydrogenase (LDH), ferritin, D‐dimer, fibrinogen, interleukin 6 (IL‐6)) as well as total testosterone (TT), calculated free T (cFT), sex hormone–binding globulin (SHBG), and luteinizing hormone (LH) were determined.

Results

Lower TT and cFT were found in the transferred to ICU/deceased in RICU group vs groups of patients transferred to IM or maintained in the RICU in stable condition. Both TT and cFT showed a negative significant correlation with biochemical risk factors (ie, the neutrophil count, LDH, and PCT) but a positive association with the lymphocyte count. Likewise, TT was also negatively associated with CRP and ferritin levels. A steep increase in both ICU transfer and mortality risk was observed in men with TT < 5 nmol/L or cFT < 100 pmol/L.

Discussion and conclusion

Our study demonstrates for the first time that lower baseline levels of TT and cFT levels predict poor prognosis and mortality in SARS‐CoV‐2‐infected men admitted to RICU.
Effect of platelet‐rich plasma on colon anastomosis in rats in which hyperthermic intra‐peritoneal chemotherapy was performed using 5‐fluorouracil
Authors: Göksu Mustafa , Alakuş Hüseyin , Ertan Siraç , Akgün Sadık
Published: May 2020

Background

Hyperthermic intra‐peritoneal chemotherapy (HIPEC) performed in patients with peritoneal carcinomatosis has a cytotoxic effect on tumour cells. This cytotoxic effect also adversely affects the wound healing of anastomosis, which is frequently undertaken in this patient group, and causes anastomotic leakage and intestinal fistulas. Platelet‐rich plasma (PRP) gel has been used in wound healing and has shown efficacy. We investigated the effect of PRP gel on colon anastomosis healing in rats treated with 5‐fluorouracil (5‐FU).

Methods

Twenty‐four rats were divided into three groups, each containing eight rats: group 1 (control) underwent colon anastomosis alone; group 2 (5‐FU) underwent a colon anastomosis and HIPEC; and group 3 (5‐FU + PRP) underwent a colon anastomosis and HIPEC and received topical PRP gel. The rats were sacrificed on the post‐operative day 7 and the anastomotic bursting pressure (ABP) was measured. Tissue samples were obtained to measure the hydroxyproline level and investigate the histopathological changes on the anastomosis line.

Results

ABP was higher in the control and 5‐FU + PRP groups than in the 5‐FU group (P = 0.009, P = 0.047). The tissue hydroxyproline levels were higher in the control and 5‐FU + PRP groups than in the 5‐FU group (P = 0.001, P = 0.030). The histopathological findings of the 5‐FU + PRP group were better than those of the 5‐FU group.

Conclusion

This study showed that the application of PRP gel to colon anastomoses increased ABP in rats treated with HIPEC using 5‐FU. It also showed positive effects on anastomotic healing by increasing the tissue hydroxyproline levels on the anastomosis line and reducing the inflammatory response.
Anti‐clogging mechanisms of a motion‐activated chest tube patency maintenance system: Histology and high‐speed camera assessment
Authors: Okano Shinji , Lobosky Mark , Dessoffy Raymond , Horvath David J. , Fukamachi Kiyotaka , Karimov Jamshid H.
Published: May 2020

The motion‐activated system (MAS) employs vibration to prevent intraluminal chest tube clogging. We evaluated the intraluminal clot formation inside chest tubes using high‐speed camera imaging and postexplant histology analysis of thrombus. The chest tube clogging was tested (MAS vs. control) in acute hemothorax porcine models (n = 5). The whole tubes with blood clots were fixed with formalin–acetic acid solution and cut into cross‐sections, proceeded for H&E‐stained paraffin‐embedded tissue sections (MAS sections, n = 11; control sections, n = 11), and analyzed. As a separate effort, a high‐speed camera (FASTCAM Mini AX200, 100‐mm Zeiss lens) was used to visualize the whole blood clogging pattern inside the chest tube cross‐sectional view. Histology revealed a thin string‐like fibrin deposition, which showed spiral eddy or aggregate within the blood clots in most sections of Group MAS, but not in those of the control group. Histology findings were compatible with high‐speed camera views. The high‐speed camera images showed a device‐specific intraluminal blood “swirling” pattern. Our findings suggest that a continuous spiral flow in blood within the chest tube (MAS vs. static control) contributes to the formation of a spiral string‐like fibrin network during consumption of coagulation factors. As a result, the spiral flow may prevent formation of thick band‐like fibrin deposits sticking to the inner tube surface and causing tube clogging, and thus may positively affect chest tube patency and drainage.
Children and young adults with anophthalmia and microphthalmia: Diagnosis and Management
Authors: Taha Najim Rezhna , Topa Alexandra , Jugård Ylva , Casslén Beatrice , Odersjö Marie , Andersson Grönlund Marita
Published: May 2020

Purpose

Congenital anophthalmia (A) and microphthalmia (M) are rare developmental defects, which could be isolated or syndromic. Our objective was to describe a cohort of children and young adults with A/M treated with ocular prosthesis, emphasizing clinical features, diagnosis, treatment, and follow‐up.

Methods

Eighteen individuals (10 female) with unilateral A (n = 3) and M (n = 15) with a mean age of 9.5 years (range 0.8–31.8) and treated with ocular prosthesis were included. Data on medical history, clinical examinations and management of ocular prosthesis were collected. Genetic screening with microarray and whole‐exome sequencing targeting 121 A/M‐related genes was performed.

Results

A/M appeared isolated (seven cases) or as part of a syndromic condition (11 cases). In 4/16 patients, mutations were detected in TFAP2A, CHD7, FOXE3 and BCOR‐genes. In one patient, a possibly causal microdeletion 10q11 was shown. Associated ocular anomalies such as cataract and cysts were found in 16 (89%) of the A/M eyes, and in nine (50%) ophthalmological findings were found in the fellow eyes. The median ages at which the conformer and ocular prosthesis first were initiated were 7.8 months and 1.5 years. 16/17 patients fulfilled satisfactory orbital growth and cosmetic results when treated with ocular prosthesis from an early age.

Conclusion

Based upon our findings, a multidisciplinary approach, including genetic assessment, is necessary to cover all aspects of A/M. Imaging, ultrasound and visual evoked potentials should be included. Early management is crucial for the outcome, in terms of non‐ocular findings, vision in the fellow eye, and for facial cosmetic development.
Application of electron microprobe analysis to identify the origin of ancient pottery production from the Castillo de Huarmey, Peru
Authors: Kałaska M. , Druc I. C. , Chyla J. , Pimentel R. , Syczewski M. , Siuda R. , Makowski K. , Giersz M.
Published: May 2020

A vast amount of ceramics (among other grave goods) were recovered from Castillo de Huarmey, a Wari culture (650–1050 ce) archaeological site on the north coast of Peru. In order to assess ceramic production area(s) and possible trade, political or cultural interactions with other regions, and to complement earlier petrographic analysis, electron microprobe analysis (EMPA) was conducted following a rarely used methodology in archaeology. The chemical composition of individual minerals in ceramics and sediments samples from the Huarmey Valley was obtained, focusing mainly on amphiboles, feldspars and pyroxenes. The results of the analyses clearly indicate that the majority of the ceramic analysed was made of raw material of local origin.
Development of prescribing safety indicators related to mental health disorders and medications: Modified e‐Delphi study
Authors: Khawagi Wael Y. , Steinke Douglas T. , Nguyen Joanne , Pontefract Sarah , Keers Richard N.
Published: May 2020

Aim

To develop a set of prescribing safety indicators related to mental health disorders and medications, and to estimate the risk of harm associated with each indicator.

Method

A modified two‐stage electronic Delphi. The first stage consisted of two rounds in which 31 experts rated their agreement with a set of 101 potential mental health related prescribing safety indicators using a five‐point scale and given the opportunity to suggest other indicators. Indicators that achieved 80% agreement were accepted. The second stage comprised a single round in which 29 members estimated the risk of harm for each accepted indicator by assessing the occurrence likelihood and outcome severity using two five‐point scales. Indicators were considered high or extreme risk when at least 80% of participants rated each indicator as high or extreme.

Results

Seventy‐five indicators were accepted in the first stage. Following the second stage, 42 (56%) were considered to be high or extreme risk for patient care. The 42 indicators comprised different types of hazardous prescribing, including drug‐disease interactions (n = 12), drug‐drug interactions (n = 9), inadequate monitoring (n = 5), inappropriate duration (n = 4), inappropriate dose (n = 4), omissions (n = 4), potentially inappropriate medications (n = 3) and polypharmacy (n = 1). These indicators also covered different mental health related medication classes, including antipsychotics (n = 14), mood stabilisers (n = 8), antidepressants (n = 6), sedative, hypnotics and anxiolytics (n = 6), anticholinergic (n = 6) and nonspecific psychotropics (n = 2).

Conclusion

This study has developed the first suite of prescribing safety indicators related to mental health disorders and medications, which could inform the development of future safety improvement initiatives and interventional studies.
Triage tool for the rationing of blood for massively bleeding patients during a severe national blood shortage: guidance from the National Blood Transfusion Committee
Authors: Doughty Heidi , Green Laura , Callum Jeannie , Murphy Michael F. ,   National Blood Transfusion Committee
Published: May 2020

The emerging COVID‐19 pandemic has overwhelmed healthcare resources worldwide, and for transfusion services this could potentially result in rapid imbalance between supply and demand due to a severe shortage of blood donors. This may result in insufficient blood components to meet every patient's needs resulting in difficult decisions about which patients with major bleeding do and do not receive active transfusion support. This document, which was prepared on behalf of the National Blood Transfusion Committee in England, provides a framework and triage tool to guide the allocation of blood for patients with massive haemorrhage during severe blood shortage. Its goal is to provide blood transfusions in an ethical, fair, and transparent way to ensure that the greatest number of life years are saved. It is based on an evidence‐ and ethics‐based Canadian framework, and would become operational where demand for blood greatly exceeds supply, and where all measures to manage supply and demand have been exhausted. The guidance complements existing national shortage plans for red cells and platelets.
Genotype–phenotype correlation in children with hereditary spherocytosis
Authors: Tole Soumitra , Dhir Priya , Pugi Jakob , Drury Luke J. , Butchart Sheila , Fantauzzi Michelle , Langer Jacob C. , Baker Jillian M. , Blanchette Victor S. , Kirby‐Allen Melanie , Carcao Manuel D.
Published: May 2020

Hereditary spherocytosis (HS) is a common inherited haemolytic anaemia attributed to disturbances in five different red cell membrane proteins. We performed a retrospective study of 166 children with HS and describe the clinical phenotype according to the genotype. In 160/166 (97%) children with HS a disease‐causing mutation was identified. Pathogenic variants in ANK1, SPTB, SLC4A1 and SPTA1 were found in 49%, 33%, 13% and 5% of patients. Children with SLC4A1‐HS had the mildest phenotype, showing the highest haemoglobin (P < 0·001), lowest reticulocyte counts (P < 0·001) and lowest unconjugated bilirubin levels (P = 0·006), and none required splenectomy in childhood (P < 0·001). Conversely, children with autosomal recessive SPTA1‐HS had the most severe clinical phenotype, with almost all patients undergoing splenectomy in early childhood. Patients with ANK1 and SPTB variants showed a similar clinical phenotype. Within each gene, variant type or location did not predict disease severity or likelihood of splenectomy. Among patients with a genetic diagnosis, 47 (29%) underwent splenectomy (23 partial; 24 total) while 57 (36%) underwent cholecystectomy. Total splenectomy led to greater improvements in haemoglobin (P = 0·02). Select use of genetic testing (especially in patients without a family history) may help predict clinical phenotype in childhood and guide family counselling.
Multiparametric MRI‐ultrasonography software fusion prostate biopsy: initial results using a stereotactic robotic‐assisted transperineal prostate biopsy platform comparing systematic vs targeted biopsy
Authors: Lee Alvin Y.M. , Yang Xin Yan , Lee Han Jie , Law Yan Mee , Huang Hong Hong , Lau Weber K.O. , Lee Lui Shiong , Ho Henry S.S. , Tay Kae Jack , Cheng Christopher W.S. , Yuen John S.P. , Chen Kenneth
Published: May 2020

Objective

To compare the detection rates of prostate cancer between systematic biopsy and targeted biopsy using a stereotactic robot‐assisted transperineal prostate platform.

Materials and Methods

We identified consecutive patients with suspicious lesion(s) on multiparametric magnetic resonance imaging (mpMRI), who underwent both systematic and MRI‐transrectal ultrasonography (US) fusion targeted biopsy using our proprietary transperineal robot‐assisted prostate biopsy platform between January 2015 and January 2019 at our institution, for retrospective analysis. Comparative analysis was performed between systematic and targeted biopsy using McNemar’s test, and the cohort was further stratified by prior biopsy status and Prostate Imaging Reporting and Data System (PI‐RADS) v2.0 score. International Society of Urological Pathology (ISUP) grade group (GG) ≥2 cancers (previously known as Gleason grade ≥7) were considered to be clinically significant.

Results

A total of 500 patients were included in our final analysis, of whom 67 (13%) were patients with low‐risk cancer on active surveillance. Of the 433 patients without prior diagnosis of cancer, 288 (67%) were biopsy‐naïve. A total of 248 (57%) were diagnosed with prostate cancer, with 199 (46%) having clinically significant prostate cancer (ISUP GG ≥2). There were no statistically significant differences in the overall prostate cancer and clinically significant prostate cancer detection rate between systematic and targeted biopsy (51% vs 49% and 40% vs 38% respectively; P = 0.306 and P = 0.609). Of the 248 prostate cancers detected, 75% (187/248) were detected on both systematic and targeted biopsy, 14% (35/248) were detected on systematic biopsy alone and 11% (26/248) were detected on targeted biopsy alone. Of the 199 clinically significant cancers detected, 69% (138/199) were detected on both systematic and targeted biopsy, 17% (33/199) on systematic biopsy alone and 14% (28/199) on targeted biopsy alone. There were no statistically significant differences in the detection rate between systematic and targeted biopsy for both overall and clinically significant prostate cancer, even when the cohort was stratified by prior biopsy status and PI‐RADS score. Targeted biopsy has greater sampling efficiency compared to systematic biopsy for both overall and clinically significant prostate cancer (23.2% vs 9.8%, P < 0.001 and 14.8% vs 5.6%, P < 0.001).

Conclusions

Using our robot‐assisted transperineal prostate platform, combined MRI‐US targeted biopsy with concurrent systematic prostate systematic biopsy probably represents the optimal method for the detection of clinically significant prostate cancer.
Transgenic LQT2, LQT5, and LQT2‐5 rabbit models with decreased repolarisation reserve for prediction of drug‐induced ventricular arrhythmias
Authors: Hornyik Tibor , Castiglione Alessandro , Franke Gerlind , Perez‐Feliz Stefanie , Major Péter , Hiripi László , Koren Gideon , Bősze Zsuzsanna , Varró András , Zehender Manfred , Brunner Michael , Bode Christoph , Baczkó István , Odening Katja E.
Published: May 2020

Background and Purpose

Reliable prediction of pro‐arrhythmic side effects of novel drug candidates is still a major challenge. Although drug‐induced pro‐arrhythmia occurs primarily in patients with pre‐existing repolarisation disturbances, healthy animals are employed for pro‐arrhythmia testing. To improve current safety screening, transgenic long QT (LQTS) rabbit models with impaired repolarisation reserve were generated by overexpressing loss‐of‐function mutations of human HERG (HERG‐G628S, loss of IKr; LQT2), KCNE1 (KCNE1‐G52R, decreased IKs; LQT5), or both transgenes (LQT2‐5) in the heart.

Experimental Approach

Effects of K+ channel blockers on cardiac repolarisation and arrhythmia susceptibility were assessed in healthy wild‐type (WT) and LQTS rabbits using in vivo ECG and ex vivo monophasic action potential and ECG recordings in Langendorff‐perfused hearts.

Key Results

LQTS models reflect patients with clinically “silent” (LQT5) or “manifest” (LQT2 and LQT2‐5) impairment in cardiac repolarisation reserve: they were more sensitive in detecting IKr‐blocking (LQT5) or IK1/IKs‐blocking (LQT2 and LQT2‐5) properties of drugs compared to healthy WT animals. Impaired QT‐shortening capacity at fast heart rates was observed due to disturbed IKs function in LQT5 and LQT2‐5. Importantly, LQTS models exhibited higher incidence, longer duration, and more malignant types of ex vivo arrhythmias than WT.

Conclusion and Implications

LQTS models represent patients with reduced repolarisation reserve due to different pathomechanisms. As they demonstrate increased sensitivity to different specific ion channel blockers (IKr blockade in LQT5 and IK1 and IKs blockade in LQT2 and LQT2‐5), their combined use could provide more reliable and more thorough prediction of (multichannel‐based) pro‐arrhythmic potential of novel drug candidates.
High glucose‐mediated PICALM and mTORC1 modulate processing of amyloid precursor protein via endosomal abnormalities
Authors: Chae Chang Woo , Lee Hyun Jik , Choi Gee Euhn , Jung Young Hyun , Kim Jun Sung , Lim Jae Ryong , Kim Seo Yihl , Hwang In Koo , Seong Je Kyung , Han Ho Jae
Published: May 2020

Background and Purpose

Although diabetes mellitus (DM) is an important risk factor for Alzheimer's disease (AD), the detailed mechanism(s) by which DM regulates amyloid β (Aβ) processing is still unclear. The longer residence time of amyloid precursor protein (APP) in endosomes is critical for Aβ production and DM is known to cause endosomal dysregulation. Here we have examined the effects of high glucose on APP‐producing endosomes and related signaling pathways.

Experimental Approach

To identify the underlying mechanisms, we investigated the effects of high glucose on abnormalities in early endosomes and related signalling pathways in human neuroblastoma cells. In vivo, diabetic mice treated with pharmacological inhibitors were used to examine endosomal dysfunction.

Key Results

The hippocampus of diabetic animals presented endosomal abnormalities and Aβ up‐regulation. High glucose increased Aβ production through early endosomal enlargement achieved by increased lipid raft‐mediated APP endocytosis. High glucose induced ROS‐stimulated Sp1 activation, up‐regulating phosphatidylinositol binding clathrin assembly protein (PICALM), clathrin heavy chain, and adaptor‐related protein complex 2 alpha 1. PICALM facilitated clathrin‐mediated APP endocytosis resulting in early endosomal enlargement. Meanwhile, AMPK/mTORC1‐mediated autophagy defect and ROS‐ and mTORC1‐mediated lysosomal dysfunction aggravated early endosomal enlargement under high glucose. Moreover, the increased Aβ production and cognitive deficits in diabetic mice were reversed by inhibition of early endosomal enlargement.

Conclusion and Implications

High glucose induces early endosomal abnormalities through PICALM‐induced APP endocytosis and mTORC1‐inhibited endosomal clearance, up‐regulating Aβ production. Thus, targeting PICALM and mTORC1 to prevent endosomal disorders is a promising strategy for managing diabetes‐induced AD.
Signalling, trafficking and glucoregulatory properties of glucagon‐like peptide‐1 receptor agonists exendin‐4 and lixisenatide
Authors: Pickford Philip , Lucey Maria , Fang Zijian , Bitsi Stavroula , de la Serna Jorge Bernardino , Broichhagen Johannes , Hodson David J. , Minnion James , Rutter Guy A. , Bloom Stephen R. , Tomas Alejandra , Jones Ben
Published: May 2020

Background and Purpose

Amino acid substitutions at the N‐termini of glucagon‐like peptide‐1 (GLP‐1) receptor agonist peptides result in distinct patterns of intracellular signalling, sub‐cellular trafficking and efficacy in vivo. Here, we to determine whether sequence differences at the ligand C‐termini of clinically approved GLP‐1 receptor agonists exendin‐4 and lixisenatide lead to similar phenomena.

Experimental Approach

Exendin‐4, lixisenatide and N‐terminally substituted analogues with biased signalling characteristics were compared across a range of in vitro trafficking and signalling assays in different cell types. Fluorescent ligands and new time‐resolved FRET approaches were developed to study agonist behaviours at the cellular and sub‐cellular level. Anti‐hyperglycaemic and anorectic effects of each parent ligand and their biased derivatives were assessed in mice.

Key Results

Lixisenatide and exendin‐4 showed equal binding affinity, but lixisenatide was fivefold less potent for cAMP signalling. Both peptides induced extensive GLP‐1 receptor clustering in the plasma membrane and were rapidly endocytosed, but the GLP‐1 receptor recycled more slowly to the cell surface after lixisenatide treatment. These combined deficits resulted in reduced maximal sustained insulin secretion and reduced anti‐hyperglycaemic and anorectic effects in mice with lixisenatide. N‐terminal substitution of His1 by Phe1 to both ligands had favourable effects on their pharmacology, resulting in improved insulin release and lowering of blood glucose.

Conclusion and Implications

Changes to the C‐terminus of exendin‐4 affect signalling potency and GLP‐1 receptor trafficking via mechanisms unrelated to GLP‐1 receptor occupancy. These differences were associated with changes in their ability to control blood glucose and therefore may be therapeutically relevant.
Heterogeneous expression of GABA receptor‐like subunits LCCH3 and GRD reveals functional diversity of GABA receptors in the honeybee Apis mellifera
Authors: Henry Christopher , Cens Thierry , Charnet Pierre , Cohen‐Solal Catherine , Collet Claude , van‐Dijk Juliette , Guiramand Janique , de Jésus‐Ferreira Marie‐céleste , Menard Claudine , Mokrane Nawfel , Roussel Julien , Thibaud Jean‐Baptiste , Vignes Michel , Rousset Matthieu
Published: May 2020

Background and Purpose

Despite a growing awareness, annual losses of honeybee colonies worldwide continue to reach threatening levels for food safety and global biodiversity. Among the biotic and abiotic stresses probably responsible for these losses, pesticides, including those targeting ionotropic GABA receptors, are one of the major drivers. Most insect genomes include the ionotropic GABA receptor subunit gene, Rdl, and two GABA‐like receptor subunit genes, Lcch3 and Grd. Most studies have focused on Rdl which forms homomeric GABA‐gated chloride channels, and a complete analysis of all possible molecular combinations of GABA receptors is still lacking.

Experimental Approach

We cloned the Rdl, Grd, and Lcch3 genes of Apis mellifera and systematically characterized the resulting GABA receptors expressed in Xenopus oocytes, using electrophysiological assays, fluorescence microscopy and co‐immunoprecipitation techniques.

Key Results

The cloned subunits interacted with each other, forming GABA‐gated heteromeric channels with particular properties. Strikingly, these heteromers were always more sensitive than AmRDL homomer to all the pharmacological agents tested. In particular, when expressed together, Grd and Lcch3 form a non‐selective cationic channel that opens at low concentrations of GABA and with sensitivity to insecticides similar to that of homomeric Rdl channels.

Conclusion and Implications

For off‐target species like the honeybee, chronic sublethal exposure to insecticides constitutes a major threat. At these concentration ranges, homomeric RDL receptors may not be the most pertinent target to study and other ionotropic GABA receptor subtypes should be considered in order to understand more fully the molecular mechanisms of sublethal toxicity to insecticides.
Preparing for attack and recovering from battle: Understanding child sexual abuse survivors' experiences of dental treatment
Authors: Fredriksen Therese Varvin , Søftestad Siri , Kranstad Vibeke , Willumsen Tiril
Published: May 2020

Objective

The aim of this paper was to explore child sexually abused survivors' experiences of dental treatment in order to obtain a deeper understanding of them as dental patients.

Methods

Data were drawn from qualitative semi‐structured interviews with 16 adult informants recruited from four different Centres against Sexual Abuse in Norway. Data analysis was developed according to the principles of grounded theory suggested by Charmaz.

Results

A conceptual framework was generated, and a core concept was constructed from the informants' reports of their experiences of dental treatment: Preparing for attack and recovering from battle based on four main categories: (a) Expecting danger, (b) Battling anxiety, (c) Reliving abuse and (d) Struggling with the aftermath.

Conclusions

The analyses increase the understanding of how child sexual abuse survivors prepare before—battle during—and recover after dental treatment. This study revealed child sexual abuse survivors' experiences of extensive anxiety, triggered by sensory stimuli such as sensations, movement, muscles, touch, sight, sound, smell and taste, associated with dental procedures per se, but also sensory stimuli similar to previous traumatic experiences. The findings suggest that child sexual abuse survivors' dental anxiety is primarily trauma‐driven and possibly being one of the long‐term effects of child sexual abuse. This may be an important contribution to the understanding of CSA survivors and should affect the approach of clinicians treating dental patients with such a history.
Caesarean delivery and the risk of atopic dermatitis in children
Authors: Richards Megan , Ferber Jeannette , Chen Hong , Swor Erin , Quesenberry Charles P. , Li De‐Kun , Darrow Lyndsey A.
Published: May 2020

Background

Caesarean delivery (C‐section) may disrupt maternal‐infant microbial transfer and alter immune system development and subsequent risk for atopic dermatitis.

Objective

Investigate the association between C‐section and atopic dermatitis by age four and examine potential sources of bias in the relationship in a large cohort study.

Methods

Maternal and child information was collected through Kaiser Permanente Northern California's (KPNC) integrated healthcare system. Data sources included electronic medical records, pharmacy databases, state birth records, and prospectively collected breastfeeding surveys. Children were eligible if they were born in a KPNC or contracting hospital between 2005 and 2014 and had continuous enrolment in the KPNC system for at least four years (n = 173 105). Modified Poisson regression with robust variance estimation was used to estimate the association between C‐section and atopic dermatitis overall and when stratified by demographic and labour and delivery characteristics.

Results

Although unadjusted analyses showed a positive association between C‐section and atopic dermatitis [RR(95%CI): 1.06(1.03, 1.10)], this effect was attenuated towards the null after adjustment [aRR(95%CI): 1.02(0.99, 1.05)]. In stratified analyses, there was evidence that C‐section increased atopic dermatitis risk among certain subgroups (eg firstborns, overweight/obese pre‐pregnancy BMI), but associations were weak. C‐section delivery conditions indicative of the least exposure to maternal microbiome (ie no labour, short interval between membrane rupture and delivery) showed no evidence of association with atopic dermatitis. Estimated associations were not strongly influenced by intrapartum antibiotics, breastfeeding, missing data, or familial factors.

Conclusion

Caesarean delivery was not associated with atopic dermatitis by age four in this large US cohort. This association did not appear to be biased by intrapartum antibiotics, breastfeeding behaviour, C‐section indication, missing covariates, or familial factors.
Application of autologous SOX9+ airway basal cells in patients with bronchiectasis
Authors: Sun Fengjun , Cheng Lin , Guo Haiqing , Sun Yufen , Ma Yu , Wang Yu , Feng Wei , Yuan Qian , Dai Xiaotian
Published: May 2020

Introduction

Bronchiectasis is a common condition and a leading cause of respiratory morbidity and mortality. The treatment method for bronchiectasis is mainly symptomatic treatment or surgery; however, this condition is extremely prone to recurrence.

Objectives

To preliminarily evaluate the safety and efficacy of applying SOX9+ autologous airway basal cells (BCs) in patients with bronchiectasis.

Methods

SOX9+ BCs were isolated from microscale tissue of a grade 3‐5 bronchus by bronchoscopic brushing and expanded in vitro for approximately 4 weeks. Subsequently, the autologous SOX9+ BCs were transplanted into the diseased bronchus to treat patients with bronchiectasis.

Results

The forced expiratory volume in1 second (FEV1)%, forced vital capacity (FVC)%, total lung capacity (TLC)%, residual volume (RV)% and RV/TLC ratio of predicted value in patients with bronchiectasis were improved at 4, 12, 24 and 48 weeks after cell transplantation, although the differences were not statistically significant (P > .05). Chest CT scans showed that the lesions in the pulmonary segment had not progressed at 4, 12 and 24 weeks after transplantation. No patients died during the follow‐up. At 4, 12 and 24 weeks after transplantation, routine blood tests, liver function tests, renal function tests and myocardial enzymatic indexes were normal (P > .05).

Conclusion

Transplantation of autologous SOX9+ BCs has positive effects and is safe for patients with bronchiectasis.
Relationship between colonic diverticulosis and colon neoplasms in Japanese patients
Authors: Nakahara Ryotaro , Amano Yuji , Murakami Daisuke , Ogawa Sayaka , Ujihara Tetsuro , Iwaki Tomoyuki , Katsuyama Yasushi , Hayasaka Kenji , Harada Hideaki , Tada Yasumasa , Yuki Takafumi , Miyaoka Youichi , Kushiyama Yoshinori , Fujishiro Hirofumi , Ishihara Shunji
Published: May 2020

Background and Aim

Colonic diverticulosis (CD) has been reported to be associated with presence of colon neoplasms (CNs) in Western patients, since most of the associated risk factors are common between them. However, such correlation has not been fully investigated in Asian patients. In this study, the association of CNs with CD was evaluated in a multicenter investigation.

Methods

We enrolled 5633 patients who underwent both colonoscopy and esophagogastroduodenoscopy due to annual follow‐up, screening for positive occult blood testing and abdominal symptoms between January 2016 and December 2017 at three institutions. The relationship between the presence of CNs and CD was investigated, and predictors for presence of CNs were determined by multivariate logistic analysis.

Results

The enrolled patients consisted of 1799 (31.9%) with CD (average age 70.0 years, male 64.0%) and 3834 without CD (66.0 years, male 52.9%), with the prevalence of CNs in those groups 46.6% and 44.2%, respectively (P = 0.090). Predictors for early colon cancer were shown to be age (OR 1.02, 95% CI 1.01–1.04, P = 0.010), laxatives use (OR 1.76, 95% CI 1.17–2.64, P = 0.007), gastric neoplasms (OR 2.16, 95% CI 1.23–3.81, P = 0.008), and CD (OR 1.64, 95% CI 1.16–2.31, P = 0.005). Early colon cancer in the distal colon was most frequently detected in patients with right‐sided CD (RR 2.50, P = 0.001).

Conclusion

In Japanese patients, early colon cancer was more frequently found in those with as compared to those without CD. The presence of CD may be an important indicator for an index colonoscopy examination to detect colon cancer. (Clinical‐trial‐registry: UMIN000038985).