bluuebunny/crossref_metadata_2025_split huggingface dataset:
Preoperative PD1 checkpoint blockade and receptor activator of NFkB ligand (RANKL) inhibition in non-small cell lung cancer (NSCLC) (POPCORN).
Authors: Ahern Elizabeth Stephanie , Cubitt Annette , Ballard Emma , Teng Michele W.L. , Dougall William C. , Smyth Mark J. , Hughes Brett Gordon Maxwell 
Published: July 2019

TPS129 Background: Preclinical studies indicate Receptor Activator of NF-κB Ligand (RANKL) blockade improves anti-tumor efficacy of immune checkpoint blockade (ICB). Clinical trials combining denosumab (anti-RANKL mAb) with ICB are underway in various cancers although the hypothesized mechanism of action of such combinations remains incomplete. RANKL and its receptor, RANK, are frequently expressed in NSCLC (tumor and immune cells). Denosumab demonstrated survival advantage over bisphosphonate in metastatic NSCLC (mNSCLC) to bone; a recent retrospective case series suggests a relationship between concurrent ICB and denosumab duration and survival in mNSCLC. Neoadjuvant nivolumab recently showed encouraging pathologic response rates in resectable NSCLC; neoadjuvant trials lend themselves to translational research. Methods: POPCORN is a multicenter phase 1b/2 study to determine the mechanism of action, activity and safety of neoadjuvant nivolumab plus denosumab versus nivolumab alone. 30 patients with resectable stage 1A (tumor > 2cm) – 3A NSCLC will be randomized 1:1 to two arms (Table). Exclusion criteria include uncontrolled autoimmune disease, steroid contraindications, and unhealed dental disease. Tumor tissue at baseline, surgery and relapse, and peripheral blood at various timepoints (including on-therapy) will be collected. The primary endpoint is to define pharmacodynamic correlates of the two arms through investigations including T-cell receptor clonality, RNA/transcription profile changes (tumor and peripheral blood), and expression of tumor/immune markers of interest via multiplex immunohistochemistry, compared between groups. Secondary endpoints include pathologic response rates, toxicity, R0 resection, and PFS/OS (exploratory). Statistical analysis will be primarily descriptive on the intention-to-treat population. The trial is sponsored by Metro North Hospital and Health Service (Queensland, Australia) with funding from AMGEN, Inc. Clinical trial information: ACTRN12618001121257. [Table: see text]
A pilot study of pembrolizumab in combination with decitabine and hypofractionated index lesion radiation in pediatric and young adult patients with relapsed and refractory solid tumors or lymphoma.
Authors: Turpin Brian , Vatner Ralph 
Published: July 2019

TPS25 Background: A potential limitation to the use of immune checkpoint inhibitors in younger patients with immune-resistant histologies is related to low tumor associated antigen expression and an immunosuppressive microenvironment. Low dose decitabine, as an inhibitor of DNA methyltransferase, can unrepress immunogenic cancer testes antigen expression, while hypofractionated radiation promotes infiltration of immune effector cells, stimulation of toll-like receptors on dendritic cells, and induction of type I interferons and other cytokines. As induced PD-L1 expression may also result, we hypothesize that decitabine, radiation, and the PD-1 inhibitor, pembrolizumab, will be synergistic. Here, we aim to verify the safety and preliminary activity of the combination. Correlative studies include an investigation of changes in antigen expression, the kinetics of immune effector and regulatory cell phenotype and function, and microbiome. Methods: Treatment program: Every 28 day cycle, patients receive 10 mg/m2 IV decitabine on days 1-5 and 2 mg/m2 (max dose 200 mg) IV pembrolizumab on day 8. Hypofractionated radiation (8 Gy x 3) to one or more lesion(s) is given on days 5-7 of the second cycle only. Adult patients may consent to optional biopsy of an irradiated lesion. Beyond cycle 3, patients may undergo elective surgery of one or more lesions. Patients remain on therapy for 27 cycles, absent progression by irRECIST or unacceptable toxicity. Patient eligibility: Patients 12 months to 40 years with available archived tissue may be considered, and must have adequate organ function including an absolute neutrophil count ≥ 750/mm3 and platelet count ≥ 75,000/mm3. Patients may have stable central nervous system metastases. Patients previously treated with radiotherapy may be eligible. Patients previously treated with PD-1 inhibitor therapy may be eligible, unless treated for an immune related adverse event. Current enrollment: This trial has been open to enrollment since February of 2018. No dose limiting toxicities have been observed in 2 patients evaluable for toxicity. Clinical trial information: NCT03445858.
Genetic Deletion of Esr1 in the Mouse Preoptic Area Disrupts the LH Surge and Estrous Cyclicity
Authors: Porteous Robert , Herbison Allan E 
Published: July 2019

Abstract
Estrogen receptor α (ESR1) is critical for the generation of the preovulatory LH surge. Experiments in rodents have indicated a role for neurons located in the anteroventral periventricular area and preoptic periventricular nucleus [termed the rostral periventricular area of the third ventricle (RP3V)] in surge generation. In the current study, we aimed to examine whether ESR1 expressed by RP3V neurons was necessary for the LH surge. The estrous cycles of mice with estrogen receptor α (Esr1) exon 3 flanked by LoxP sites (Esr1 flox) and controls were monitored before and after bilateral stereotactic injection of adeno-associated virus encoding Cre recombinase into the RP3V. This resulted in 84% and 72% decreases in ESR1-immunoreactive cell numbers in the anteroventral periventricular area and preoptic periventricular nucleus, respectively, with no changes in the arcuate nucleus. Beginning three weeks after the adeno-associated virus injection, Esr1 flox mice began to show a loss of estrous cyclicity going, primarily, into constant estrus. Wild-type mice and Esr1 flox mice with injections outside the RP3V or unilateral ablations of ESR1 continued to exhibit normal estrous cycles. Mice were then gonadectomized and given an estradiol replacement regimen to generate the LH surge. This resulted in an absence of cFOS expression in GnRH neurons (1 ± 1% vs 28 ± 4% of GnRH neurons; P < 0.01) and markedly reduced LH surge levels (2.5 ± 0.6 vs 9.1 ± 1.0 ng/mL; P < 0.01) in Esr1 flox mice compared with controls. These results demonstrate that neurons expressing ESR1 within the RP3V are critical for the generation of the LH surge and estrous cyclicity in the mouse.
Hydroxylated long-chain acylcarnitines are biomarkers of mitochondrial myopathy
Authors: Vissing Christoffer Rasmus , Duno Morten , Wibrand Flemming , Christensen Mette , Vissing John 
Published: July 2019

Abstract

Context
Plasma acylcarnitines are biomarkers of beta-oxidation and are useful in diagnosing several inborn errors of metabolism but has never been systematically investigated in patients with mitochondrial myopathy.

Objective
We hypothesized that acylcarnitines can also be biomarkers of mitochondrial myopathy and sought to investigate the prevalence and pattern of elevated acylcarnitines.

Design
The study was a prospective cohort study of patients with confirmed mitochondrial myopathy followed at Copenhagen Neuromuscular Center, Rigshospitalet, Copenhagen, Denmark

Patients
We included 35 patients (44±15 years, 15 women) with mitochondrial myopathy caused by single, large-scale deletions of mt-DNA (n=17), pathogenic variants in mt-tRNA (n=13) or in proteins of the respiratory chain complexes (n=5).
Concentrations of 35 acylcarnitines were measured using ultra-high-performance liquid-chromatography and tandem mass-spectrometry. Findings were compared to muscle mutation load in all patients, and to respiratory chain activity in 26 patients.

Main outcome measures
Prevalence of elevated concentrations of acylcarnitines related to acyl-CoA dehydrogenases in patients with mitochondrial myopathy and relation to geno-/phenotypes.

Results
In total, 27 (77%) patients had elevated concentrations of acylcarnitines related to acyl-CoA dehydrogenases. Elevated concentrations of seven acylcarnitine species were significantly more common in patients compared to a control cohort of> 900 individuals, and a specific pattern involving hydroxylated long-chain acylcarnitines occurred in 22 (63%) patients. Severity of derangements was correlated with muscle mutation load and geno-/phenotypes.

Conclusion
In conclusion, elevated concentrations of acylcarnitines is common in patients with mitochondrial myopathy and shows a specific pattern affecting hydroxylated long-chain acylcarnitines, which can have implications for future diagnostic work-up of patients.
A Question of Personal Status
Authors: Hyndman-Rizk Nelia 
Published: July 2019

Abstract
Amid an enduring political deadlock in Parliament, the first civil marriage contracted in Lebanon in 2013 received significant media coverage in a country where the personal status law of eighteen recognized religious sects governs marriage. This case study examines the debate on civil marriage reform and the implications for women’s rights in Lebanon. For advocates, the recognition of civil marriage legalizes interreligious marriages, strengthens secular citizenship, shifts the jurisdiction of marriage from religious to civil law, and ensures women’s rights. Opponents, meanwhile, fear the loss of religious autonomy, the transformation of self-identification in Lebanon from sect to nation, and the destabilization of the confessional system. To date, civil marriage reform has been incremental, given clerical and social opposition, but the winds of change are blowing as couples increasingly take matters into their own hands to reform Lebanon’s system of personal status from the ground up.
Improving the Diagnosis of Nonfunctional Overreaching and Overtraining Syndrome
Authors: BUYSE LUK , DECROIX LIESELOT , TIMMERMANS NIELS , BARBÉ KURT , VERRELST RUTH , MEEUSEN ROMAIN 
Published: July 2019

ABSTRACT

Introduction
This study aimed to simplify and optimize the distinction between nonfunctional overreaching (NFO) and overtraining syndrome (OTS) by developing a multivariate approach (discriminant analysis [DA]) including hormonal and psychological changes measured during the Training Optimization (TOP) test.

Methods
Sensitivity of previously defined cutoff values for hypothalamic–pituitary–adrenal axis hormonal changes were recalculated on a larger database (n = 100). Discriminant analysis including hormonal and psychological variables measured during the TOP test was used to discriminate between NFO and OTS and predict the diagnosis of new cases.

Results
Adrenocorticotrophic hormone (ACTH) and prolactin (PRL) responses to the second exercise test were most sensitive to NFO and OTS. Cutoff values for ACTH and PRL response to the second test (NFO > cutoff value (200%) > OTS), showed a sensitivity of 67% for ACTH and 93% for PRL in case of OTS and 74% for both ACTH and PRL in case of NFO. A DA including hormonal and psychological changes measured during the TOP test, resulted in the accurate diagnosis of NFO and OTS with 98% sensitivity. The ACTH and PRL responses to the first and second exercise tests and feeling of fatigue were the most discriminating variables.

Conclusions
The ACTH and PRL responses during the TOP test are the most sensitive markers to discriminate between NFO and OTS. Discriminant analysis including hormonal and psychological responses during the TOP test, can be used to optimize the diagnosis of NFO and OTS.
Stratification of chronic and complex wounds according to healing characteristics: a retrospective study
Authors: Spruijt Nicole E. , Hoogbergen Maarten M. , Buijs Servaas J.E. , Grosveld Marcel J.W. , Buth Jaap 
Published: July 2019

Objective: Wound risk-stratified analyses are clinically relevant as they can assist in identifying hard-to-heal wounds. The aim of the study is to develop risk categories for wound healing based on a limited number of reliably recordable clinical data. Method: This retrospective study used observational data. The primary outcome measure was wound healing at the end of treatment and the secondary outcome measure was the time to wound healing. A stratification model using regression analyses was developed to assign the patients to risk categories for wound healing and the time-to-heal. Results: The study cohort comprised of 540 patients. The most common wound diagnoses were diabetic ulcers, wounds in irradiated areas and wound dehiscence after surgery. Average wound duration before starting treatment at the wound centre was 11.7 months. Healing was achieved in 382 (71%) wounds, after an average treatment time of 4.4 months. A total of four risk categories for wound healing were developed by combining wound diagnosis (favourable versus unfavourable) and duration (<3 months versus >3 months). These risk categories demonstrated healing percentages ranging from 69–97% (p=0.0004) and mean time-to-healing varying from 2.7–5.9 months (p=0.01). Conclusion: Using two clinical wound variables, diagnosis and duration, stratification categories were identified with significant associations with wound healing outcomes. Longer wound duration and unfavourable diagnoses, when combined into unfavourable risk categories, were associated with a lower percentage of wound healing and a longer treatment time until healing.
Hyaluronic acid and metallic silver treatment of chronic wounds: healing rate and bacterial load control
Authors: Gazzabin Luca , Serantoni Simone , Palumbo Francesco Paolo , Giordan Nicola 
Published: July 2019

Objective: To confirm the safety and wound healing activity of a topical spray powder containing hyaluronic acid (HA) and metallic silver (Hyalosilver, Fidia Farmaceutici S.p.A., Italy), and investigate its effect on the control of bacterial load in vascular ulcers or category I-II pressure ulcers (PU). Methods: This is a single site, prospective, open label study involving patients with a vascular ulcer or category I-II PUs, presenting signs of critical bacterial colonisation. Patients with a wound size of ≤15cm2 were enrolled. At baseline, a swab was taken of each wound for a semi-quantitative analysis of bacterial load and the first treatment of topical spray powder was applied. The patient was then requested to self-apply the medication once a day for 28 consecutive days and to return on days one, seven and 28 for clinical and microbiological assessments. Results: A total of 25 patients were enrolled in the study. Treatment with the topical spray powder enhanced the healing rate of chronic wounds in terms of a reduction of wound area as well as bacterial load (p<0.025) and the overall clinical status of wound (odour, exudate, erythema of periwound skin; p<0.017). Moreover, the spray powder increased overall patient perception of improvement in the wound (p<0.05). Conclusion: The data demonstrated good safety and tolerability of the topical spray powder suggesting that the product is effective not only in reducing wound area, due to the presence of HA, but in keeping the bacterial colonisation under control.
Health professionals' perspectives on delivering patient-focused wound management: a qualitative study
Authors: Kuhnke Janet L. , Keast David , Rosenthal Sue , Evans Robyn Jones 
Published: July 2019

Objective: This study examined the perspectives of health professionals on the barriers and solutions to delivery of patient-focused wound management and outcomes. Methods: A qualitative, descriptive study design was used. Participants were health-care managers, clinical leaders, nurses and allied health members who are part of wound care services. Open-ended surveys were distributed to participants in a series of learning workshops, and data analysed to identify leading themes. Results: A total of 261 participants took part and 194 surveys were returned (response rate: 74%). From the analysis five themes emerged: patient/family wound-related education; health professional wound-related education; implementation of evidence-based wound care and dissemination of evidence-based wound information across professions and contexts; teamwork and respectful communication within teams; and a higher value and priority placed on wound care through collaborative teams by managers, leaders and policymakers. Conclusion: Findings suggest that ongoing, system-wide education is needed to improve prevention, assessment, treatment and management of four wound types: venous leg ulcer (VLU), diabetic foot ulcer (DFU), pressure ulcer (PU) and surgical wounds. Health professionals are committed to delivering best practice in wound care. Participants identified that effective patient-focused, evidence-based wound care involves having a health-care system with a clear mandate to ensure wound care is a priority. A high value placed on wound care by managers and clinical leadership could transform the present systems. Additionally, effective and widespread dissemination of evidenced-informed practice information is crucial to positive patient outcomes. Education and team commitment for consistent and respectful communication would improve care delivery.
Book Reviews
Authors: Zehelein Eva-Sabine , Havlin Tetiana 
Published: July 2019

Random Families: Genetic Strangers, Sperm Donor Siblings, and the Creation of New Kin, Rosanna Hertz and Margaret K. Nelson (2019) 1st ed., New York: Oxford University Press, 296 pp., ISBN 978-0-19088-827-5, h/bk, $27.95; ISBN 978-0-19088-829-9, e/bk, $17.00
Connecting Families? Information & Communication Technologies, Generations, and the Life Course, Barbara Barbosa Neves and Cláudia Casimiro (eds) (2018) Bristol: Policy Press, 324 pp., ISBN 978-1-44733-994-6, h/bk, £60
Prucalopride in Gastroparesis: A Randomized Placebo-Controlled Crossover Study
Authors: Carbone Florencia , Van den Houte Karen , Clevers Egbert , Andrews Christopher N. , Papathanasopoulos Athanassos , Holvoet Lieselot , Van Oudenhove Lukas , Caenepeel Philip , Arts Joris , Vanuytsel Tim , Tack Jan 
Published: July 2019

OBJECTIVES:
Prokinetics are considered the preferred treatment option for gastroparesis, but evidence of their efficacy is scarce. Prucalopride, a selective 5-hydroxytryptamine 4 receptor agonist used in the treatment of constipation, is able to enhance the gastric emptying rate. In a double-blind, randomized, placebo-controlled crossover study, we evaluated the efficacy of prucalopride to improve the gastric emptying rate and symptoms in patients with gastroparesis.

METHODS:
Thirty-four patients with gastroparesis (28 idiopathic, 7 men, mean age 42 ± 13 years) were evaluated in a double-blind crossover trial of 4-week treatment periods with placebo or prucalopride 2 mg q.d., separated by 2 weeks of washout. The primary end point was the change in symptom severity, assessed by the Gastroparesis Cardinal Symptom Index; secondary end points comprised the Patient Assessment of Upper Gastrointestinal Disorders–Symptom Severity Index, the Patient Assessment of Upper Gastrointestinal Disorders–Quality of Life, and daily diaries, and the gastric emptying rate was assessed by the 13C-octanoic acid breath test.

RESULTS:
Three patients were lost to follow-up. One serious adverse event occurred (small bowel volvulus in the prucalopride group), and 3 patients dropped out because of adverse events of nausea and headache (all prucalopride). For the entire patient group, compared with placebo, prucalopride significantly improved the total Gastroparesis Cardinal Symptom Index (1.65 ± 0.19 vs 2.28 ± 0.20, P < 0.0001) and the subscales of fullness/satiety, nausea/vomiting, and bloating/distention. Prucalopride significantly improved the overall Patient Assessment of Upper Gastrointestinal Disorders–Quality of Life score (1.15 ± 0.16 vs 1.44 ± 0.16, P < 0.05) and the domains of clothing and diet. The gastric half emptying time was significantly enhanced by prucalopride compared with placebo and baseline (98 ± 10 vs 143 ± 11 and 126 ± 13 minutes, P = 0.005 and <0.001, respectively). These significant improvements were also found when considering only the idiopathic gastroparesis subgroup.

DISCUSSION:
In a cohort of patients with predominantly idiopathic gastroparesis, 4 weeks of prucalopride treatment significantly improved symptoms and quality of life and enhanced gastric emptying compared with placebo.
Kemandirian masyarakat desa wisata dalam perspektif community based tourism: Studi kasus Desa Ketengger, Kabupaten Banyumas
Authors: Marlina Neny 
Published: July 2019

Pengembangan pariwisata adalah salah satu dari tiga sektor utama pembangunan di Indonesia, selain pertanian dan perikanan. Tidak hanya bergantung pada bantuan pemerintah, pengembangan bisnis pariwisata juga membutuhkan peran aktif masyarakat setempat. Hal ini bertujuan untuk mengeksplorasi potensi industri pariwisata dan untuk melestarikan sejarah lokal serta keberadaan warisan budaya. Adapun tulisan ini akan menggunakan pendekatan Community Based Tourism (CBT) untuk melihat eksistensi Desa Wisata Ketengger Kabupaten Banyumas. Dalam pendekatan ini, komunitas dilihat bukan sekadar sebagai objek pengembangan pariwisata, tetapi juga sebagai subjek dalam perumusan dan pelaksanaan kegiatan pengembangan pariwisata di desa. Dengan menerapkan manajemen pariwisata berbasis CBT, maka partisipasi masyarakat Desa Wisata Ketenger dalam pengembangan desanya bisa berjalan baik. Hasil dari penerapan CBT di Desa Ketengger adalah terjadi peningkatan keahlian dan kesadaran akan kepariwisataan, yang kemudian secara tidak langsung ikut meningkatkan jumlah wisatawan yang berkunjung dan menaikan jumlah PADes setempat.
Preliminary evaluation of a new flow cytometry method for the routine hematology workflow
Authors: Seghezzi Michela , Moioli Valentina , Previtali Giulia , Manenti Barbara , Lopez Ramon-Simon , Kono Mari , Tirloni Ezio , Alessio Maria Grazia , Buoro Sabrina 
Published: July 2019

Abstract

Background
In a generalist laboratory, the integration of the data obtained from hematology analyzers (HAs) with those from multiparametric flow cytometry (FMC) could increase the specificity and sensitivity of first level screening to identify the pathological samples. The aim of this study was to perform a preliminary evaluation of a new simple hybrid method (HM). The method was obtained by integration between HAs reagents into FCM, with a basic monoclonal antibodies panel for the leukocytes differential count.

Methods
Eighty-one peripheral blood samples, collected in K3EDTA tubes, were analyzed by XN-module, and CyFlow Space System, using both standard MoAbs and HM method analysis, and with the optical microscopy (OM). Within-run imprecision was carried out using normal samples, the carryover was evaluated, data comparison was performed with Passing-Bablok regression and Bland-Altman plots.

Results
The within-run imprecision of HM methods ranged between 1.4% for neutrophils (NE) and 10.1% for monocytes (MO) always equal or lower to the OM. The comparison between HM methods vs. OM shows Passing-Bablok regression slopes comprised between 0.83 for lymphocyte (LY) and 1.14 for MO, whilst the intercepts ranged between −0.18 for NE and 0.25 for LY. Bland-Altman relative bias was comprised between −12.43% for NE, and 19.77% for eosinophils. In all 11 pathological samples the agreement between the methods was 100%.

Conclusions
The new hybrid method generates a leukocytes differential count suitable for routine clinical use and it is also useful for identifying morphological abnormalities with a reduction in cost and improvement of screening for first level hematology workflow.