bluuebunny/crossref_metadata_2025_split huggingface dataset:
Risk of long-term benzodiazepine and Z-drug use following the first prescription among community-dwelling adults with anxiety/mood and sleep disorders: a retrospective cohort study
Authors: Brandt Jaden , Janzen Donica , Alessi-Severini Silvia , Singer Alexander , Chateau Dan , Enns Murray , Leong Christine 
Published: November 2021

ObjectiveTo measure the incidence of long-term benzodiazepine receptor agonist (BZRA) use among individuals with anxiety, mood and/or sleep disorders. To identify factors associated with long-term use following the first prescription.MethodsThis was a population-based retrospective cohort study using administrative databases in Manitoba, Canada. Individuals with anxiety/mood or sleep disorder who received their first BZRA between 1 April 2001 and 31 March 2015 were included. Long-term use was defined as ≥180 days. Logistic regression modelling was used to examine predictors of long-term use.ResultsAmong 206 933 individuals included, long-term BZRA use in the first episode of use was 4.5% (≥180 days) following their first prescription. Factors associated with ≥180 days of use included male sex (adjusted OR (aOR) 1.33, 95% CI 1.27 to 1.39), age ≥65 (aOR 5.15, 95% CI 4.81 to 5.52), income assistance (aOR 1.68, 95% CI 1.55 to 1.81), previous non-BZRA psychotropic (aOR 1.93, 95% CI 1.83 to 2.02) or opioid use (aOR 1.16, 95% CI 1.11 to 1.22), high comorbidity (aOR 1.43, 95% CI 1.32 to 1.55), high healthcare use (aOR 1.46, 95% CI 1.33 to 1.60) and psychiatrist prescriber (aOR 2.11, 95% CI 1.93 to 2.32).ConclusionsLess than 1 in 20 patients use BZRAs ≥180 days in their first treatment episode. Several factors were associated with long-term use following the first prescription and further investigation into whether these factors need to be considered at the point of prescribing is warranted. In light of these findings, future research should examine the predictors of cumulative repeat episodes of BZRA exposure.
Can birth outcome inequality be reduced using targeted caseload midwifery in a deprived diverse inner city population? A retrospective cohort study, London, UK
Authors: Hadebe Ruth , Seed Paul T , Essien Diana , Headen Kyle , Mahmud Saheel , Owasil Salwa , Fernandez Turienzo Cristina , Stanke Carla , Sandall Jane , Bruno Mara , Khazaezadeh Nina , Oteng-Ntim Eugene 
Published: November 2021

Objectives(1) To report maternal and newborn outcomes of pregnant women in areas of social deprivation in inner city London. (2) To compare the effect of caseload midwifery with standard care on maternal and newborn outcomes in this cohort of women.DesignRetrospective observational cohort study.SettingFour council wards (electoral districts) in inner city London, where over 90% of residents are in the two most deprived quintiles of the English Index of Multiple Deprivation (IMD) (2019) and the population is ethnically diverse.ParticipantsAll women booked for antenatal care under Guys and St Thomas’ National Health Service Foundation Trust after 11 July 2018 (when the Lambeth Early Action Partnership (LEAP*) caseload midwifery team was implemented) until data collection 18 June 2020. This included 523 pregnancies in the LEAP area, of which 230 were allocated to caseload midwifery, and 8430 pregnancies from other areas.Main outcome measuresTo explore if targeted caseload midwifery (known to reduce preterm birth) will improve important measurable outcomes (preterm birth, mode of birth and newborn outcomes).ResultsThere was a significant reduction in preterm birth rate in women allocated to caseload midwifery, when compared with those who received traditional midwifery care (5.1% vs 11.2%; risk ratio: 0.41; p=0.02; 95% CI 0.18 to 0.86; number needed to treat: 11.9). Caesarean section births were significantly reduced in women allocated to caseload midwifery care, when compared with traditional midwifery care (24.3% vs 38.0%; risk ratio: 0.64: p=0.01; 95% CI 0.47 to 0.90; number needed to treat: 7.4) including emergency caesarean deliveries (15.2% vs 22.5%; risk ratio: 0.59; p=0.03; 95% CI 0.38 to 0.94; number needed to treat: 10) without increase in neonatal unit admission or stillbirth.ConclusionThis study shows that a model of caseload midwifery care implemented in an inner city deprived community improves outcome by significantly reducing preterm birth and birth by caesarean section when compared with traditional care. This data trend suggests that when applied to targeted groups (women in higher IMD quintile and women of diverse ethnicity) that the impact of intervention is greater.
Use of virtual and augmented reality-based interventions in health education to improve dementia knowledge and attitudes: an integrative review
Authors: Jones Cindy , Jones Dominique , Moro Christian 
Published: November 2021

ObjectivesImmersive technologies such as virtual (VR) and augmented reality (AR) can potentially help health professionals and trainees understand psychological symptoms and responsive behaviours associated with dementia within a safe and supportive learning environment. This integrative review sought to ascertain the types of VR and AR-based interventions used in dementia education and training and its efficacy to improve knowledge and attitudes of health professionals or trainees.DesignThe protocol was submitted to PROSPERO and literature published from 2000 onwards was searched in eight databases: CINAHL, MEDLINE, Web of Science, Cochrane, Embase, PsycINFO, ERIC and Scopus. A total of 19 articles were included and assessed with the Mixed Methods Appraisal Tool. Methodological quality varied across studies.ResultsVR rather than AR-based intervention are used in dementia education and training for health professional and trainees. Immersive virtual learning potentially enhance knowledge, attitudes, empathy and sensitivity of health professionals and trainees.ConclusionsWhile promising, there remains a lack of conclusive and robust evidence to fully recommend the introduction and inclusion of immersive virtual learning in dementia education and training. Additional rigorously designed research studies with larger sample sizes are needed to confirm the benefits on attitudes, empathy, sensitivity and knowledge.PROSPERO registration numberCRD42020182083.
BT7480, a novel fully synthetic Bicycle tumor-targeted immune cell agonist™ (Bicycle TICA™) induces tumor localized CD137 agonism
Authors: Hurov Kristen , Lahdenranta Johanna , Upadhyaya Punit , Haines Eric , Cohen Heather , Repash Elizabeth , Kanakia Drasti , Ma Jun , Kristensson Julia , You Fanglei , Campbell Carly , Witty David , Kelly Mike , Blakemore Stephen , Jeffrey Phil , McDonnell Kevin , Brandish Philip , Keen Nicholas 
Published: November 2021

BackgroundCD137 (4-1BB) is an immune costimulatory receptor with high therapeutic potential in cancer. We are creating tumor target-dependent CD137 agonists using a novel chemical approach based on fully synthetic constrained bicyclic peptide (Bicycle®) technology. Nectin-4 is overexpressed in multiple human cancers that may benefit from CD137 agonism. To this end, we have developed BT7480, a novel, first-in-class, Nectin-4/CD137 Bicycle tumor-targeted immune cell agonist™ (Bicycle TICA™).MethodsNectin-4 and CD137 co-expression analyses in primary human cancer samples was performed. Chemical conjugation of two CD137 Bicycles to a Nectin-4 Bicycle led to BT7480, which was then evaluated using a suite of in vitro and in vivo assays to characterize its pharmacology and mechanism of action.ResultsTranscriptional profiling revealed that Nectin-4 and CD137 were co-expressed in a variety of human cancers with high unmet need and spatial proteomic imaging found CD137-expressing immune cells were deeply penetrant within the tumor near Nectin-4-expressing cancer cells. BT7480 binds potently, specifically, and simultaneously to Nectin-4 and CD137. In co-cultures of human peripheral blood mononuclear cells and tumor cells, this co-ligation causes robust Nectin-4-dependent CD137 agonism that is more potent than an anti-CD137 antibody agonist. Treatment of immunocompetent mice bearing Nectin-4-expressing tumors with BT7480 elicited a profound reprogramming of the tumor immune microenvironment including an early and rapid myeloid cell activation that precedes T cell infiltration and upregulation of cytotoxicity-related genes. BT7480 induces complete tumor regressions and resistance to tumor re-challenge. Importantly, antitumor activity is not dependent on continuous high drug levels in the plasma since a once weekly dosing cycle provides maximum antitumor activity despite minimal drug remaining in the plasma after day 2. BT7480 appears well tolerated in both rats and non-human primates at doses far greater than those expected to be clinically relevant, including absence of the hepatic toxicity observed with non-targeted CD137 agonists.ConclusionBT7480 is a highly potent Nectin-4-dependent CD137 agonist that produces complete regressions and antitumor immunity with only intermittent drug exposure in syngeneic mouse tumor models and is well tolerated in preclinical safety species. This work supports the clinical investigation of BT7480 for the treatment of cancer in humans.
Nitrous Fume Poisoning–An Insidious Hazard of Naval Warfare
Authors: Ellis F. P. 
Published: November 2021

Summary(1) The general features of nitrous fume poisoning and their correlation with the pathological findings is discussed.(2) The likelihood of meeting this danger in fires in ammunition lockers and magazines, or in gun turrets when the air blast fails, is emphasized.(3) The insidious nature of the fumes, and the urgent necessity for prompt donning of respirators and employment of prophylactic measures is stressed.(4) The primary factors in treatment are early and adequate oxygen therapy and complete rest. Patients must not be transfused.
Smoking associates with increased BAFF and decreased interferon-γ levels in patients with systemic lupus erythematosus
Authors: Raymond Warren David , Hamdorf Matthew , Furfaro Michael , Eilertsen Gro Ostli , Nossent Johannes Cornelis 
Published: November 2021

ObjectiveIn SLE, smoking increases the burden of cutaneous disease and organ damage, and leads to premature mortality. However, the effect of smoking on disease manifestations and cytokine levels of patients with SLE is unclear. This study compared characteristics of patients with SLE across smoking status, and determined the association of smoking with serum cytokine levels.MethodA cross-sectional study of patients with SLE (n=99) during a research visit in which smoking status was ascertained. Smoking status was compared across classification criteria (American College of Rheumatology Classification Criteria for SLE (ACR97)), disease activity (SLE Disease Activity Index), autoantibody levels, accrued damage (Systemic Lupus International Collaborating Clinics/ACR Damage Index), and circulating concentrations of serum interferon-gamma (IFN-γ), interleukin (IL)-1β, IL-4, IL-6, IL-10, IL-12, IL-17, B cell-activating factor (BAFF), tumour necrosis factor-alpha, transforming growth factor beta 1 (TGF-β1), macrophage inflammatory protein 1 alpha (MIP-1α), MIP-1β and monocyte chemoattractant protein 1. Linear regression models determined the association between smoking and cytokine levels, adjusting for age and sex, clinical characteristics (model 1), and anti-inflammatory (IL-4, IL-10 and TGF- β1) and regulatory (IL-1β) cytokines (model 2).ResultsAmong patients with SLE (97.9% ANA+; mean 48.48 years old; 86.9% female; mean 10 years of disease duration), 35.4% (n=35 of 99) were smoking (an average of 7 cigarettes/day for 24 years). Smokers had increased odds of prevalent ACR97 malar rash (OR 3.40, 95% CI 1.23 to 9.34) and mucosal ulcers (OR 3.31, 95% CI 1.36 to 8.05). Smokers had more arthritis (OR 3.19, 95% CI 1.19 to 8.60), migraine (OR 2.82, 95% CI 1.07 to 7.44), Raynaud’s phenomenon (OR 5.15, 95% CI 1.95 to 13.56) and increased non-steroidal anti-inflammatory drug use (OR 6.88, 95% CI 1.99 to 23.72). Smoking associated with 27% increased BAFF levels (95% CI 6% to 48%) and 42% decreased IFN-γ levels (95% CI −79% to −5%) in model 2.ConclusionIn patients with SLE, smoking independently associated with increased BAFF and decreased IFN-γ levels, and an increased frequency of arthritis, migraine and Raynaud’s phenomenon. Smoking cessation is advisable to reduce systemic inflammation, reduce disease activity and improve host defence.
Mechanisms of Resistance to CDK4/6 Blockade in Advanced Hormone Receptor–positive, HER2-negative Breast Cancer and Emerging Therapeutic Opportunities
Authors: Lloyd Maxwell R. , Spring Laura M. , Bardia Aditya , Wander Seth A. 
Published: November 2021

Abstract
The cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) have become the standard of care, in combination with antiestrogen therapy, for patients with hormone receptor–positive (HR+)/HER2− advanced breast cancer. Various preclinical and translational research efforts have begun to shed light on the genomic and molecular landscape of resistance to these agents. Drivers of resistance to CDK4/6i therapy can be broadly subdivided into alterations impacting cell-cycle mediators and activation of oncogenic signal transduction pathways. The resistance drivers with the best translational evidence supporting their putative role have been identified via next-generation sequencing of resistant tumor biopsies in the clinic and validated in laboratory models of HR+ breast cancer. Despite the diverse landscape of resistance, several common, therapeutically actionable resistance nodes have been identified, including the mitotic spindle regulator Aurora Kinase A, as well as the AKT and MAPK signaling pathways. Based upon these insights, precision-guided therapeutic strategies are under active clinical development. This review will highlight the emerging evidence, in the clinic and in the laboratory, implicating this diverse spectrum of molecular resistance drivers.
Radiosensitizing Pancreatic Cancer via Effective Autophagy Inhibition
Authors: Yazal Taha , Bailleul Justine , Ruan Yangjingyi , Sung David , Chu Fang-I , Palomera Daisy , Dao Amy , Sehgal Anahita , Gurunathan Vibha , Aryan Laila , Eghbali Mansoureh , Vlashi Erina 
Published: November 2021

AbstractDespite aggressive treatments, pancreatic ductal adenocarcinoma (PDAC) remains an intractable disease, largely because it is refractory to therapeutic interventions. To overcome its nutrient-poor microenvironment, PDAC heavily relies on autophagy for metabolic needs to promote tumor growth and survival. Here, we explore autophagy inhibition as a method to enhance the effects of radiotherapy on PDAC tumors. Hydroxychloroquine is an autophagy inhibitor at the focus of many PDAC clinical trials, including in combination with radiotherapy. However, its acid-labile properties likely reduce its intratumoral efficacy. Here, we demonstrate that EAD1, a synthesized analogue of HCQ, is a more effective therapeutic for sensitizing PDAC tumors of various KRAS mutations to radiotherapy. Specifically, in vitro models show that EAD1 is an effective inhibitor of autophagic flux in PDAC cells, accompanied by a potent inhibition of proliferation. When combined with radiotherapy, EAD1 is consistently superior to HCQ not only as a single agent, but also in radiosensitizing PDAC cells, and perhaps most importantly, in decreasing the self-renewal capacity of PDAC cancer stem cells (PCSC). The more pronounced sensitizing effects of autophagy inhibitors on pancreatic stem over differentiated cells points to a new understanding that PCSCs may be more dependent on autophagy to counter the effects of radiation toxicity, a potential mechanism explaining the resistance of PCSCs to radiotherapy. Finally, in vivo subcutaneous tumor models demonstrate that combination of radiotherapy and EAD1 is the most successful at controlling tumor growth. The models also confirmed a similar toxicity profile between EAD1 and Hydroxychloroquine.
The Novel Dual Topoisomerase Inhibitor P8-D6 Shows Anti-myeloma Activity In Vitro and In Vivo
Authors: Klausz Katja , Kellner Christian , Gehlert Carina Lynn , Krohn Steffen , Wilcken Hauke , Floerkemeier Inken , Günther Andreas , Bauerschlag Dirk O. , Clement Bernd , Gramatzki Martin , Peipp Matthias 
Published: November 2021

Abstract
P8-D6 is a novel dual inhibitor of human topoisomerase I (TOP1) and II (TOP2) with broad pro-apoptotic antitumor activity. NCI-60 screening revealed markedly improved cytotoxicity of P8-D6 against solid and leukemia cell lines compared with other single and dual topoisomerase inhibitors, for example, irinotecan, doxorubicin, or pyrazoloacridine. In this study, we investigated the capacity of P8-D6 to inhibit myeloma cell growth in vitro and in vivo. Growth inhibition assays demonstrated significant anti-myeloma effects against different myeloma cell lines with IC50 values in the low nanomolar range. Freshly isolated plasma cells of patients with multiple myeloma were killed by P8-D6 with similar doses. P8-D6 activated caspase 3/7 and induced significant apoptosis of myeloma cells. Supportive effects of bone marrow stromal cells on IL6-dependent INA-6 myeloma cells were abrogated by P8-D6 and apoptosis occurred in a time- and dose-dependent manner. Of note, healthy donor peripheral blood mononuclear cells and human umbilical vein endothelial cells were not affected at concentrations toxic for malignant plasma cells. Treatment of myeloma xenografts in immunodeficient SCID/beige mice by intravenous and, notably, also oral application of P8-D6 markedly inhibited tumor growths, and significantly prolonged survival of tumor-bearing mice.
Вікові особливості реакції ендокринної системи у постраждалих із травматичними переломами нижньої щелепи
Authors: Нагірний Я. П. , Денефіль О. В. , Твердохліб Н. О. , Беденюк О. С. , Стефанів І. В. 
Published: November 2021

Вивчено особливості вікових змін концентрації кортизолу, паратиреоїдного гормону, тироксину в динаміці у постраждалих із травматичними переломами нижньої щелепи. Встановлено, що впродовж усього терміну спостереження концентрація усіх гормонів відрізнялася від норми і мала свої вікові особливості. Найбільше підвищення рівня кортизолу і паратиреоїдного гормону встановлено у постраждалих вікової групи 20–29 років, а тироксину – в пацієнтів вікової групи 40–49 років.
Мета дослідження – вивчити динаміку концентрації гормонів крові, які впливають на синтез і мінералізацію кісткової мозолі в ділянці перелому при лікуванні постраждалих із травматичними відкритими переломами нижньої щелепи різного віку.
Матеріали і методи. Проведено дослідження гормонального статусу 38 постраждалих із травматичними переломами нижньої щелепи 20–49 років на 1-й, 10-й, 20-й дні спостереження. Для цього у сироватці крові визначали рівень кортизолу за допомогою тест-системи FK 210R (версія 03.2002), паратиреоїдного гормону – за допомогою набору DSL ACTIVE I-PTH, тироксину – за допомогою тест-системи FK 212 R (версія 12.2001). Лікування перелому проводили із застосуванням назубних шин і стандартного медикаментозного забезпечення.
Результати досліджень та їх обговорення. Підсумовуючи отримані результати, можна стверджувати, що гормони щитоподібної залози мають моделюючий вплив на кістковий метаболізм. Метаболічні ефекти пояснюються синтезом та підвищенням активності багатьох клітинних ферментів, впливом їх на проникність клітинних і мітохондріальних мембран, а також стимуляцією метаболізму в мітохондріях. Вони контролюють синтез РНК в ядрах клітин, регулюють синтез білка в рибосомах, проявляють пермісивний ефект на генетично детерміновані процеси і дію інших гормонів.
Висновки. У хворих із травматичними переломами нижньої щелепи в усі вікові періоди встановлено дисбаланс гормонів, що впливають на синтез і мінералізацію кісткової мозолі.
The New Merger Guidelines—A Blueprint for Microeconomic Analysis
Authors: Fox Eleanor M. 
Published: November 2021

The following article on the new merger guidelines describes the guidelines for merger analysis issued this summer by the Department of Justice and demonstrates how they work. It compares the Justice Department guidelines with the contemporaneous statement by the Federal Trade Commission on horizontal mergers, with the superseded 1968 Guidelines of the Department of Justice, and with the Supreme Court case law. The author concludes that the new guidelines provide an excellent methodology for analyzing when a merger will give the merging parties a significant increment in the power to raise price above the current market price. She observes that such increased power over current price is one reason but not the only reason why the effect of a merger “may be substantially to lessen competition” within the meaning of the Celler-Kefauver Amendment to section 7 of the Clayton Act. In appendices, the author provides a historical note on the derivation of the concentration index used in the guidelines, and a table applying the new guideline standards to each Supreme Court case decided under amended section 7 of the Clayton Act.
A survey of practice in the management of haemolysis, icterus and lipaemia in blood specimens in the United Kingdom and Republic of Ireland
Authors: Costelloe Seán J. , Rico Rios Natividad , Goulding Nicola , Mistry Hema , Stretton Adam , De la Salle Barbara , Hepburn Sophie , Thomas Annette , Atherton Jennifer , Cornes Michael 
Published: November 2021

Background Haemolysis, icterus and lipaemia (HIL) are common interferants in laboratory medicine, potentially impacting patient care. This survey investigates HIL management in medical laboratories across the UK and Republic of Ireland (ROI). Methods A survey was sent to members of key professional organisations for laboratory medicine in the UK and ROI. Questions related to the detection, monitoring, quality control, and management of HIL. Results In total, responses from 124 laboratories were analysed, predominantly from England (52%) and ROI (36%). Most responses were from public hospitals with biochemistry services (90%), serving primary care (91%), inpatients (91%), and outpatients (89%). Most laboratories monitored H (98%), I (88%), and L (96%) using automated indices (93%), alone or in combination with visual inspection. Manufacturer-stated cut-offs were used by 83% and were applied to general chemistries in 79%, and immunoassays in 50%. Where HIL cut-offs are breached, 64% withheld results, while 96% reported interference to users. HIL were defined using numeric scales (70%) and ordinal scales (26%). HIL targets exist in 35% of laboratories, and 54% have attempted to reduce HIL. Internal Quality Control for HIL was lacking in 62% of laboratories, and just 18% of respondents have participated in External Quality Assurance. Laboratories agree manufacturers should: standardise HIL reporting (94%), ensure comparability between platforms (94%), and provide information on HIL cross-reactivity (99%). Respondents (99%) showed interest in evidence-based, standardised HIL cut-offs. Conclusions Most respondents monitor HIL, although the wide variation in practice may differentially affect clinical care. Laboratories seem receptive to education and advice on HIL management.