bluuebunny/crossref_metadata_2025_split huggingface dataset:
Combination of inhibitors for two glycolytic enzymes portrays high synergistic efficacy against
Cryptosporidium parvum
Authors: Khan Shahbaz M. , Bajwa Muhammad Rashid , Lahar Rachael Y. , Witola William H. 
Published: September 2023

ABSTRACT

Cryptosporidium
is an intracellular protozoan parasite that causes serious enteric disease in humans and in a wide range of animals worldwide. Despite its high prevalence, no effective therapeutic drugs are available against life-threatening cryptosporidiosis in at-risk populations including malnourished children, immunocompromised patients, and neonatal calves. Thus, new efficacious drugs are urgently needed to treat all susceptible populations with cryptosporidiosis. Unlike other apicomplexans,
Cryptosporidium parvum
lacks the tricarboxylic acid cycle and the oxidative phosphorylation steps, making it solely dependent on glycolysis for metabolic energy production. We have previously reported that individual inhibitors of two unique glycolytic enzymes, the plant-like pyruvate kinase (CpPyK) and the bacterial-type lactate dehydrogenase (CpLDH), are effective against
C. parvum
, both
in vitro
and
in vivo
. Herein, we have derived combinations of CpPyK and CpLDH inhibitors with strong synergistic effects against the growth and survival of
C. parvum
, both
in vitro
and in an infection mouse model. In infected immunocompromised mice, compound combinations of NSC303244 + NSC158011 and NSC252172 + NSC158011 depicted enhanced efficacy against
C. parvum
reproduction and ameliorated intestinal lesions of cryptosporidiosis at doses fourfold lower than the total effective doses of individual compounds. Importantly, unlike individual compounds, NSC303244 + NSC158011 combination was effective in clearing the infection completely without relapse in immunocompromised mice. Collectively, our study has unveiled compound combinations that simultaneously block two essential catalytic steps for metabolic energy production in
C. parvum
to achieve improved efficacy against the parasite. These combinations are, therefore, lead compounds for the development of a new generation of efficacious anti-cryptosporidial drugs.
Isolation of ACE2-dependent and -independent sarbecoviruses from Chinese horseshoe bats
Authors: Guo Hua , Li Ang , Dong Tian-Yi , Si Hao-Rui , Hu Ben , Li Bei , Zhu Yan , Shi Zheng-Li , Letko Michael 
Published: September 2023

ABSTRACT

While the spike proteins from severe acute respiratory syndrome coronaviruses-1 and 2 (SARS-CoV and SARS-CoV-2) bind to host angiotensin-converting enzyme 2 (ACE2) to infect cells, the majority of bat sarbecoviruses cannot use ACE2 from any species. Despite their discovery almost 20 years ago, ACE2-independent sarbecoviruses have never been isolated from field samples, leading to the assumption these viruses pose little risk to humans. We have previously shown how spike proteins from a small group of ACE2-independent bat sarbecoviruses may possess the ability to infect human cells in the presence of exogenous trypsin. Here, we adapted our earlier findings into a virus isolation protocol and recovered two new ACE2-dependent viruses, RsYN2012 and RsYN2016A, as well as an ACE2-independent virus, RsHuB2019A. Although our stocks of RsHuB2019A rapidly acquired a tissue-culture adaption that rendered the spike protein resistant to trypsin, trypsin was still required for viral entry, suggesting limitations on the exogenous entry factors that support bat sarbecoviruses. Electron microscopy revealed that ACE2-independent sarbecoviruses have a prominent spike corona and share similar morphology to other coronaviruses. Our findings demonstrate a broader zoonotic threat posed by sarbecoviruses and shed light on the intricacies of coronavirus isolation and propagation
in vitro
.

IMPORTANCE
Several coronaviruses have been transmitted from animals to people, and 20 years of virus discovery studies have uncovered thousands of new coronavirus sequences in nature. Most of the animal-derived sarbecoviruses have never been isolated in culture due to cell incompatibilities and a poor understanding of the in vitro requirements for their propagation. Here, we built on our growing body of work characterizing viral entry mechanisms of bat sarbecoviruses in human cells and have developed a virus isolation protocol that allows for the exploration of these understudied viruses. Our protocol is robust and practical, leading to successful isolation of more sarbecoviruses than previous approaches and from field samples that had been collected over a 10-year longitudinal study.
COVID-19-associated pulmonary aspergillosis in mechanically ventilated patients: a prospective, multicentre UK study
Authors: Hurt William , Youngs Jonathan , Ball Jonathan , Edgeworth Jonathan , Hopkins Philip , Jenkins David R , Leaver Susannah , Mazzella Andrea , Molloy Síle F , Schelenz Silke , Wise Matt P , White P Lewis , Yusuff Hakeem , Wyncoll Duncan , Bicanic Tihana 
Published: September 2023

BackgroundInvasive pulmonary aspergillosis is a complication of severe COVID-19, with regional variation in reported incidence and mortality. We describe the incidence, risk factors and mortality associated with COVID-19-associated pulmonary aspergillosis (CAPA) in a prospective, multicentre UK cohort.MethodsFrom March 2020 to March 2021, 266 mechanically ventilated adults with COVID-19 were enrolled across 5 UK hospital intensive care units (ICUs). CAPA was defined using European Confederation for Medical Mycology and the International Society for Human and Animal Mycology criteria and fungal diagnostics performed on respiratory and serum samples.ResultsTwenty-nine of 266 patients (10.9%) had probable CAPA, 14 (5.2%) possible CAPA and none proven CAPA. Probable CAPA was diagnosed a median of 9 (IQR 7–16) days after ICU admission. Factors associated with probable CAPA after multivariable logistic regression were cumulative steroid dose given within 28 days prior to ICU admission (adjusted OR (aOR) 1.16; 95% CI 1.01 to 1.43 per 100 mg prednisolone-equivalent), receipt of an interleukin (IL)-6 inhibitor (aOR 2.79; 95% CI 1.22 to 6.48) and chronic obstructive pulmonary disease (COPD) (aOR 4.78; 95% CI 1.13 to 18.13). Mortality in patients with probable CAPA was 55%, vs 46% in those without. After adjustment for immortal time bias, CAPA was associated with an increased risk of 90-day mortality (HR 1.85; 95% CI 1.07 to 3.19); however, this association did not remain statistically significant after further adjustment for confounders (adjusted HR 1.57; 95% CI 0.88 to 2.80). There was no difference in mortality between patients with CAPA prescribed antifungals (9 of 17; 53%) and those who were not (7 of 12; 58%) (p=0.77).InterpretationIn this first prospective UK study, probable CAPA was associated with corticosteroid use, receipt of IL-6 inhibitors and pre-existing COPD. CAPA did not impact mortality following adjustment for prognostic variables.
Empower the Potential of Trastuzumab Deruxtecan with Novel Combinations
Authors: Rolfo Christian , Del Re Marzia , Russo Alessandro 
Published: September 2023

Summary
Trastuzumab deruxtecan (T-DXd) is reshaping the therapeutic landscape of HER2-positive tumors. A recent article reports on the preclinical activity of the combination of T-DXd plus adavosertib, WEE1 kinase inhibitor, which promises to expand the use of this antibody–drug conjugate in HER2-positive tumors with CCNE1 coamplification.
See related article by DiPeri et al., p. 4385
Managemen Continuous Renal Replacement Therapy (CRRT) pada Pasien Gagal Ginjal Akut dan Syok Sepsis di ICU
Authors: Fatoni Arie Zainul , Rusly Andri , Hartono Ruddi 
Published: September 2023

Angka Kejadian sepsis sekitar 6% pasien yang ada di rumah sakit. Sepsis yang tidak tertangani dengan baik akan berkembang menjadi syok septik yang akan meningkatkan mortalitas sebesar 50 – 70 %. Gagal Ginjal Akut (GGA) terjadi pada 58-87% pasien dengan syok sepsis. Pada 70% kasus GGA yang disebabkan oleh sepsis dapat memburuk dan memerlukan renal replacement therapy (RRT). Continuous Renal Replacement Therapy (CRRT) merupakan salah satu modalitas RRT yang baik untuk pasien syok septik.
Seorang Laki-laki berusia 51 tahun, rujukan dari ICU Rumah sakit lain dengan diagnosa respiratory failure, syok sepsis, pneumonia Hospital Assosiated Pneumonia (HAP), diabetic foot dengan osteomyelitis pedis dextra, GGA Stage 3 dan Diabetes Mellitus (DM) Tipe 2. Dari klinis pasien sesak, penurunan kesadaran, disertai syok yang membutuhkan vasopressor dan dari laboratorium didapatkan ureum 277 mg/dl serta foto thorax didapatkan kesan pneumonia. Tatalaksana pada pasien ini dilakukan pemberian antibiotik, amputasi kaki kanan dan CRRT sebagai modalitas terapi GGA. CRRT dilakukan dengan mode Continuous Venovenous Hemodialysis elama 3 hari. Pada hari ke lima klinis pasien membaik sehingga dapat pindah keluar dari ICU.
Pada kondisi syok sepsis dengan GGA, CRRT dapat menjaga stabilitas hemodinamik pasien, mengeluarkan toksin dari ginjal, menyaring sitokin dan endotoksin, mengoreksi asam-basa dan elektrolit, mengontrol volume cairan dengan tepat, memodulasi respon imun sehingga mempercepat renal recovery dan memperbaiki kondisi klinis pasien.
Situating “Deformalization” within the International Court of Justice: Understanding Institutionalised Informality
Authors: Mohanty Rahul 
Published: September 2023

Abstract
This article approaches the International Court of Justice (ICJ) and its decisions from the lens of “deformalization”. It conceptualises “deformalization” not in a de-institutionalised sense, but as implying informality within the functioning of formal institutions. It posits that it may be useful to adopt this perspective to examine some of the actions of the ICJ, which may not be adequately explained from a purely formal standpoint. It examines various areas of deformalization within the ICJ, such as its approach towards evidence or provisional measures. It attempts to understand why and when deformalization is needed by the ICJ and concludes that the ICJ walks a tightrope between formal rules and informal application, in order to improve its effectiveness and legitimacy.
Preliminary results from the Australian Genetics of Bipolar Disorder Study: A nation-wide cohort
Authors: Lind Penelope A , Siskind Dan J , Hickie Ian B , Colodro-Conde Lucía , Cross Simone , Parker Richard , Martin Nicholas G , Medland Sarah E 
Published: September 2023

Objective: The Australian Genetics of Bipolar Disorder Study is a nation-wide cohort of adults living with bipolar disorder. The study aims to detect the relationships between genetic risk, symptom severity, and the lifetime prevalence of bipolar disorder, treatment response and medication side effects, and patterns and costs of health care usage. Methods: A total of 6682 participants (68.3% female; aged 44.8 ± 13.6 years [range = 18–90]) were recruited in three waves: a nation-wide media campaign, a mail-out based on prescriptions for lithium carbonate and through the Australian Genetics of Depression Study. Participants completed a self-report questionnaire. A total of 4706 (70%) participants provided a saliva sample and were genotyped and 5506 (82%) consented to record linkage of their Pharmaceutical and Medicare Benefits Schedule data. Results: Most participants were living with bipolar I disorder ( n = 4068) while 1622 participants were living with bipolar II disorder and 992 with sub-threshold bipolar disorder. The mean age of bipolar disorder diagnosis was 32.7 ± 11.6 years but was younger in bipolar I ( p = 2.0E-26) and females ( p = 5.7E-23). Excluding depression with onset prior to bipolar disorder diagnosis, 64.5% of participants reported one or more co-occurring psychiatric disorders: most commonly generalised anxiety disorder (43.5%) and posttraumatic stress disorder (20.7%). Adverse drug reactions were common and resulted in discontinuation rates ranging from 33.4% for lithium to 63.0% for carbamazepine. Conclusion: Our findings highlight the high rate of comorbidities and adverse drug reactions among adults living with bipolar disorder in the general Australian population. Future genomic analyses focus on identifying genetic variants influencing pharmacotherapy treatment response and side effects.
Management of trigeminal neuralgia: A multi-centre case study in general practice
Authors: Zakrzewska Zofia J , Hosseini-Ashrafi Parinaz , Hussain Ishrat , Moulder Zachary James , Subhash Jithu , Tan Melissa , Johnson Martin Ewart , Zakrzewska Joanna M 
Published: September 2023

Background and aims Patients often first present with symptoms of trigeminal neuralgia (TN) to primary care. However, there has been little research to determine whether the diagnosis and management of this condition is carried out according to current guidelines. Furthermore, there is little up-to-date information regarding the prevalence of TN in the UK. The aim is to estimate the prevalence of TN and to audit the diagnosis and management process of TN in primary care. Methods Between 2019 and 2020 a search was made at five UK GP practices with a total patient population of 55,842 using EMIS and SystmOne patient record systems to review patient consultations to identify patients coded with TN or facial pain (FP). These records were reviewed to ascertain the basis for diagnosis, management in primary care and referral to secondary care. Results 157 patients were identified; 54 coded with FP and 103 with TN. These results indicate a prevalence of 22.3 in 10,000. There was no difference in documented symptoms between the two groups. Seven patients had all ICDH3 criteria recorded, with two meeting the requirements for TN diagnosis. 58.8% of patients with TN were started on carbamazepine, the current gold standard treatment, compared with 16.7% in the FP group. 38.2% of TN patients were referred to a range of different specialities. Conclusion The prevalence of TN may be higher than previously thought. Key diagnostic criteria are often omitted, leading to potential misdiagnosis or delays in diagnosis. Relatively few referrals are made, though all patients should be considered for imaging.
Single-cell analysis of human prepuce reveals dynamic changes in gene regulation and cellular communications
Authors: Tan Fei , Xuan Yuan , Long Lan , Yu Yang , Zhang Chunhua , Liang Pengchen , Wang Yaoqun , Chen Meiyu , Wen Jiling , Chen Geng 
Published: September 2023

Abstract
Background
The cellular and molecular dynamics of human prepuce are crucial for understanding its biological and physiological functions, as well as the prevention of related genital diseases. However, the cellular compositions and heterogeneity of human prepuce at single-cell resolution are still largely unknown. Here we systematically dissected the prepuce of children and adults based on the single-cell RNA-seq data of 90,770 qualified cells.

Results
We identified 15 prepuce cell subtypes, including fibroblast, smooth muscle cells, T/natural killer cells, macrophages, vascular endothelial cells, and dendritic cells. The proportions of these cell types varied among different individuals as well as between children and adults. Moreover, we detected cell-type-specific gene regulatory networks (GRNs), which could contribute to the unique functions of related cell types. The GRNs were also highly dynamic between the prepuce cells of children and adults. Our cell–cell communication network analysis among different cell types revealed a set of child-specific (e.g., CD96, EPO, IFN-1, and WNT signaling pathways) and adult-specific (e.g., BMP10, NEGR, ncWNT, and NPR1 signaling pathways) signaling pathways. The variations of GRNs and cellular communications could be closely associated with prepuce development in children and prepuce maintenance in adults.

Conclusions
Collectively, we systematically analyzed the cellular variations and molecular changes of the human prepuce at single-cell resolution. Our results gained insights into the heterogeneity of prepuce cells and shed light on the underlying molecular mechanisms of prepuce development and maintenance.
The link between cognitive health and neighbourhood: perceptions of the public, and of policy-makers, about problems and solutions
Authors: Stevens Madeleine , Matosevic Tihana , Suarez-Pinilla Marta , Pais Sarah , Rossor Martin , Knapp Martin 
Published: September 2023

Abstract
Background
Growing evidence indicates associations between neighbourhood-related factors such as pollution, social isolation and physical inactivity, and cognition, that is, our ability to think clearly, learn and remember. The evidence raises the possibility of neighbourhood intervention playing a role in protecting population cognitive health. However, there is little understanding of these associations among the public and policy-makers, what they mean and how they might be acted on. In this study we explored perceptions of the public and policy-makers about influences of neighbourhood factors on brain functioning, and how they should inform policy.

Methods
Qualitative methods were used in three phases; the study ran in parallel with a quantitative study looking at neighbourhood influences on cognition. In phase one, focus groups were conducted with middle-aged (40–69) members of the public to inform statistical modelling. In phase two, similar focus groups were held in four case study areas chosen based on the modelling results. In phase three, interviews with people in public health and policy roles were conducted, including people in the case study sites.

Results
Participants described effects on their cognition from community, culture and social interactions, access to green spaces and nature, upkeep and safety of the area, and pollution, traffic and noise. Solutions included better local consultation and involvement in policy and planning, support for community interactions and active and public transport, and education on cognition. There was little awareness, but much interest, from local policy-makers and implementers, about links between cognition and place. Barriers to implementation included lack of: effective engagement with local communities, local funding and joined-up health and neighbourhood policy.

Conclusions
People can perceive impacts of neighbourhoods on brain functioning and suggest ways local areas can be improved to support cognitive health. There is support for the idea of population-level interventions to support cognitive health.
Epidemiological and therapeutic profiles of lung cancer patients in the Hokushin Region Japan: a retrospective hospital administrative database study
Authors: Kobayashi Takashi , Nishino Yoshikazu , Takiguchi Tomoya , Kanda Shintaro , Otsuki Kengo , Tanaka Yuriko , Nakazawa Yozo , Ito Ken-ichi , Hayashi Ryuji , Yasumoto Kazuo , Uramoto Hidetaka , Hirono Yasuo , Makino Tomoe , Nakada Mitsutoshi , Yano Seiji , Koizumi Tomonobu 
Published: September 2023

Abstract
Objective
This study was performed to validate the epidemiology, initial treatment, and clinical practice of lung cancer patients in the Hokushin region, Japan.

Methods
We retrospectively surveyed data of 5503 newly diagnosed and registered lung cancer patients in 22 principal hospital-based cancer registries in Hokushin region linked with health insurance claims data for registered patients between 2016 and 2017.

Results
The patients consisted of 3677 (66.8%) men and 1826 (33.2%) women with a mean (range) age of 72.2 (27–103) years). Diagnoses were small cell lung cancer (n = 512, 9.4%), squamous cell carcinoma (n = 1083, 19.7%), and non-squamous non-small cell lung cancer (NSCLC; n = 3906, 70.9%). The population with stage I disease in Toyama prefecture (41.1%) was smaller than in the other three prefectures associated with reduced selection of initial surgical therapy and increased frequencies of stage IV disease (33.2%) and best supportive care (18.6%). Initial chemotherapy for stage IV non-squamous NSCLC consisted of tyrosine kinase inhibitors in 39.3% of cases for EGFR and 4% of cases for ALK-positive non-squamous NSCLC, followed by platinum compounds (25.9%) non-platinum compounds (12.9%), and immune checkpoint inhibitors (10.2%). Carboplatin was the commonly prescribed first-line cytotoxic chemotherapeutic agent (65.4% of patients under 75 years and in 96.7% of patients over 75 years).

Conclusion
This study revealed real-world data on epidemiological and treatment status in lung cancer in four prefectures in Hokushin region, Japan. Simultaneous analysis of nationwide registry and insurance data could provide valuable insights for the development of lung cancer screening and medical treatment strategies. In addition, the comparative data analysis with other lesions or countries will be useful for evaluating the differences in clinical practice of cancer managements.
The association of FGF-21 with the risk of newly diagnosed type-2 diabetes mellitus: a cross-sectional study in Southern China
Authors: You Lili , Hong Xiaosi , Wu Hongshi , Liang Diefei , Li Feng , Zheng Dinghao , Zhang Xiuwei , Liu Dan , Chen Qingyu , Yan Li , Ren Meng , Wang Wei 
Published: September 2023

Abstract
Background
This study investigated the relationship between fibroblast growth factor 21 (FGF-21) and newly diagnosed type-2 diabetes mellitus (T2DM).

Methods
In this cross-sectional study, FGF-21 and T2DM risk were analyzed using restricted cubic splines with univariate or multivariate logistic regression analysis. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated via logistic regression analysis. Cluster and subgroup analyses were conducted to evaluate the associations between FGF-21 and diabetes in different subpopulations. Nomograms and ROC curves were used to explore the clinical utility of FGF-21 in the diabetes assessment model.

Results
High levels of FGF-21 were significantly associated with a high risk of T2DM after adjusting for confounding factors in both the total population and subpopulations (P for trend < 0.001). In the total population, the ORs of diabetes with increasing FGF-21 quartiles were 1.00 (reference), 1.24 (95% CI 0.56–2.80; quartile 2), 2.47 (95% CI 1.18–5.33; quartile 3), and 3.24 (95% CI 1.53–7.14; quartile 4) in Model 4 (P < 0.001), and the trend was consistent in different subpopulations. In addition, compared with the model constructed with conventional noninvasive indicators, the AUC of the model constructed by adding FGF-21 was increased from 0.668 (95% CI: 0.602–0.733) to 0.715 (95% CI: 0.654–0.777), indicating that FGF-21 could significantly improve the risk-assessment efficiency of type-2 diabetes.

Conclusion
This study demonstrated that a high level of circulating FGF-21 was positively correlated with diabetes, and levels of FGF-21 could be an important biomarker for the assessment of diabetes risk.