bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pharmacogenetics at scale in real-world bioresources: CYP2C19 and clopidogrel outcomes in UK Biobank
Authors: Bedair Khaled F. , Smith Blair , Palmer Colin N.A. , Doney Alex S.F. , Pearson Ewan R. 
Published: January 2024

Objective
The impact of CYP2C19 genotype on clopidogrel outcomes is one of the most well established pharmacogenetic interactions, supported by robust evidence and recommended by the Food and Drug Administration and clinical pharmacogenetics implementation consortium. However, there is a scarcity of large-scale real-world data on the extent of this pharmacogenetic effect, and clinical testing for the CYP2C19 genotype remains infrequent. This study utilizes the UK Biobank dataset, including 10 365 patients treated with clopidogrel, to offer the largest observational analysis of these pharmacogenetic effects to date.

Methods
Incorporating time-varying drug exposure and repeated clinical outcome, we adopted semiparametric frailty models to detect and quantify exposure-based effects of CYP2C19 (*2,*17) variants and nongenetic factors on the incidence risks of composite outcomes of death or recurrent hospitalizations due to major adverse cardiovascular events (MACE) or hemorrhage in the entire cohort of clopidogrel-treated patients.

Results
Out of the 10 365 clopidogrel-treated patients, 40% (4115) experienced 10 625 MACE events during an average follow-up of 9.23 years. Individuals who received clopidogrel (coverage >25%) with a CYP2C19*2 loss-of-function allele had a 9.4% higher incidence of MACE [incidence rate ratios (IRR), 1.094; 1.044–1.146], but a 15% lower incidence of hemorrhage (IRR, 0.849; 0.712-0.996). These effects were stronger with high clopidogrel exposure. Conversely, the gain-of-function CYP2C19*17 variant was associated with a 5.3% lower incidence of MACE (IRR, 0.947; 0.903–0.983). Notably, there was no evidence of *2 or *17 effects when clopidogrel exposure was low, confirming the presence of a drug-gene interaction.

Conclusion
The impact of CYP2C19 on clinical outcomes in clopidogrel-treated patients is substantial, highlighting the importance of incorporating genotype-based prescribing into clinical practice, regardless of the reason for clopidogrel use or the duration of treatment. Moreover, the methodology introduced in this study can be applied to further real-world investigations of known drug-gene and drug-drug interactions and the discovery of novel interactions.
A Systematic Critical Review of Clinical Pharmacokinetics of Torasemide
Authors: Sherazi Abdul Wasay , Zamir Ammara , Rehman Anees ur , Ashraf Waseem , Imran Imran , Saeed Hamid , Majeed Abdul , Saleem Zikria , Aziz Majid , Alqahtani Faleh , Rasool Muhammad Fawad 
Published: January 2024

Purpose:
Torasemide is a potassium-sparing loop diuretic used to treat fluid retention associated with congestive heart failure and kidney and hepatic diseases. This systematic review was conducted to combine all accessible data on the pharmacokinetics (PK) of torasemide in healthy and diseased populations, which may help clinicians avert adverse drug reactions and determine the correct dosage regimen.

Methods:
Four databases were systematically searched to screen for studies associated with the PK of torasemide, and 21 studies met the eligibility criteria. The review protocol was registered in the PROSPERO database (CRD42023390178).

Results:
A decrease in maximum plasma concentration (Cmax) was observed for torasemide after administration of the prolonged-release formulation in comparison to that after administration of the immediate-release formulation, that is, 1.12 ± 0.17 versus 1.6 ± 0.2 mcg/mL. After administering an oral dose of torasemide, a 2-fold increase in the area under the concentration–time curve (AUC) was reported in patients with congestive heart failure compared with the healthy population. Moreover, the patients with renal failure (clearance < 30 mL/min) showed an increase in value of AUC0–∞ that is, 42.9 versus 8.091 mcg.h−1.mL−1 compared with healthy subjects. In addition, some studies have reported interactions with different drugs, in which irbesartan showed a slight increase in the AUC0–∞ of torasemide, whereas losartan and empagliflozin did not.

Conclusions:
The current review summarizes all available PK parameters of torasemide that may be beneficial for avoiding drug–drug interactions in subjects with renal and hepatic dysfunction and for predicting doses in patients with different diseases.
Serum lactate and mean arterial pressure thresholds in patients with cirrhosis and septic shock
Authors: Smith Thomas N. , Choi Chansong , Rattan Puru , Piccolo Serafim Laura , Kassmeyer Blake A. , Lennon Ryan J. , Gajic Ognjen , Olson Jody C. , Kamath Patrick S. , Gallo De Moraes Alice , Simonetto Douglas A. 
Published: January 2024

Background:
The Sepsis-3 guidelines have incorporated serum lactate levels of >2 mmol/L in septic shock definition to account for higher observed mortality. Further evidence is needed to support this threshold in cirrhosis, as well as target mean arterial pressure (MAP) during resuscitation.

Methods:
This observational cohort study investigated the association between initial serum lactate and resuscitation MAP levels on in-hospital mortality in patients with and without cirrhosis. Patients admitted to the intensive care unit for the treatment of septic shock between 2006 and 2021 in a quaternary academic center were included. Patients with cirrhosis documented on imaging and International Classification of Disease codes (n=595) were compared to patients without cirrhosis (n=575). The association of intensive care unit admission lactate levels and median 2-hour MAP with in-hospital mortality and the need for continuous renal replacement therapy was assessed. The association between median 24-hour MAP and in-hospital mortality was analyzed post hoc.

Results:
Within the cirrhosis group, admission lactate levels of 2–4 and >4 mmol/L were associated with increased in-hospital mortality compared to lactate <2 mmol/L [adjusted odds ratio (aOR): 1.69, CI: 1.03–2.81, aOR: 4.02, CI: 2.53–6.52]. Median 24-hour MAP 60–65 and <60 mm Hg were also associated with increased in-hospital mortality compared with MAP >65 mm Hg (aOR: 2.84, CI: 1.64–4.92 and aOR: 7.34, CI: 3.17–18.76). In the noncirrhosis group, associations with in-hospital mortality were weaker for lactate 2–4 and >4 mmol/L (aOR: 1.32, CI: 0.77–2.27 and aOR: 2.25, CI: 1.40–3.67) and median 24-hour MAP 60–65 and <60 mm Hg (aOR: 1.70, CI: 0.65–4.14 and aOR: 4.41, CI: 0.79–29.38).

Conclusions:
These findings support utilizing lactate >2 mmol/L in the definition of septic shock, as well as a target MAP of >65 mm Hg during resuscitation in patients with cirrhosis.
The clinical courses of HBV-related acute-on-chronic liver failure and a multi-state model to predict disease evolution
Authors: Yu Xia , Liu Xinxin , Tan Wenting , Wang Xiaobo , Zheng Xin , Huang Yan , Chen Jinjun , Li Beiling , Meng Zhongji , Gao Yanhang , Qian Zhiping , Liu Feng , Lu Xiaobo , Shang Jia , Yan Huadong , Zheng Yubao , Zhang Weituo , Yin Shan , Gu Wenyi , Deng Guohong , Xiang Xiaomei , Zhou Yi , Hou Yixin , Zhang Qun , Xiong Shue , Liu Jing , Chen Ruochan , Long Liyuan , Jiang Xiuhua , Luo Sen , Chen Yuanyuan , Jiang Chang , Zhao Jinming , Ji Liujuan , Mei Xue , Li Jing , Li Tao , Zheng Rongjiong , Zhou Xinyi , Ren Haotang , Sheng Jifang , Li Hai , Shi Yu 
Published: January 2024

Background and Aims:
Acute-on-chronic liver failure (ACLF) is a highly dynamic syndrome. The objective of this study was to delineate the clinical course of patients with HBV-ACLF and to develop a model to estimate the temporal evolution of disease severity.

Methods:
We enrolled eligible patients from 2 large, multicenter prospective cohorts. The ACLF grade, organ failures, and outcomes were assessed at multiple time points (days 1/4/7/14/21/28). Probabilities for ACLF transitions between these disease states and to death within 28 days were calculated using a multi-state model that used baseline information and updated ACLF status. The model was validated in independent patients.

Results:
Among all the 445 patients with HBV-ACLF, 76 represented disease progression, 195 had a stable or fluctuating course, 8 with improvement, and the remaining 166 with resolution within 28-day follow-up. New coagulation (63.64%) or renal failure (45.45%) was frequently observed during early progression. Patients with disease progression had a higher incidence of new episodes of ascites [10 (13.16%) vs. 22 (5.96%), p = 0.027] and HE [13(17.11%) vs. 21 (5.69%), p = 0.001], and a significant increase in white blood cell count. The multi-state model represented dynamic areas under the receiver operating characteristic curves ranging from 0.71 to 0.84 for predicting all ACLF states and death at 4, 7, 14, 21, and 28 days post-enrollment and from 0.73 to 0.94 for predicting death alone, performing better than traditional prognostic scores.

Conclusions:
HBV-ACLF is a highly dynamic syndrome with reversibility. The multi-state model is a tool to estimate the temporal evolution of disease severity, which may inform clinical decisions on treatment.
Donut-shaped Corneal Allogeneic Intrastromal Segment as an Alternative to Deep Anterior Lamellar Keratoplasty in Advanced Keratoconus
Authors: Coscarelli Sandro , Coscarelli Sandro P. , Torquetti Leonardo 
Published: January 2024

Purpose:
The aim of this study was to describe a new technique of selective corneal stromal transplantation for keratoconus treatment, donut-shaped CAIRS (corneal allogeneic intrastromal ring segment).

Methods:
A donut-shaped corneal graft is obtained using a double-bladed trephine. Descemet membrane, endothelium, and epithelium are all removed from the graft. Only stromal tissue is transplanted. A wide 360-degree intrastromal tunnel is created using the femtosecond laser, with a 30-degree angulation. The diameter is from 5.4 mm to 8 mm optical zone. After dehydration, the corneal graft is inserted into the tunnel. We report the clinical and tomographic outcomes after the procedure in 3 patients.

Results:
The mean follow-up time after donut-shaped CAIRS was 6.01 ± 1.02 months. In case 1, best spectacle–corrected visual acuity improved from 20/150 to 20/40. In case 2, it improved from 20/400 to 20/40, and in case 3 from 20/200 to 20/40. The mean preoperative K was 57.3 ± 4.5 D and reduced to 44.2 ± 2.5 D after donut-shaped CAIRS. The mean spherical equivalent decreased from −9.8 ± 3.2 preoperatively to −3.2 ± 2.2 postoperatively. No intraoperative or postoperative complications were observed. Anterior segment OCT showed a mid-stroma implant, fusiform in shape, equidistant from the epithelium and endothelium.

Conclusions:
Donut-shaped CAIRS is a variation of the traditional CAIRS technique and showed to be an alternative option for keratoconus treatment, especially in moderate to advanced cases with a central clear cornea without scars. The technique is minimally invasive, and the visual axis remains untouched.
Would hyaluronic acid-induced mental bone resorption be a concern? A prospective controlled cohort study and an updated retrospective cohort study
Authors: Guo Xiaoshuang , Zong Xianlei , Song Guodong , Zhao Jingyi , Lai Chenzhi , Zhang Dong , Jin Xiaolei 
Published: January 2024

Background:
Hyaluronic acid (HA) is a widely used filler for face contouring and is generally believed to be safe and effective. However, there have been reports of HA-related bone erosion in the chin area without clear scientific data regarding its existence, incidence, and severity. This exploratory study was to evaluate HA-related mental bone resorption through a prospective, controlled, observer-blind, nonrandomized clinical trial and a retrospective cohort study.

Methods:
On the one hand, a prospective, controlled, nonrandomized, single-shot HA-injection clinical trial was conducted. Computed tomographic scans were collected at baseline and at 6–12 months of follow-up for both HA-injection and control groups. On the other hand, an updated retrospective cohort study compared the HA-injection with a blank control group. The primary outcomes composed of three quantitative parameters [bone resorption index (BRIM and BRIN), bone resorption thickness ratio] and one subjective evaluation index (severity ranking). Information about demographics, complications, and injection volume were also recorded.

Results:
From June 2021 to March 2023, 78 patients were prospectively recruited for the study. There was a significant association between HA-injection and bone resorption [BRIM: pre (84.24±8.10%) vs post (79.21±8.70%), P<0.001; BRIN: pre 92.50% (73, 144%) vs 87.99% (63, 132%), P<0.001; bone thickness ratio: HA 24.08% (0, 48%) vs control 0 (0, 17%), P<0.001]. However, there was no difference in large-volume (>1 ml) and small-volume (≦1 ml) injection subgroups [bone resorption thickness ratio: (21.50±10.91%) vs (24.51±11.92%), P=0.350]. The imaging manifestation revealed discernible bone resorption in 35.90% of the patients, with an median bone resorption thickness ratio of 24.08%. Between October of 2019 and March 2023, 95 HA-injection patients (190 semimandibular cases), 95 normal controls were enrolled. The BRIM was significantly lower in the HA-injection group compared to the controls (P<0.001).

Conclusions:
HA may induce bone resorption in the mentum. Large-scale randomized controlled clinical trial is warranted for further confirmation. Patients should be informed of this potential complication.
Patients with early-stage alcohol-associated liver disease are at increased risk of hospital readmission and death
Authors: Aryan Mahmoud , Qian Steve , Chen Zhiguo , Louissaint Jeremy , Qian Xia , Rosenblatt Russell , Verna Elizabeth , Brown Robert , Wong Robert , Clark Virginia , Zhang Wei 
Published: January 2024

Background and aims
Patients with alcohol use disorder (AUD) can develop alcohol-associated fatty liver disease (AFLD). However, the impact of AFLD on outcomes remains unclear. We studied the impact of AFLD on readmission, 30-day mortality, and overall mortality in patients admitted with AUD.

Methods
Hospitalized patients with AUD between 2011 and 2019 at a tertiary medical center were retrospectively evaluated. Our population included patients with AUD with AFLD: AST and ALT elevation and serum bilirubin <3 mg/dl. Patients with AUD without evidence of liver disease served as control and were labeled as no ALD. Patients with alcohol-associated cirrhosis (AC) and alcohol-associated hepatitis (AH) were included for comparison. Kaplan–Meier survival analysis and multivariable regression for predictors of mortality and survival were performed.

Results
There were 7522 patients of which 32.44% were female with mean age of 51.86 ± 14.41 years. Patient distribution included no ALD (n = 3775), AFLD (n = 2192), AC (n = 1017) and AH (n = 538) groups. Compared to no ALD group, AFLD group was associated with significantly higher 30-day mortality [4.43% vs. 1.56%, hazard ratio (HR): 2.84; P < 0.001], overall mortality [15.97% vs. 12.69%, HR 1.40, P < 0.001], and 30-day readmission [21.85% vs. 18.49%, odds ratio: 1.21; P < 0.01].

Conclusion
We demonstrated that AFLD is not a benign entity and poses significant mortality risk. Our results suggest that AFLD may be under-recognized and highlight the need for focused management and close follow-up after discharge.
Syphilis prevalence among people living with and without HIV in sub-Saharan Africa: A systematic review and meta-analysis
Authors: Mussa Aamirah , Jarolimova Jana , Ryan Rebecca , Wynn Adrianne , Ashour Dina , Bassett Ingrid V. , Philpotts Lisa L. , Freyne Bridget , Morroni Chelsea , Dugdale Caitlin M. 
Published: January 2024

Abstract

Background
Syphilis is a curable sexually transmitted infection which, untreated, is associated with significant morbidity and mortality. In people living with HIV (PLWH), syphilis carries greater risks of disease progression. We estimated syphilis prevalence among PLWH in the general population in sub-Saharan Africa and compared prevalence among PLWH and without HIV.

Methods
We searched for studies published 1st January 2011 to 28th March 2022 reporting syphilis prevalence among PLWH in sub-Saharan Africa (PROSPERO#: CRD42020167328). We excluded studies in high-risk subpopulations. We estimated pooled syphilis prevalence among PLWH using random effects modelling and compared prevalence to people without HIV when included in the same study. We examined influences of region, study setting, and test type in subgroup analyses.

Results
We identified 926 studies; 53 were included in the meta-analysis. Pooled syphilis prevalence among PLWH was 7.3% (95% CI: 6.3-8.5%). Prevalence differed by region: 3.1% (95% CI: 2.2-4.0%) in Southern, 5.5% (95% CI: 2.3-9.3%) in West/Central, and 10.5% (95% CI: 8.0-13.1%) in Eastern Africa. Prevalence also differed by study setting: 13.8% (95% CI 5.7-23.0%) in SRH/STI care, 8.7% (95% CI 5.0-12.8%) in HIV care, 7.1% (95% CI 5.8-8.5%) in antenatal care and 3.8% (95% CI 2.0-5.8%) household/community-based settings. Syphilis prevalence was higher among PLWH than without HIV (RR: 3.5, 95% CI: 2.8-4.5).

Conclusions
Syphilis is highly prevalent among PLWH in sub-Saharan Africa and is more common among PLWH than without HIV. Integration of syphilis screening and management into HIV care may reduce complications of HIV-syphilis co-infection among PLWH in sub-Saharan Africa.
Development of a proposed organizational framework for undergraduate research training in prosthetics and orthotics education
Authors: Siriwatsopon Juthamas , Samala Manunchaya , Guerra Garry , Kongsatan Pattaraporn , Rayothee Pitchaya 
Published: January 2024

Background:
An undergraduate research project gives prosthetic and orthotic (P&O) students the chance to acquire both foundational research knowledge and in-depth knowledge in a specific area of interest in P&O research. Undergraduates frequently enter the field of research with less experience or understanding of research instruments, presenting them with significant obstacles when conducting research.

Objective:
This study's objective was to establish a framework for undergraduate research training in prosthetics and orthotics education.

Methods:
Using narrative qualitative methodology, 4 successive phases of research were conducted. Phase I: A document analysis was conducted to determine the presence of research training in Thailand's undergraduate P&O curriculum taught in 2021; phase II: document analysis of student P&O program feedback reports using manifest content analysis; phase III: strengths, weaknesses, opportunities, and threats analysis of lecturer P&O program feedback reports; and phase IV: data sets from phases I, II, and III were applied to the formulation of a unifying framework. Using grounded theory's three-stage thematic analysis—open, axial, and selective coding—data were analyzed.

Conclusions:
The novel organizational research framework is presented as the result and conclusion of the study. The framework for enhancing this important foundational research program at the undergraduate level was derived through discussion with colleagues and based on the results and discussion from this investigation. Although the framework for undergraduate research training was designed for use by the undergraduate prosthetics and orthotics program in Thailand, it is believed to be applicable and relevant to P&O education worldwide.
Design and characterization of a variable-stiffness ankle-foot orthosis
Authors: Rong Haochen , Ramezani Sepehr , Ambro Alex , Lei Chi Hou , Choi Hwan 
Published: January 2024

Background:
Ankle-foot orthoses (AFOs) are a type of assistive device that can improve the walking ability of individuals with neurological disorders. Adjusting stiffness is a common way to customize settings according to individuals' impairment.

Objective:
This study aims to design a variable-stiffness AFO by stiffness module and characterize the AFO stiffness range to provide subject-specific settings for the users.

Methods:
We modeled AFO using bending beams with varying fulcrum positions to adjust the stiffness. To characterize the stiffness range and profile, we used the superposition method to generate the theoretical model to analyze the AFO numerically. The intrinsic deformation of the bending beam in the AFO is considered a combination of 2 bending deformations to replicate actual bending conditions. The corresponding experiments in different fulcrum positions were performed to compare with and optimize the theoretical model. The curve fitting method was applied to tune the theoretical model by adding a fulcrum position–related coefficient.

Results:
The AFO stiffness increased as the fulcrum moved to the proximal position. The maximum stiffness obtained was 1.77 Nm/° at a 6-cm fulcrum position, and the minimum stiffness was 0.82 Nm/° at a 0.5-cm fulcrum position with a 0.43-cm thick fiberglass beam. The corresponding theoretical model had maximum and minimum stiffness of 1.71 and 0.80 Nm/°, respectively. The theoretical model had a 4.08% difference compared with experimental values.

Conclusions:
The stiffness module can provide adjustable stiffness with the fulcrum position and different kinds of fiberglass bars, especially the thickness and material of the beam. The theoretical model with different fulcrum positions can be used to profile the real-time stiffness of the AFO in a dynamic motion and to determine the appropriate dimensions of the bending beam.
Evaluation of the prevention of mother-to-child transmission of HIV programs at the second immunization visit in Burkina Faso and Zambia
Authors: Tassembedo Souleymane , Mwiya Mwiya , Mennecier Anais , Kankasa Chipepo , Fao Paulin , Molès Jean Pierre , Kania Dramane , Chunda-Liyoka Catherine , Sakana Béninwendé Leticia Delphine , D’Ottavi Morgana , Taofiki Ajani Ousmane , Rutagwera David , Wilfred-Tonga Maria Melany , Tylleskär Thorkild , Nagot Nicolas , Van de Perre Philippe ,   for the PROMISE-EPI Study Group∗
Published: January 2024

Objective:
Our study aimed to assess the PMTCT indicators in Burkina Faso and Zambia using a patient-orientated innovative strategy based on the second visit in the Expanded Program on Immunization (EPI-2) visit at 6–8 weeks.

Design:
This was a cross sectional study.

Methods:
We assessed women attending EPI-2 at primary healthcare facilities in Burkina Faso and Zambia with their children about their exposure to PMTCT interventions. For women living with HIV (WLHIV), viral load was measured and their children were tested for HIV DNA using point of care devices.

Results:
Overall, 25 093 were enrolled from Burkina Faso and 8961 women from Zambia. Almost, all women attended at least one antenatal care visit. Among those aware of their HIV-positive status, 95.8 and 99.2% were on antiretroviral therapy (ART) in Burkina Faso and Zambia, respectively. Among WLHIV on ART, 75 and 79.2% achieved a viral load suppression (viral load <1000 copies/ml) in Burkina Faso and Zambia, respectively. Infant postnatal prophylaxis was administered from birth until EPI-2 to 60.9 and 89.7% of HIV-exposed children in Burkina Faso and Zambia, respectively. In Burkina Faso, only 60 of 192 (31.3%) of HIV-exposed children were sampled at day 42 for early infant diagnosis (EID) and 3 (1.6%) received a result by EPI-2. In Zambia, these figures were 879 of 1465 (64.0%) and 9.9% (145/1465), respectively for HIV-exposed children sampled at birth.

Conclusion:
This evaluation strategy at EPI-2 visit could strengthen program monitoring and help identifying gaps to be addressed on the last mile towards elimination of MTCT of HIV.