bluuebunny/crossref_metadata_2025_split huggingface dataset:
β-Hemolysin, not
agrA
mutation, inhibits the hemolysis of α-hemolysin in
Staphylococcus aureus
laboratory and clinical strains
Authors: Liu Lin , Zhuang Hemu , Wang Yanfei , Tu Yuexing , Yu Yunsong , Chen Yan , Wu Xueqing 
Published: January 2024

ABSTRACT

Staphylococcus aureus
produces various hemolysins regulated by the Agr-QS system, except β-hemolysin encoded by the gene
hlb
. A classical laboratory
S. aureus
strain RN4220 displays only the β-hemolysin phenotype. It was suspected that the 8A mutation at the end of its
agrA
gene delayed the expressions of
hla
and
RNAIII
, then failed to express α- and δ-hemolysins. However,
hla
gene expression was detected at the later culture time without α-hemolysin phenotype, the reason for such a phenotype has not been clearly understood. We created
hlb
knockout and complementary mutants via homologous recombination in RN4220 and NRS049, two strains that normally produce β-hemolysin and carry
agrA
mutation. We found interestingly that the presence or absence of α-hemolysin phenotype in such strains depended on the expression of β-hemolysin instead of
agrA
mutations, which only inhibited δ-hemolysin expression. The hemolysis phenotype was verified by the Christie-Atkinson-Munch-Peterson (CAMP) test. Quantitative reverse transcription PCR was carried out to evaluate the relative gene expressions of
hlb
,
hla
, and
RNAIII
. The construction of mutants did not affect the
agrA
mutation status. We demonstrate that the absence of α-hemolysin in
S. aureus
RN4220 and NRS049 strains is attributed to their production of β-hemolysin instead of
agrA
mutation. Our findings broaden the understanding of the molecular mechanisms that control hemolysin expression in
S. aureus
that is crucial for the development of new therapeutic strategies to combat
S. aureus
infections.

IMPORTANCE

α-Hemolysin is a critical virulence factor in
Staphylococcus aureus
and its expression is largely controlled by the Agr-QS system. Nonetheless, the hemolysis phenotype and the regulation of the Agr-QS system in
S. aureus
still hold many mysteries. Our study finds that it is the expression of β- hemolysin rather than the
agrA
mutation that inhibits the function of the α-hemolysin in an important
S. aureus
strain RN4220 and a clinical strain presents a similar phenotype, which clarifies the misunderstood hemolytic phenotype and mechanism of
S. aureus
. Our findings highlight the interactions among different toxins and their biological roles, combined with QS system regulation, which is ultimately the true underlying cause of its virulence. This emphasizes the importance of considering the collaborative action of various factors in the infection process caused by this significant human pathogen.
Fault activity in the San Gabriel Mountains, southern California, USA: Insights from landscape morphometrics, erosion rates, and fault-slip rates
Authors: Mere Andre M. , McPhillips Devin 
Published: January 2024

Abstract
Many studies use landscape form to determine spatial patterns of tectonic deformation, and these are particularly effective when paired with independent measures of rock uplift and erosion. Here, we use morphometric analyses and 10Be catchment-averaged erosion rates, together with reverse slip rates from the Sierra Madre–Cucamonga fault zone, to reveal patterns in uplift, erosion, and fault activity in the range front of the San Gabriel Mountains in southern California, USA. Our analysis tests two prevailing hypotheses: (1) the range front of the San Gabriel Mountains is at steady state, in which rock uplift balances erosion and topographic elevations are stable throughout time, and (2) that west-to-east increases in elevation, relief, erosion rate, and stream-channel steepness across the interior of the massif reflect a parallel reverse-slip rate gradient on the range-bounding Sierra Madre–Cucamonga fault zone. We show that although deviations from steady state occur, the range-front hillslopes and stream channels are typically both well-connected and adjusted to patterns in Quaternary uplift driven by motion on the range-front fault network. Accordingly, landscape morphometrics, 10Be erosion rates, and model erosion rates effectively image spatial and temporal patterns in uplift. Interpreted jointly, these data reveal comparable peak slip rates on the Sierra Madre–Cucamonga fault zone and show that they do not monotonically increase from west to east. Thus, the eastward-increasing gradients developed within the interior of the massif are not solely related to reverse slip on the range-front faults. Evaluated on shorter length scales (&lt;10 km), morphometric data corroborate earlier descriptions of the Sierra Madre–Cucamonga fault zone as multiple individual faults or fault sections, with slip rates tapering toward fault tips. We infer that these patterns imply the predominance of independent fault or fault section ruptures throughout the Quaternary, though data cannot rule out the possibility of large, connected Sierra Madre–Cucamonga fault zone ruptures. Deeper in the hanging wall of the Sierra Madre–Cucamonga fault zone, secondary faults accommodate range-front uplift. Motion on these faults may contribute to active uplift of the highest topography within the massif, in addition to partly reconciling differences between geologic and geodetic Sierra Madre–Cucamonga fault zone reverse-slip rates. This study provides a new, unified perspective on tectonics and landscape evolution in the San Gabriel Mountains.
Ferroptosis in the Pathogenesis of Alzheimer’s Disease: The New Evidence for Validation of FAB Model
Authors: Aghajanov M. I. , Harutyunyan H. S. , Khamperyan A. Kh. , Karapetyan G. A. , Fereshetyan K. S. , Yenkoyan K. B. 
Published: January 2024

Abstract
Alzheimer’s disease is an age-associated progressive disorder, characterized by neurodegeneration and following cognitive decline. Several pathological alterations are implicated in its pathogenesis, hence etiology is still poorly understood. Ferroptosis is an alternative form of cell death, driven by intracellular accumulation of iron with subsequent reactive oxygen species formation, which damages membranes, proteins, and DNA, causing cell death. The imbalance in iron homeostasis is rapidly gaining weight as a neurodegeneration cause, increasing the need to develop in vivo and in vitro models to understand the role of ferroptosis in Alzheimer’s disease pathogenesis. This review focuses on the mechanisms of ferroptosis in the pathogenesis of AD, giving a detailed overview of the available in vivo and in vitro methods and their applications, as well as describing in detail the ferrous amyloid buthionine (FAB) model.
Heterogeneity in disease activity, frequency of treatments, and visual outcomes among patients with retinal vein occlusion: relationship between injection need and vision with as-needed ranibizumab
Authors: Bhisitkul Robert B , Campochiaro Peter A , Blotner Steven , Quezada-Ruiz Carlos , Liu Mimi , Haskova Zdenka 
Published: January 2024

Background/aimsWe characterised the relationships between monitoring frequency, ranibizumab injection need and vision in patients receiving as-needed (pro re nata; PRN) ranibizumab for macular oedema due to branch retinal vein occlusion (BRVO) or central retinal vein occlusion (CRVO) in this post-hoc analysis of SHORE and HORIZON.MethodsPatients aged 18 years and older with macular oedema due to BRVO/CRVO were included in this analysis. Injection frequency and best-corrected visual acuity (BCVA) were evaluated by PRN injection frequency in the PRN dosing phase (months (M) 7–15) of SHORE and through 12 months of HORIZON. Prespecified PRN re-treatment criteria for each trial were based on protocol-prespecified BCVA and optical coherence tomography outcomes.ResultsAfter the initial 7 monthly ranibizumab injections, patients in SHORE gained a mean of 18.3 letters from baseline. Patients randomised to PRN, on average, maintained these gains. However, some patients experienced additional mean gains, whereas others suffered losses (range 4.0 (95% CI 0.7 to 7.3) to −4.6 (95% CI −11.8 to 2.6) letters in patients who received 0 and 6–7 PRN injections, respectively). In BRAVO and CRUISE (lead-in trials), patients experienced mean gains from baseline to M6 (monthly dosing) of 19.3 and 15.0 letters, respectively, with gains maintained with PRN from M6 to M12. However, mean BCVA changes from baseline to M12 varied in HORIZON (range −0.4 (95% CI −2.5 to 1.6) to −3.6 (95% CI −6.2 to −1.0) letters in patients who received zero and six injections, respectively, during the preceding PRN phase of BRAVO and CRUISE).ConclusionThe BRVO/CRVO population is heterogenous with a varied response to ranibizumab treatment.
Two-year outcomes of different subretinal fluid drainage techniques during vitrectomy for fovea-off rhegmatogenous retinal detachments: ELLIPSOID-2 study
Authors: McKay Bryon R , Bansal Aditya , Kryshtalskyj Michael , Wong David T , Berger Alan R , Muni Rajeev H 
Published: January 2024

BackgroundThe purpose of the study is to compare visual acuity, complications and outer retinal integrity following subretinal fluid (SRF) drainage from the peripheral retinal breaks (PRBs) versus posterior retinotomy (PR) versus perfluorocarbon liquid (PFCL) for macula-off rhegmatogenous retinal detachments (RRDs) at 2 years post-surgery.MethodsRetrospective analysis of 300 consecutive patients with primary RRD undergoing 23-gauge pars plana vitrectomy with SRF drainage through (1) PRB (n=100), (2) PR (n=100) or (3) with PFCL (n=100). Primary outcomes were visual acuity (best-corrected visual acuity (BCVA)) and complications (cystoid macular oedema (CMO) and epiretinal membrane (ERM)). Secondary outcomes were discontinuity of the external limiting membrane (ELM), ellipsoid zone (EZ) and interdigitation zone (IDZ) at 2 years post-surgery.ResultsMean (±SD) logMAR BCVA at 24 months was better in the PRB compared with PR and PFCL, with PFCL having the worst BCVA (PRB 0.5±0.6; PR 0.7±0.5; PFCL 0.9±0.7, p=0.001). CMO was higher with PFCL (PRB 29.7%; PR 30.2%; PFCL 45.9%, p=0.0015) and ERM formation was higher in PR (PRB 62.6%; PR 93.0%; PFCL 68.9%, p=0.002). There were no differences in ELM or EZ discontinuity. However, IDZ discontinuity was higher in PFCL (PRB 34%; PR 27%; PFCL 46%, p=0.002) at 2 years.ConclusionsVisual acuity was worse and discontinuity of the IDZ and CMO was greater in eyes with PFCL-assisted drainage compared with PRB or PR. Drainage technique may impact long-term visual acuity and photoreceptor integrity.
Low-dose atropine 0.01% for the treatment of childhood myopia: a pan-India multicentric retrospective study
Authors: Saxena Rohit , Gupta Vinay , Dhiman Rebika , Joseph Elizabeth , Agarkar Sumita , Neena R , Magdalene Damaris , Jethani Jitendra , Ganesh Sandra C , Patil Minal , Gogri Pooja , Gadaginamath Shailesh , Sen Pradhnya , Sukhija Jaspreet , Mishra Deepak , Matalia Jyoti H , Sahu Anupam , Kapoor Smita , Nishanth Shruti , Chaurasia Shweta , Pawar Neelam , Deori Nilutparna , Sivaraman Viswanathan , Bordoloi Anamika , Tibrewal Shailja , Singh Davinder , Prasad Priyanka , Phuljhele Swati , Sharma Namrata 
Published: January 2024

ObjectiveThe objective of this study was to assess the efficacy of low-dose atropine 0.01% in controlling myopia progression among Indian children over a 2-year period.MethodsThis retrospective study, conducted across 20 centres in India, monitored the progression of myopia over 2 years after initiating treatment with 0.01% atropine eye drops. This included children between 6 and 14 years with baseline myopia ranging from −0.5 D to −6 D, astigmatism≤−1.5 D, anisometropia ≤ −1 D and documented myopia progression of ≥0.5 D in the year prior to starting atropine. Subjects with any other ocular pathologies were excluded.ResultsA total of 732 children were included in the data analysis. The mean age of the subjects was 9.3±2.7 years. The mean myopia progression at baseline (1 year before starting atropine) was −0.75±0.31 D. The rate of myopia progression was higher in younger subjects and those with higher baseline myopic error. After initiating atropine, myopia progression significantly decreased to −0.27±0.14 D at the end of the first year and −0.24±0.15 D at the end of the second year (p<0.001). Younger children (p<0.001) and higher baseline myopia (p<0.001) was associated with greater myopia progression and poor treatment response (p<0.001 for both).ConclusionLow-dose atropine (0.01%) effectively reduces myopia progression over 2 years in Indian children.
European priority review vouchers for neglected disease product development
Authors: Ridley David B , Lasanta Agustín Martín , Storer Jones Ffion , Ridley Sarah K 
Published: January 2024

IntroductionNeglected diseases are a significant global health challenge. Encouraging the development of therapeutics and vaccines for these diseases would address an important unmet medical need. We propose a priority review voucher programme for the European Union (EU). The developer of a drug or vaccine for a neglected disease would receive a voucher for accelerated assessment of a different product at the European Medicines Agency (EMA).MethodsThis study uses retrospective observational data to estimate the potential commercial value of the proposed voucher programme using a five-step approach: (1) estimating the time saved in the EMA accelerated regulatory review; (2) gauging time reductions in accelerated pricing and reimbursement decisions by EU member states; (3) selecting 10 high-revenue products launched between 2015 and 2020 representing typical voucher users; (4) analysing IQVIA MIDAS sales data for the selected products and (5) calculating the net present value (NPV) of the voucher based on the 10 products.ResultsThe accelerated EMA review would reduce regulatory time by an average of 182 days. Additionally, products could save more than a year in many member states through an expedited 120-day pricing and reimbursement review. The estimated NPV of regulatory acceleration by two quarters would be €100 million. In addition, if France, Italy and Spain reviewed pricing and reimbursement in only 120 days, then the value would double.ConclusionAn EU voucher estimated at more than €100 million, coupled with a US$100 million counterpart, offers a meaningful incentive for novel product development. However, the voucher programme should be part of a comprehensive strategy for tackling neglected diseases, rather than a standalone solution.
Rapidly scalable and low-cost public health surveillance reporting system for COVID-19
Authors: Jayaraj Vivek Jason , Ng Chiu-Wan , Hoe Victor Chee-Wai , Chong Diane Woei-Quan , Rampal Sanjay 
Published: January 2024

ObjectiveData-driven innovations are essential in strengthening disease control. We developed a low-cost, open-source system for robust epidemiological intelligence in response to the COVID-19 crisis, prioritising scalability, reproducibility and dynamic reporting.MethodsA five-tiered workflow of data acquisition; processing; databasing, sharing, version control; visualisation; and monitoring was used. COVID-19 data were initially collated from press releases and then transitioned to official sources.ResultsKey COVID-19 indicators were tabulated and visualised, deployed using open-source hosting in October 2022. The system demonstrated high performance, handling extensive data volumes, with a 92.5% user conversion rate, evidencing its value and adaptability.ConclusionThis cost-effective, scalable solution aids health specialists and authorities in tracking disease burden, particularly in low-resource settings. Such innovations are critical in health crises like COVID-19 and adaptable to diverse health scenarios.
Advising parents when their child has a fever: a phenomenographic analysis of nurses’ perceptions when working at a telephone helpline, at primary care or at a paediatric emergency department in Sweden
Authors: Westin Emma , Gustafsson Ingrid L , Svensson Anders , Sund-Levander Märta , Elmqvist Carina 
Published: January 2024

ObjectivesTo describe nurses’ perceptions of advising parents when their child has a fever.Design/methodInductive, descriptive study with a qualitative, phenomenographic approach.Participants and settingA purposive sampling was used. To be included, the 24 online interviewed nurses had to have experience advising parents of febrile children between birth and 5 years of age. They were recruited from three different parts of the healthcare system from four regions in the south of Sweden.ResultsThe nurses described advising parents when their child has a fever as four different kinds of balancing acts: balancing between the parents’ story and objective assessment, balancing between listening and teaching, balancing between self-confidence and trust in the expert, and balancing between independence and having someone by one’s side.ConclusionsGiving advice to parents when their child has a fever is a process where the nurse needs to listen, assess and give advice based on the situation. This requires a correct assessment that depends on the parents’ story. Creating a trusting relationship is perceived as necessary for parents to assimilate the advice that is provided. What dominates are the nurses’ perceptions of the inner qualities required to achieve a balance in the process, for example, the importance of experience and security in their professional role, while it is also necessary to get support from colleagues.
Non-indicated initiation of proton pump inhibitor and risk of adverse outcomes in patients with underlying chronic kidney disease: a nationwide, retrospective, cohort study
Authors: Kim Seong Geun , Cho Jeong Min , Han Kyungdo , Joo Kwon-Wook , Lee Soojin , Kim Yaerim , Cho Semin , Huh Hyuk , Kim Minsang , Kang Eunjeong , Kim Dong Ki , Park Sehoon 
Published: January 2024

ObjectiveEvidence related to the risk of kidney damage by proton pump inhibitor (PPI) initiation in patients with ‘underlying’ chronic kidney disease (CKD) remains scarce, although PPI use is generally associated with acute interstitial nephritis or incident CKD. We aimed to investigate the association between PPI initiation and the risk of adverse outcomes in patients with CKD in the absence of any deterministic indications for PPI usage.DesignRetrospective observational study.SettingKorea National Health Insurance Service database from 2009 to 2017.ParticipantsA retrospective cohort of new PPI and histamine H2-receptor antagonists (H2RA) users among people with CKD. Patients with a history of gastrointestinal bleeding or those who had an endoscopic or image-based upper gastrointestinal tract evaluation were excluded.Primary and secondary outcome measuresThe study subjects were followed to ascertain clinical outcomes including mortality, end-stage kidney disease (ESKD), myocardial infarction and stroke. The HRs of outcomes were measured using a Cox regression model after adjusting for multiple variables. We applied an inverse probability of treatment weighting (IPTW) model to control for residual confounders.ResultsWe included a total of 1038 PPI and 3090 H2RA users without deterministic indications for treatment. IPTW-weighted Cox regression analysis showed that PPI initiation was more significantly associated with a higher ESKD risk compared with that of H2RA initiation (adjusted HR 1.72 (95% CI 1.19 to 2.48)), whereas the risks of mortality or cardiovascular outcomes were similar between the two groups. In the subgroup analysis, multivariable Cox regression analysis showed that the association between PPI use and the progression to ESKD remained significant in non-diabetic and low estimated glomerular filtration rate (<60 mL/min/1.73 m2) groups (adjusted HR 1.72 (95% CI 1.19 to 2.48) and 1.63 (95% CI 1.09 to 2.43), respectively).ConclusionsInitiation of PPI administration may not be recommended in patients with CKD without deterministic indication, as their usage was associated with a higher risk of ESKD.
Protocol for the combined cardiometabolic deep phenotyping and registry-based 20-year follow-up study of the Inter99 cohort
Authors: Bjørnsbo Kirsten Schroll , Brøns Charlotte , Aadahl Mette , Kampmann Freja Bach , Friis Bryde Nielsen Camilla , Lundbergh Bjørn , Wibaek Rasmus , Kårhus Line Lund , Madsen Anja Lykke , Hansen Christian Stevns , Nørgaard Kirsten , Jørgensen Niklas Rye , Suetta Charlotte , Kjaer Michael , Grarup Niels , Kanters Jørgen , Larsen Michael , Køber Lars , Kofoed Klaus Fuglsang , Loos Ruth JF , Hansen Torben , Linneberg Allan , Vaag Allan 
Published: January 2024

IntroductionThe population-based Inter99 cohort has contributed extensively to our understanding of effects of a systematic screening and lifestyle intervention, as well as the multifactorial aetiology of type 2 diabetes (T2D) and cardiovascular disease. To understand causes, trajectories and patterns of early and overt cardiometabolic disease manifestations, we will perform a combined clinical deep phenotyping and registry follow-up study of the now 50–80 years old Inter99 participants.Methods and analysisThe Inter99 cohort comprises individuals aged 30–60 years, who lived in a representative geographical area of greater Copenhagen, Denmark, in 1999. Age-stratified and sex-stratified random subgroups were invited to participate in either a lifestyle intervention (N=13 016) or questionnaires (N=5264), while the rest served as a reference population (N=43 021). Of the 13 016 individuals assigned to the lifestyle intervention group, 6784 (52%) accepted participation in a baseline health examination in 1999, including screening for cardiovascular risk factors and prediabetic conditions. In total, 6004 eligible participants, who participated in the baseline examination, will be invited to participate in the deep phenotyping 20-year follow-up clinical examination including measurements of anthropometry, blood pressure, arterial stiffness, cardiometabolic biomarkers, coronary artery calcification, heart rate variability, heart rhythm, liver stiffness, fundus characteristics, muscle strength and mass, as well as health and lifestyle questionnaires. In a subsample, 10-day monitoring of diet, physical activity and continuous glucose measurements will be performed. Fasting blood, urine and faecal samples to be stored in a biobank. The established database will form the basis of multiple analyses. A main purpose is to investigate whether low birth weight independent of genetics, lifestyle and glucose tolerance predicts later common T2D cardiometabolic comorbidities.Ethics and disseminationThe study was approved by the Medical Ethics Committee, Capital Region, Denmark (H-20076231) and by the Danish Data Protection Agency through the Capital Region of Denmark’s registration system (P-2020-1074). Informed consent will be obtained before examinations. Findings will be disseminated in peer-reviewed journals, at conferences and via presentations to stakeholders, including patients and public health policymakers.Trial registration numberNCT05166447.