bluuebunny/crossref_metadata_2025 huggingface dataset:
Adrenaline intravenous therapy persistence grade I severe allergic reaction: A case report and literature review
Authors: Wang Wei , Zhang Ying , Tao Li , Jiang Tong-Xue , Wang Ning , Zhai Wen-Hui
Published: August 2024

Rationale:

At present, there is still insufficient understanding of the progression from persistent allergic reactions to severe reactions. Adrenaline remains the preferred medication for severe allergic reactions, and intramuscular injection of adrenaline can also be considered for patients with grade I reactions that are difficult to alleviate gastrointestinal symptoms. It is worth further discussing whether it is possible to break the conventional intramuscular injection recommended by the guidelines when the effect of intramuscular injection is not ideal for persistent grade I severe allergic reactions.

Patient concerns:

A young male, 20 years of age, was admitted to emergency department because of repeated rash for 3 days and abdominal pain for 6 hours after taking traditional Chinese medicine. After hormone therapy, the rash continued to recur and secondary gastrointestinal symptoms occurred on the 3th day. Adrenaline intramuscular injection was given to temporarily relieve the rash and abdominal pain, but symptoms still persisted.

Diagnosis:

The patient was diagnosed with persistent severe allergic reaction (grade I).

Interventions:

Continuous intravenous infusion of low-dose adrenaline under electrocardiographic monitoring, real-time monitoring of heart rate and blood pressure, and routine treatment with methylprednisolone, diphenhydramine, calcium gluconate, and cetirizine. During this period, adrenaline intramuscular injection is temporarily added when abdominal pain symptoms are obvious. The entire treatment process used a total of 6.8 mg of adrenaline.

Outcomes:

During the entire period of adrenaline intervention, the patient did not experience any new discomfort, and there were no abnormal fluctuations in heart rate, rhythm, or blood pressure. The symptoms of rash and abdominal pain gradually improved.

Lessons:

For patients with persistent grade I severe allergic reactions, intravenous administration of low-dose adrenaline under close vital sign monitoring is safe, feasible, and highly effective in preventing biphasic, persistent, or worsening allergic reactions.
A case report of interstitial pneumonia induced by vedolizumab in a patient with ulcerative colitis
Authors: Liu Ailing , Ye Susu , Diao Zeyuan , Liu Hua , Xu Yonghong , Wu Jun , Mao Tao , Tian Zibin , Ding Xueli
Published: August 2024

Rationale:

The interstitial pneumonia (IP) linked to vedolizumab (VDZ) in patients with ulcerative colitis (UC) is rare. Prompt diagnosis and treatment can improve patient outcomes.

Patient concerns:

A 39-year-old man with UC who received VDZ as sole therapy developed symptoms such as chest tightness, cough, and suffocation.

Diagnoses:

IP was confirmed through pulmonary function tests, chest computed tomography, and bronchoscopic biopsy.

Interventions:

The patient was given methylprednisolone and VDZ cessation.

Outcomes:

The patient’s symptoms improved and remained symptom-free after nearly 2 years.

Lessons:

VDZ-induced IP should be considered when evaluating pulmonary infections in UC patients treated with VDZ.
Central nervous system nocardiosis in a 54-year-old man with lateral ventricular choroid plexitis and diffused meningitis: A case report
Authors: Yu Qiujian , Dai Shujuan , Pang Ailan
Published: August 2024

Introduction:

Nocardiosis is an unusual infection caused by aerobic gram-positive bacteria in the genus Nocardia. Infections resulting from Nocardia species are frequent in immunosuppressive patients. Weakened immune systems caused by human immunodeficiency virus infection, diabetes, cancer, and other conditions such as chronic lung disease, renal failure, etc, are the main risk factors for nocardiosis. Central nervous system (CNS) nocardiosis has been reported to represent ~2% of all and to be present in 15% to 50% of patients with systemic infection. The patient in our case had an isolated CNS nocardiosis caused by Nocardia terpenica infection, a rare reclassified Nocardia pathogen of CNS nocardiosis.

Case:

We here present a 54-year-old Chinese male with a fever and headache for 15 days who showed positive meningeal irritation signs. Magnetic resonance imaging showed the right trigone of the lateral ventricular choroid plexitis and diffused leptomeningeal meningitis involving the bilateral cerebral hemisphere, cerebellar hemisphere, and brain stem. The patient was quickly diagnosed with CNS Nocardia infection by next-generation sequencing within 48 hours after admission. Meanwhile, the diagnosis was validated by Nocardia-positive staining in cerebral spinal fluid culturing. The patient was given trimethoprim-sulfamethoxazole, and his symptoms recovered after 3 days.

Conclusions:

In this case, the clinical, radiological, and microbiological findings highlight the importance of suspecting Nocardia as the potential pathogen in patients with central nervous system inflammation of doubted immune incompetence. In addition, next-generation sequencing as an effective test is also highly recommended for suspicious CNS infection patients to perform a rapid diagnosis and treatment.
Viewpoint: The impending pandemic of resistant organisms – a paradigm shift towards source control is needed
Authors: Kavanagh Kevin T. , Maiwald Matthias , Cormier Lindsay E.
Published: August 2024

The United States needs a paradigm shift in its approach to control infectious diseases. Current recommendations are often made in a siloed feedback loop. This may be the driver for such actions as the abandonment of contact precautions in some settings, the allowance of nursing home residents who are carriers of known pathogens to mingle with others in their facility, and the determination of an intervention’s feasibility based upon budgetary rather than health considerations for patients and staff. Data from both the U.S. Veterans Health Administration and the U.K.’s National Health Service support the importance of carrier identification and source control. Both organizations observed marked decreases in methicillin-resistant Staphylococcus aureus (MRSA), but not methicillin-susceptible Staphylococcus aureus infections with the implementation of MRSA admission screening measures. Facilities are becoming over-reliant on horizontal prevention strategies, such as hand hygiene and chlorhexidine bathing. Hand hygiene is an essential practice, but the goal should be to minimize the risk of workers’ hands becoming contaminated with defined pathogens, and there are conflicting data on the efficacy of chlorhexidine bathing in non-ICU settings. Preemptive identification of dedicated pathogens and effective source control are needed. We propose that the Centers for Disease Control and Prevention should gather and publicly report the community incidence of dedicated pathogens. This will enable proactive rather than reactive strategies. In the future, determination of a patient’s microbiome may become standard, but until then we propose that we should have knowledge of the main pathogens that they are carrying.
Poor intraoperative visibility and postoperative astigmatism associated with trabecular micro-bypass stent for corneal dystrophy: A case report
Authors: Nakagawa Suguru , Ishii Kiyoshi
Published: August 2024

Rationale:

There are reports of safe cataract surgery in eyes with posterior polymorphous corneal dystrophy (PPCD); however, to our knowledge, there are no reports of minimally invasive glaucoma surgery (MIGS) in eyes with PPCD. Herein, we report a case of poor intraoperative visibility with gonioscopy, postoperative corneal edema, and corneal astigmatism in eyes with PPCD treated with trabecular micro-bypass stent combined with cataract surgery.

Patient concerns/Diagnosis:

A 78-year-old man was referred to our hospital for MIGS. He presented with bilateral corneal endothelial vesicular changes and band lesions. Endothelial cell density was 2983/2871 cells/mm2 (right/left eye), central corneal thickness was 581 μm/572 μm, best-corrected visual acuity values (Snellen equivalent) were 20/32 (right) and 20/100 (left), and corneal astigmatism was −2.7D in the right eye and −2.5D in the left eye.

Intervensions/ Outcoms:

After phacoemulsification and aspiration with intraocular lens implantation with a 2.4-mm corneal incision in both eyes, trabecular micro-bypass stents were inserted successfully despite the poor intraoperative visibility with gonioscopy. One week after surgery, the central corneal thickness was 614 μm/609 μm, and Descemet’s membrane folds and mild corneal edema were observed. Best-corrected decimal visual acuity was 20/40 for the right eye and 20/50 for the left eye. In the left eye, total corneal astigmatism increased from −2.5D to −5.5D. Corneal astigmatism and edema showed gradual improvement.

Lessons:

Although reports have shown that cataract surgery can be safely performed in eyes with PPCD, MIGS in eyes with PPCD may require caution regarding intraoperative visibility with gonioscopy and visual function in the early postoperative period.
Novel splice site and nonsense variants in PKHD1 cause autosomal recessive polycystic kidney disease in a Chinese Zhuang ethnic family
Authors: Qian Chen , Yan Jie , Huang Ximei , Wang Zila , Lin Faquan
Published: August 2024

Background:

This study aims to report the clinical characteristics of a child with autosomal recessive polycystic kidney disease (ARPKD) within a Chinese Zhuang ethnic family.

Methods:

We used whole exome sequencing (WES) in the family to examine the genetic cause of the disease. Candidate pathogenic variants were validated by Sanger sequencing.

Results:

We identified previously unreported mutations in the PKHD1 gene of the proband with ARPKD through WES: a splice site mutation c.6809-2A > T, a nonsense mutation c.4192C > T(p.Gln1398Ter), and a missense mutation c.2181T > G(p.Asn727Lys). Her mother is a heterozygous carrier of c.2181T > G(p.Asn727Lys) mutation. Her father is a carrier of c.6809-2A > T mutation and c.4192C > T(p.Gln1398Ter) mutation.

Conclusions:

The identification of novel mutations in the PKHD1 gene through WES not only expands the spectrum of known variants but also potentially enhances genetic counseling and prenatal diagnostic approaches for families affected by ARPKD.
Rehabilitation after musculoskeletal injury: Israeli and South African perspectives
Authors: Bernstein Brian , Berry Kirsty , Moreh Elior , Schwartz Isabella , Weil Yoram A. , Scott Lindsay , Nyathi Nomalungelo
Published: August 2024

Rehabilitation for patients sustaining isolated and multiple musculoskeletal injuries due to trauma remains a mainstay of recovery. There are a wide variety of systems in place to manage the rehabilitation process. This article describes the post-traumatic rehabilitation procedures from 2 member countries of the International Orthopaedic Trauma Association, Israel and South Africa. The systems are reflective of the clear differences between these 2 countries with vastly different economic strata and health care systems. In Israel, the rehabilitation programs and resources are most likely the result of the mature social support systems and the trauma experience. In South Africa, the programs are reflective of a two-tier health care system, with patients exposed to varying levels of rehabilitation resources.
Impact of rosuvastatin on pulse-wave velocity in men with HIV at moderate cardiovascular risk
Authors: Trevillyan Janine M. , Dart Anthony , Paul Eldho , Dewar Elizabeth M. , Hall Victoria G. , Hoy Jennifer F.
Published: August 2024

This single-centre substudy of a double-blind, randomized, placebo-controlled trial aimed to determine the effect of 96 weeks of rosuvastatin on pulse wave velocity (PWV) in men (n = 55, 54 years) with HIV at moderate cardiovascular risk (Framingham risk score 10–15%). PWV increased in both rosuvastatin [0.54 m/s standard error of difference (SED) 0.26] and placebo [0.50 m/s (SED 0.26), P = 0.896] arms, leading to no difference in PWV at week 96 [rosuvastatin 9.40 m/s (SE 0.31); placebo 9.21 m/s (SE0.31), P = 0.676].
Biodistribution and Radiation Dosimetry for 68Ga-DOTA-CCK-66, a Novel CCK2R-Targeting Compound for Imaging of Medullary Thyroid Cancer
Authors: Viering Oliver , Rinscheid Andreas , Holzleitner Nadine , Dierks Alexander , Kircher Malte , Wienand Georgine , Patt Marianne , Wester Hans-Jürgen , Bundschuh Ralph A. , Günther Thomas , Lapa Constantin , Pfob Christian H.
Published: August 2024

Cholecystokinin 2 receptor (CCK2R) is a promising target for imaging and treatment of medullary thyroid cancer due to its overexpression in over 90% of tumor cells. 68Ga-DOTA-CCK-66 is a recently introduced PET tracer selective for CCK2R, which has shown favorable pharmacokinetics in vivo in preclinical experiments. In order to further investigate safety and suitability of this tracer in the human setting, whole-body distribution and radiation dosimetry were evaluated.

Patients and Methods

Six patients with a history of medullary thyroid cancer were injected intravenously with 169 ± 19 MBq of 68Ga-DOTA-CCK-66. Whole-body PET/CT scans were acquired at 10 minutes, 1 hour, 2 hours, and 4 hours after tracer injection. Time-activity curves per organ were determined, and mean organ-absorbed doses and effective doses were calculated using OLINDA/EXM.

Results

Injection of a standard activity of 150 MBq of 68Ga-DOTA-CCK-66 results in an effective dose of 4.5 ± 0.9 mSv. The highest absorbed organ doses were observed in the urinary bladder wall (40 mGy) and the stomach (15 mGy), followed by the kidneys (6 mGy), as well as the liver and the spleen (3 mGy each). CCK2R-expressing tumor manifestations could be detected in 2 of the 6 patients, including lymph node, bone, and liver metastases.

Conclusions

68Ga-DOTA-CCK-66 exhibits a favorable dosimetry. Beyond physiologic receptor expression of the stomach, no other relevant tracer accumulation could be observed, rendering this organ at risk in case of subsequent radioligand therapy using 177Lu-DOTA-CCK-66.
Exploring patient and system factors impacting undertriage of injured patients meeting national field triage guideline criteria
Authors: Beiriger Jamison , Puyana Jacob , Deeb Andrew-Paul , Silver David , Lu Liling , Boland Sebastian , Brown Joshua B.
Published: August 2024

BACKGROUND

Trauma systems save lives by coordinating timely and effective responses to injury. However, trauma system effectiveness varies geographically, with worse outcomes observed in rural settings. Prior data suggest that undertriage may play a role in this disparity. Our aim was to explore potential driving factors for decision making among clinicians for undertriaged trauma patients.

METHODS

We performed a retrospective analysis of the National Emergency Medical Services Information System database among patients who met physiologic or anatomic national field triage guideline criteria for transport to the highest level of trauma center. Undertriage was defined as transport to a non–level I/II trauma center. Multivariable logistic regression was used to determine demographic, injury, and system characteristics associated with undertriage. Undertriaged patients were then categorized into “recognized” and “unrecognized” groups using the documented reason for transport destination to identify underlying factors associated with undertriage.

RESULTS

A total of 36,094 patients were analyzed. Patients in urban areas were more likely to be transported to a destination based on protocol rather than the closest available facility. As expected, patients injured in urban regions were less likely to be undertriaged than their suburban (adjusted odds ratio [aOR], 2.69; 95% confidence interval [95% CI], 2.21–3.31), rural (aOR, 2.71; 95% CI, 2.28–3.21), and wilderness counterparts (aOR, 3.99; 95% CI, 2.93–5.45). The strongest predictor of undertriage was patient/family choice (aOR, 6.29; 5.28–7.50), followed by closest facility (aOR, 5.49; 95% CI, 4.91–6.13) as the reason for hospital selection. Nonurban settings had over twice the odds of recognizing the presence of triage criteria among undertriaged patients (p < 0.05).

CONCLUSION

Patients with injuries in nonurban settings and those with less apparent causes of severe injury are more likely to experience undertriage. By analyzing how prehospital clinicians choose transport destinations, we identified patient and system factors associated with undertriage. Targeting these at-risk demographics and contributing factors may help alleviate regional disparities in undertriage.

LEVEL OF EVIDENCE

Diagnostic; Level IV.
Association of Moderate and Vigorous Physical Activity With Cognitive Performance
Authors: de Pais Ingryd Mayara Nascimento Martins , Rabelo Wendell Lima , Ferreira Naomi Vidal , Ferri Cleusa Pinheiro , Suemoto Claudia Kimie , Gomes Gonçalves Natalia
Published: August 2024

Objective:

It is estimated that 2% of dementia cases worldwide could be prevented with increases in physical activity. However, there is little evidence of the association between vigorous physical activity (VPA) and cognitive performance. This study aimed to investigate the association of moderate physical activity (MPA) and VPA with cognitive performance in older adults from the Brazilian Longitudinal Study of Aging (ELSI-Brasil).

Patients and Methods:

Data from 7954 participants were analyzed. Mean age was 61.8 ± 9.2 years, 61.8% were women, and 44.3% were mixed races. Cognitive performance evaluated the memory, temporal orientation, and verbal fluency domains. A global composite z-score was derived from the tests. Physical activity was assessed by self-report. We used linear regression models to verify the association of MPA and VPA with cognitive performance.

Results:

Compared with participants who did not meet the guidelines for MPA (<150 min/wk), those who met the guidelines (150 to 299 min/wk) and those who performed more than 2x the recommended amount of MPA (300 min or more/wk) had better global cognitive performance (β = 0.163, 95% CI = 0.086, 0.241; P < 0.001; β = 0.180, 95% CI = 0.107, 0.253, P < 0.001, respectively). We found no association between VPA and cognitive performance.

Conclusion:

There was no additional benefit of VPA for cognitive performance.
The complete genome sequence of five historical Escherichia coli sequence type (ST)1193 strains reveals insights into an emerging pathogen
Authors: White Rhys T. , Ashcroft Melinda A. , Bauer Michelle J. , Bell Jan , Butkiewicz Dominika , Álvarez-Fraga Laura , Gibson Justine S. , Kidsley Amanda K. , Mollinger Joanne L. , Peters Kate M. , Phan Minh-Duy , Roberts Leah W. , Rogers Benjamin A. , Schembri Mark A. , Trott Darren J. , Turnidge John , Forde Brian M. , Beatson Scott A.
Published: August 2024

Fluoroquinolone-resistant Escherichia coli sequence type (ST)1193 is a profound, emerging lineage associated with systemic, urinary tract, and neonatal infections. Humans, companion animals, and the environment are reservoirs for ST1193, which has been disseminated globally. Following its detection in 2007, ST1193 has been identified repeatedly amongst fluoroquinolone-resistant clones in Australia. However, despite the growing importance of ST1193, only three complete genomes are published in the literature, none of which are from Australia. Here we expand on the available ST1193 resources with the complete genomes of five ST1193 strains sequenced using Oxford Nanopore Technologies and Illumina. Using in silico genotyping, we found that all strains were multi-drug resistant, including resistances to fluoroquinolones and cephalosporins. In vitro antibiotic susceptibility testing mostly correlated with individual genotypes. The exception was MS8320, which had additional in vitro resistance to piperacillin/tazobactam, ampicillin/sulbactam, cefazolin and doripenem (carbapenem). Further investigation identified seven additional copies of an IS26 transposable unit carrying a blaTEM-1B beta-lactamase gene, suggesting this tandem amplification is associated with extended resistance phenotypes. Uropathogenicity factors, including three separate siderophore-encoding loci, were conserved in chromosomal and plasmid regions. Using all complete genomes, we further elucidated the recombination events surrounding the previously described K5/K1 capsular loci switch. Phenotypic confirmation of differing capsules in Australian ST1193 strains, coupled with genetic analysis revealing insertions downstream of the capsular locus, underscored the genetic distinctions between K5 and K1 capsule encoding strains. This study provides five new reference ST1193 genomes from Australia. These include the earliest complete K5-capsule ST1193 genomes on record (collected 2007), alongside our reference genome (MS10858); a clinical isolate obtained early during the ST1193 expansion and representative of the predominant K1-associated clade. These findings lay the foundations for further genomic and molecular analyses that may help understand the underlying reasons for the rapid global expansion of ST1193.
Antenatal corticosteroids for pregnant women at risk of preterm labor in low- and middle-income countries: utilization and facility readiness
Authors: Yang Wen-Chien , Arsenault Catherine , Fan Victoria Y. , Leslie Hannah H. , Farooq Fouzia , Pembe Andrea B. , Getachew Theodros , Smith Emily R.
Published: August 2024

Background

Antenatal corticosteroids (ACS) use among pregnant women with a high likelihood of preterm labor improves newborn survival. ACS adoption in low– and middle-income countries (LMICs) remains limited. Giving ACS in inadequately equipped settings could be harmful to mothers and newborns. Thus, health facilities have to demontrate readiness to administer ACS. However, the degree to which health systems are ready is unknown.

Objective

We assessed facility readiness to administer ACS based on the 2022 WHO recommendations on ACS use and ACS utilization.

Methods

The study used Service Provision Assessment surveys administered between 2013 and 2022 in nine LMICs. The primary outcome was whether facilities had ever provided ACS. We also assessed injectable corticosteroid (dexamethasone or betamethasone) availability and facility readiness to administer ACS. We used a total of 35 indicators, grouped into four readiness categories based on the WHO recommendations, to measure facility readiness.

Findings

Across eight countries with comparable sampling strategies, only 10.7% (median, range 6.7% – 35.2%) of facilities had ever provided ACS; one-fourth (median 25.3%, range 4.6% – 61.5%) of facilities had injectable corticosteroids available at the time of the survey; overall readiness indices were low ranging from 8.1% for Bangladesh to 32.9% for Senegal. Across four readiness categories, the readiness index was the lowest for criterion 1 (ability to assess gestational age accurately and identify a high likelihood of preterm birth) (7.3%), followed by criterion 2 (ability to identify maternal infections) (24.8%), criterion 4 (ability to provide adequate preterm care) (31.3%), and criterion 3 (ability to provide adequate childbirth care) (32.9%).

Conclusion

We proposed a strategy for measuring facility readiness to implement one of the most effective interventions to improve neonatal survival. Countries should operationalize readiness measurement, improve facilities readiness to deliver this life-saving intervention, and encourage ACS uptake by targeting facilities that are well-equipped.
Buruli ulcer Community Health Education and Medical Screening (BU-CHEMS) in Ga South District, Ghana
Authors: Narh Charles A. , Tetteh Edwin ,   NSPA-NMIMR
Published: August 2024

PROJECT SUMMARY

Background

The National Service Personnel Association of the Noguchi Memorial Institute for Medical Research (NSPA-NMIMR) carries out an annual community outreach project comprising health education and medical screening for some of the diseases that the institute works on. Therefore, the NSPA 2009/2010 group (40 personnel) conducted Buruli ulcer community health education and medical screening (BU-CHEMS) in the Ga South District of Ghana in July 2010.

Method

BU is caused bymycobacterium ulcerans, and starts as a painless nodule, which can progress to ulcer, particularly on the upper and lower extremities. BU is often associated with witchcraft in some Ghanaian communities, and as a result, some patients reluctantly seek medical treatment. Therefore, prior to the screening program, the NSPA and medical staff from the Obom Health Centre showed video documentaries on BU as a way of educating and dispelling myths about the disease. This was followed by screening for nodules and ulcers among 2,500 people, mostly children in primary schools, residing in four endemic communities in the Ga South District. Other medical screening activities included blood group/pressure tests, Body Mass Index (BMI) and body temperature checks.

Results and conclusion

Suspected cases of BU (N=33) ranging from nodules, plagues, oedema and ulcers of the disease on various parts of the body including the lower and upper extremities were identified, and samples were sent to NMIMR for PCR confirmation. All the PCR-positive cases (78%), including children (<15 years, 88%) were referred to the Obom Health Center for clinical treatment. The BU-CHEMS organized by NSPA 2009/2010 group (with sponsorship from corporate organizations) contributed to NMIMR mandate: improving the health and wellbeing of Ghanaians and mankind through focused and relevant quality biomedical research, human resource development and support of national public health activities.
Association of quantified cardiovascular health with all-cause mortality in prediabetic patients
Authors: Chen Aomiao , He Qiuyu , Wu Yichuan , Chen Jiaqi , Ma Xiaoqin , Hu Lingyuan , Wang Geningyue , Wang Zhuotong , Zheng Zongji , Jia Yijie
Published: August 2024

Aim:

We aimed to explore the association between all-cause mortality and cardiovascular health (CVH) lifestyle interventions (as accurately quantified by Life’s essential 8) in prediabetic patients and to observe the dose-response relationship of the potential association.

Methods and Participants:

The retrospective study included 5344 participants with prediabetes (age: 52.9 ±15.8 years; (51.6% of men)). The Life’s essential 8 (LE8) score includes four health indicators and four health behaviors. We calculated Cox proportional hazard ratios (HRS) for all-cause mortality in subgroups of high CVH (≥80), low CVH (≤50), and moderate CVH (50-79) based on the CVH quantification score of LE8, and explored the dose-response relationship of potential associations. We also performed separate analyses of the associations of all-cause mortality with each LE8 components and CVH health behaviors and indicators.

Results:

In the median follow-up period of 8.33 years, 658 deaths occurred. Compared with participants with high CVH, the covariate-adjusted HR(95%CI) for participants with moderate and low CVH were 2.55(1.23-5.31) and 3.92 (1.70-9.02), respectively. There was a dose-response relationship between the improvement of CVH status and the reduction of all-cause mortality (P-overall < 0.0001, P-nonliner = 0.7989). The improvement of CVH health behaviors has a more significant protective effect on patients with prediabetes than CVH health indicators.

Conclusion:

High CVH status, quantified by LE8, has a significant effect on preventing mortality outcomes in prediabetic adults in the U.S.
Public health impact of current and proposed age-expanded perennial malaria chemoprevention: a modelling study
Authors: Sen Swapnoleena , Braunack-Mayer Lydia , Kelly Sherrie L , Masserey Thiery , Malinga Josephine , Moehrle Joerg J , Penny Melissa A
Published: August 2024

In 2022, the World Health Organization extended their guidelines for perennial malaria chemoprevention (PMC) from infants to children up to 24 months old. However, evidence for PMC’s public health impact is primarily limited to children under 15 months. Further research is needed to assess the public health impact and cost-effectiveness of PMC, and the added benefit of further age-expansion. We integrated an individual-based model of malaria with pharmacological models of drug action to address these questions for PMC and a proposed age-expanded schedule (PMC+, for children 03-36 months). Across prevalence settings of 5-70% and different drug sensitivity assumptions, we predicted PMC and PMC+’s median efficacy of 18.6%(12.2-25.0%) and 21.9%(14.3-29.5%) against clinical disease and 9.0%(2.0-16.0%) and 10.8%(3.2-18.4%) against severe malaria, respectively, in children under three years. PMC’s total impact outweighed risk of delayed malaria in children up to age five and remained cost-effective when delivered through the Expanded Program on Immunization.
A Deep Ensemble Encoder Network Method for Improved Polygenic Risk Score Prediction
Authors: Ozdemir Okan B , Chen Raelynn , Li Ruowang
Published: August 2024

Genome-wide association studies (GWAS) of various heritable human traits and diseases have identified numerous associated single nucleotide polymorphisms (SNPs), most of which have small or modest effects. Polygenic risk scores (PRS) aim to better estimate individuals' genetic predisposition by aggregating the effects of multiple SNPs from GWAS. However, current PRS is designed to capture only simple linear genetic effects across the genome, limiting their ability to fully account for the complex polygenic architecture. To address this, we propose DeepEnsembleEncodeNet (DEEN), a new method that ensembles autoencoders and fully connected neural networks (FCNNs) to better identify and model linear and non-linear SNP effects across different genomic regions, improving its ability to predict disease risks. To demonstrate DEEN's performance, we optimized the model across binary and continuous traits from the UK Biobank (UKBB). Model evaluation on the held-out UKBB testing dataset, as well as the independent All of Us (AoU) dataset, showed improved prediction and risk stratification, consistently outperforming other methods.
Widespread male sterility and trioecy in androdioeciousMercurialis annua: an account of its distribution, its genetic basis, and estimates of its morph-specific fitness components
Authors: Nguyen M. T. , Martignier T. , Pannell J. R.
Published: August 2024

Premise

Angiosperms range from hermaphroditism through gynodioecy and androdioecy to dioecy. ‘Trioecy’, where females and males coexist with hermaphrodites, is rare. Recently, trioecy was documented in hexaploid populations of the wind-pollinated herb Mercurialis annua in Spain.

Methods

We surveyed the frequency of males, hermaphrodites and females inM. annuaacross its distribution in the Iberian Peninsula, tracked sex-ratio variation in several populations over consecutive generations, and assessed evidence for pollen limitation. In a common garden, we estimated male, female and hermaphrodite fitness. We used controlled crosses to infer the genetic basis of male sterility. Finally, we compared predictions of a deterministic model with the distribution of observed sex ratios in the field based on our fitness estimates and the inferred genetics of sex determination.

Key results

Trioecy is widespread in Spanish and Portuguese populations ofM. annua. Males are determined by a dominant (Y-linked) allele, and female expression results from the interaction between cytoplasmic male sterility and multiple nuclear male sterility restorers partially linked to the male determiner. Male pollen production is approximately 12 times while female seed production is less than 1.12 times that of hermaphrodites. The distribution of sex ratios in natural populations conforms with predictions of our deterministic simulations.

Conclusions

Our study documents and accounts for a clear case of trioecy in which sex is determined by both maternally and biparentally inherited genes.
IL-27 Stablizes Myc-Mediated Transcription In Memory-Fated, Vaccine-Elicited CD8+ T Cells
Authors: Thompson Scott B. , Harbell Michael , Manalastas John , Ivanova Daria L. , Riemondy Kent A , Lasda Erika , Chen Vincent , Hesselberth Jay R. , Phan Anthony , Christian David , Hunter Christopher A. , Brunetti Tonya , Gapin Laurent , Klarquist Jared , Kedl Ross M.
Published: August 2024

Protection from pathogens relies on both humoral (antibody-mediated) and cellular (T cell-mediated) responses. While infections robustly elicit both types of immunity, currently approved vaccine adjuvants largely fail to induce T cell responses on par with that instigated by infections. Our goal was to investigate the transcriptional programming that supports the formation of CD8+T cells elicited by subunit vaccines compared to those elicited by infections. Our data show that vaccine-elicited T cells represent a transcriptionally unique subset of activated T cells with high proliferative capacity and a memory cell fate. This relies on IL-27 signaling, which stabilizes c-Myc and thereby supports the biomass acquisition necessary for clonal expansion. Collectively, our findings reveal that subunit vaccine-elicited T cells uniquely combine aspects of both memory and effector T cell subsets, and selectively utilize IL-27 signaling to sustain the clonal expansion of cells dedicated to a memory fate.

One Sentence Summary

In contrast to infection, subunit vaccines induce a distinct population of CD8+ T cells with memory fate characteristics which maintain their proliferative capacity during the expansion phase through IL-27 receptor signaling.
Bayesianp-curve Mixture Models as a Tool to Dissociate Effect Size and Effect Prevalence
Authors: Veillette John P. , Nusbaum Howard C.
Published: August 2024

Much research in the behavioral sciences aims to characterize the “typical” person. A statistically significant group-averaged effect size is often interpreted as evidence that the typical person shows an effect, but that is only true under certain distributional assumptions for which explicit evidence is rarely presented. Mean effect size varies with bothwithin-participant effect sizeandpopulation prevalence(proportion of population showing effect). Few studies consider how prevalence affects mean effect size estimates and existing estimators of prevalence are, conversely, confounded by uncertainty about effect size. We introduce a widely applicable Bayesian method, thep-curve mixture model, that jointly estimates prevalence and effect size by probabilistically clustering participant-level data based on their likelihood under a null distribution. Our approach, for which we provide a software tool, outperforms existing prevalence estimation methods when effect size is uncertain and is sensitive to differences in prevalence or effect size across groups or conditions.
Deep Learning Reaction Network: a machine learning framework for modeling time resolved data
Authors: Alagna Nicolò , Dúzs Brigitta , Köppl Heinz , Walther Andreas , Gerber Susanne
Published: August 2024

Model-based analysis is essential for extracting information about chemical reaction kinetics in full detail from time-resolved data sets. Such analysis combines experimental hypotheses of the process with mathematical models related to the system’s physical mechanisms. This combination can provide a concise description of complex system dynamics and extrapolate kinetic model parameters, such as kinetic pathways, time constants, and species amplitudes. However, the process leading to the final kinetic model requires several intermediate steps in which different assumptions and models are tested, even using different experimental data sets. This approach requires considerable experience in modeling and data comprehension, as poor decisions at any stage of time-resolved data analysis (such as time-resolved spectra and agarose gel electrophoresis) can lead to an incorrect or incomplete kinetic model, resulting in inaccurate model parameters and amplitudes. The Deep Learning Reaction Network (DLRN) can rapidly provide a kinetic reaction network, time constants, and amplitude for the system, with comparable performance and, in part, even better than a classical fitting analysis. Additionally, DLRN works in scenarios in which the initial state is a non-emitting dark state and for multiple timescales. The utility of DLRN is also shown for more than one 2D system, as it performed well for both spectral and time-resolved agarose gel electrophoresis data.
Towards an eco-epidemiological framework for managing freshwater crayfish communities confronted with crayfish plague
Authors: Bozzuto Claudio , Schmidt-Posthaus Heike , Adrian-Kalchhauser Irene , Pisano Simone Roberto Rolando
Published: August 2024

Wildlife diseases figure prominently among the main causes of biodiversity loss worldwide. Especially fungal and fungus-like pathogens are on the rise, wreaking havoc across the tree of life by threatening species persistence and destabilizing ecosystems. A worrisome example are freshwater crayfish species in Eurasia and Oceania, facing the dual challenge of introduced competitive crayfish species and an introduced water mold (Aphanomyces astaci) causing crayfish plague.A. astacilocally extinguishes susceptible native crayfish populations, while non-native individuals (mostly from North America) remain largely unaffected. Despite its significant impact and its ∼150 years of presence in Europe, studies and disease management recommendations for crayfish plague that are firmly rooted in epidemiological theory are scarce. Here, we present a practical eco-epidemiological framework to understand how multi-species crayfish communities react to crayfish plague introductions. The framework is based on the observation that the dynamics of crayfish communities are mainly determined by life-history characteristics, within- and among-species competition, effects of generalist predators (including fishing), and host-pathogen interactions. From this ecological and epidemiological context, we derive fundamental epidemiological metrics, single-host species and community-level basic reproduction numbers (R0). We investigate how host species densities affect the likelihood of a disease outbreak in a crayfish community, and we demonstrate that a community’sR0value is simply the sum of the community’s single-host speciesR0values, adjusted for competition and predation. We further demonstrate howR0can be used to guide preventative and mitigation actions for crayfish communities. For example, we show howR0expressions – even without a detailed parametrization – can be used to construct regional risk rankings for different crayfish communities, for an effective allocation of resources to local conservation plans. Our eco-epidemiological framework will also be of interest to the management of other aquatic host-pathogen systems with water-borne pathogen transmission as the main route of pathogen spread.
PROSER1 Modulates DNA Demethylation through Dual Mechanisms to Prevent Syndromic Developmental Malformations
Authors: Fleming Anna , Knatko Elena V. , Li Xiang , Zoch Ansgar , Heckhausen Zoe , Stransky Stephanie , Brenes Alejandro J. , Sidoli Simone , Hajkova Petra , O’Carroll Dónal , Rasmussen Kasper D.
Published: August 2024

The link between DNA methylation and neurodevelopmental disorders is well established. However, how DNA methylation is fine-tuned – ensuring precise gene expression and developmental fidelity – remains poorly understood. PROSER1, a known TET2 interactor, was recently linked to a severe neurodevelopmental disorder. Here, we demonstrate that PROSER1 interacts with all TET enzymes and stabilizes chromatin-boundTET-OGT-PROSER1-DBHS (TOPD) complexes, which regulate DNA demethylation and developmental gene expression. Surprisingly, we find that PROSER1 also sequesters TET enzymes, preventing widespread demethylation and transposable element de-repression. Our findings identify PROSER1 as a key factor which both positively and negatively regulates DNA demethylation essential for mammalian neurodevelopment.
SMURF1/2 are novel regulators of WNK1 stability
Authors: Jaykumar Ankita B. , Plumber Sakina , Binns Derk , Wichaidit Chonlarat , Luby-Phelps Katherine , Cobb Melanie H.
Published: August 2024

Angiogenesis is essential for remodeling and repairing existing vessels, and this process requires signaling pathways including those controlled by transforming growth factor beta (TGF-β). We have previously reported crosstalk between TGF-β and the protein kinase With No lysine (K) 1 (WNK1). Homozygous disruption of the gene encoding WNK1 results in lethality in mice near embryonic day E12 due to impaired angiogenesis and this defect can be rescued by endothelial-specific expression of an activated form of the WNK1 substrate kinase Oxidative Stress-Responsive 1 (OSR1). However, molecular processes regulated via a collaboration between TGF-β and WNK1/OSR1 are not well understood. Here we show that WNK1 interacts with the E3 ubiquitin ligases SMURF1/2. In addition, we discovered that WNK1 regulates SMURF1/2 protein stability and vice versa. We also demonstrate that WNK1 activity regulates TGF-β receptor levels, in turn, controlling TGF-β signaling.
Pollen Partners: The Symbiotic Microbes ofPinus radiataPollen
Authors: Armstrong C , Ganasamurthy S , Walker K , Mercier C , Wakelin S
Published: August 2024

Pollen, a crucial source of nutrients and energy for pollinators. It also provides a unique habitat for ecological microbiota. Previous research on the microbiome of pollen has largely focussed on angiosperm systems, with limited research into coniferous gymnosperms. This study characterises the pollen microbiome associated with one of the world’s most widely grown tree species,Pinus radiata. Trees were sampled from locations across Canterbury, New Zealand, with repeated collections in 2020 and 2021. Metabolomic analysis revealed the main compounds present onP. radiatapollen to be amino acids (principally proline), and carbohydrates (fructose, glucose, and sucrose). Although phenolic compounds such as ρ-coumaric acid and catechin, and terpenoids such as dehydroabietic acid, were present at low concentrations, their strong bioactive natures mean they may be important in filtering of microbiome communities on pollen.Pinus radiatapollen was found to host a microbiome dominated by fungi; this directly contrasts with those for many angiosperm species. Geographic range and sampling years were evaluated as secondary drivers of microbiome assembly. Neither sampling location nor annual variation had a significant impact on the fungal component of the pine pollen microbiome, which was remarkably stable/conserved among samples. However, some bacterial taxa exhibited sensitivity to geographic distances and yearly variations, suggesting a secondary role for some. A core microbiome was identified inP. radiatapollen, characterized by a consistent presence of specific fungal and bacterial taxa across samples. While the dominant phyla, Proteobacteria and Ascomycota, align with findings from other pollen microbiome studies, unique core members were unidentified at genus level. This tree species-specific microbiome assembly emphasizes the crucial role of the host plant in shaping the pollen microbiome. These findings contribute to a deeper understanding of pollen microbiomes in gymnosperms, shedding light on the need to look further at their ecological and functional roles.
moPPIt:De NovoGeneration of Motif-Specific Binders with Protein Language Models
Authors: Chen Tong , Zhang Yinuo , Chatterjee Pranam
Published: August 2024

Abstract

The ability to precisely target specific motifs on disease-related proteins, whether conserved epitopes on viral proteins, intrinsically disordered regions within transcription factors, or breakpoint junctions in fusion oncoproteins, is essential for modulating their function while minimizing off-target effects. Current methods struggle to achieve this specificity without reliable structural information. In this work, we introduce amotif-specificPPI targeting algorithm,moPPIt, forde novogeneration of motif-specific peptide binders from the target protein sequence alone. At the core of moPPIt is BindEvaluator, a transformer-based model that interpolates protein language model embeddings of two proteins via a series of multi-headed self-attention blocks, with a key focus on local motif features. Trained on over 510,000 annotated PPIs, BindEvaluator accurately predicts target binding sites given protein-protein sequence pairs with a test AUC > 0.94, improving to AUC > 0.96 when fine-tuned on peptide-protein pairs. By combining BindEvaluator with our PepMLM peptide generator and genetic algorithm-based optimization, moPPIt generates peptides that bind specifically to user-defined residues on target proteins. We demonstrate moPPIt’s efficacy in computationally designing binders to specific motifs, first on targets with known binding peptides and then extending to structured and disordered targets with no known binders. In total, moPPIt serves as a powerful tool for developing highly specific peptide therapeutics without relying on target structure or structure-dependent latent spaces.
PDS5s control theArabidopsis3D genome by suppressing the formation of TAD-like domains
Authors: Göbel Anna-Maria , Zhou Sida , Wang Zhidan , Tzourtzou Sofia , Himmelbach Axel , Zheng Shiwei , Pradillo Mónica , Liu Chang , Jiang Hua
Published: August 2024

One key structural element in the three-dimensional (3D) chromatin organization is the Topologically Associating Domain (TAD), which facilitates the formation of distinct chromatin compartments and fosters specific chromatin interactions. Similar chromatin compartments, known as TAD-like domains, have been identified in many plant species. However, the model plantArabidopsisthaliana has been an exception. In this study, we address this long-standing issue by presenting evidence thatArabidopsisPDS5 proteins play a crucial role in preventing the formation of TAD-like domains.
Vanadium-dependent haloperoxidases from diverse microbes halogenate exogenous alkyl quinolone quorum sensing signals
Authors: Baumgartner Jackson T. , McCaughey Catherine S. , Fleming Hanna S. , Lentz Adam R. , Sanchez Laura M. , McKinnie Shaun M. K.
Published: August 2024

Site-selective vanadium-dependent haloperoxidases (VHPOs) are a unique enzyme family that catalyze selective halogenation reactions previously characterized within bacterial natural product biosynthetic pathways. However, the broader chemical roles and biological distribution of these halogenases remains to be explored. Using bioinformatic methods, we have defined a VHPO subfamily that regioselectively brominates alkyl quinolone (AQ) quorum sensing molecules.In vitroAQ halogenation activity was demonstrated from phylogenetically distinct bacteria lacking established AQ biosynthetic pathways and sourced from diverse environments. AQ-VHPOs show high sequence and biochemical similarities with negligible genomic synteny or biosynthetic gene cluster co-localization. Exposure of VHPO-containing microbes to synthetic AQs or established bacterial producers identifies the chemical and spatial response to subvert their bacteriostatic effects. The characterization of novel homologs from bacterial taxa without previously demonstrated vanadium enzymology suggests VHPO-mediated AQ bromination is a niche to manipulate the chemical ecology of microbial communities.

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Synopsis

A broadly distributed subfamily of bacterial site-selective VHPOs provides protection against exogenously encountered bacteriostatic alkyl quinolone quorum sensing signals.