bluuebunny/crossref_metadata_2025 huggingface dataset:
Genetic background and intraoperative haemodynamic instability in patients with pheochromocytoma and paraganglioma: a multicentre retrospective study
Authors: Li Minghao , Zhang Jing , Pang Yingxian , He Yao , Shen Yanting , Wang Jing , Xu Xiaowen , Liu Jiahao , Cheng Kai , Li Zhi , Liu Yujun , Gao Xin , Eisenhofer Graeme , Jiang Jingjing , Liu Longfei
Published: August 2024

Background:

Perioperative management to maintain intraoperative haemodynamic stability is crucial during surgical treatment of pheochromocytomas and paragangliomas (PPGLs). Although ~70% of PPGLs carry pathogenic variants (PVs) in susceptibility genes, whether intraoperative haemodynamic instability (IHI) is associated with genetic background remains unclear. This study aimed to analyse IHI in patients with PPGL due to PVs in different genes.

Materials and Methods:

This retrospective study recruited 756 patients with abdominal PPGL from two tertiary care centres. Clinical information including sex, age, catecholamine-associated signs and symptoms (CAS), tumour location and size, biochemistry, and perioperative characteristics were collected. Genetic mutations were investigated using next-generation sequencing.

Results:

Among the 671 patients included in the analysis, 61.8% (415/671) had IHI. IHI was significantly associated with genetic background in patients with PPGL. Most (80.9%, 89/110) patients with PPGL due to PVs in HRAS suffered IHI. In contrast, only half (31/62) of patients with PPGL due to PVs in VHL had IHI. In the multivariate regression analysis, compared to those with negative genetic testing results, patients with PPGL due to PVs in HRAS (OR 3.82, 95% CI 2.187–6.679, P<0.001), the other cluster 2 genes (OR 1.95, 95% CI 1.287–2. 569, P<0.05), and cluster 1 genes other than VHL (OR 2.35, 95% CI 1.338–4.111, P<0.05) were independent risk factors for IHI, while PVs in VHL was not independent risk factor (OR 1.09, 95% CI 0.605–1.953, P≥0.05). In addition, age at diagnosis of the primary tumour, presenting of CAS, and tumour size were identified as independent factors for IHI. The nomogram illustrated that genetic background as sharing the largest contribution to IHI, followed by tumour size, age, and presentation of CAS.

Conclusion:

IHI is associated with the genetic background in patients with PPGL. The perioperative management of patients with PPGL can be personalised according to their genetic backgrounds, tumour size, age, and presentation of CAS.
Outcomes of pediatric-focused advanced practice provider fellowship programs: An integrative review
Authors: Koppolu Rajashree , Van Graafeiland Brigit , Hansen Bryan R.
Published: August 2024

Background:

An increased demand for pediatric-focused advanced practice providers (APPs) exists to address the health care needs of children with medical complexity. Postlicensure advanced practice fellowship programs have been developed to help improve novice provider transition to practice, reducing attrition.

Objectives:

The objectives of this integrative review are to (1) identify outcome measurements of pediatric-focused advanced practice fellowship programs and (2) evaluate the outcome measures to guide future implications for practice.

Data sources:

A systematic integrative literature review was conducted in accordance with the Preferred Reporting Items for Systemic Reviews and Meta-Analyses. PubMed, CINAHL, Embase, and Google Scholar were searched in August and September 2022. Articles met inclusion criteria if they included new graduate APPs, reported the intervention of a pediatric fellowship program, and shared outcome measurements. Studies were excluded if they did not directly report on fellowship program outcome measures. Thirteen studies met inclusion criteria and were summarized and appraised for quality using the Johns Hopkins Evidence-Based Practice Model.

Conclusions:

Four themes from the literature included the favorable impact of advanced practice fellowship programs on (a) job satisfaction, (b) retention, (c) clinical and professional performance, and (d) financial outcomes. Variable strategies were used to measure outcomes across programs.

Implications for practice:

Postlicensure pediatric-focused advanced practice fellowship programs seem to improve retention and job satisfaction, increase provider confidence, and bring a favorable return on investment for the organization. Future work should include investment in developing validated, standardized assessment tools to support future development of these programs in the pediatric population.
Severe capsular contracture in a patient with a history of multiple malignancies – Hematoma or neoplasm recurrence?: A case report
Authors: Yuan Yutong , Du Fengzhou , Xiao Yiding , Huang Jiuzuo , Long Xiao
Published: August 2024

Rationale:

Complications associated with breast implants pose a significant obstacle to improving the quality of life for patients undergoing implant-based breast reconstruction. Due to the intricate nature of their presentation, diagnosis often becomes challenging and perplexing. Herein, we present a case report detailing the diagnostic and therapeutic processes employed in managing implant-related complications in a patient with multiple malignancies who underwent immediate breast reconstruction following mastectomy.

Patent concerns:

The patient, a 48-year-old woman, presented with severe pain and hardening in her left breast. She had previously undergone nipple-sparing mastectomy followed by immediate implant-based breast reconstruction 3 years ago.

Diagnoses:

Upon admission, we suspected a simple diagnosis of capsular contracture. However, upon investigation, she had a medical history of colon cancer, breast cancer, and acute B-lymphoblastic leukemia. Furthermore, she recently experienced nipple hemorrhage.

Interventions:

Considering her clinical manifestations, we postulated the possibility of tumor recurrence along with potential presence of breast implant-associated anaplastic large cell lymphoma. The situation took a new turn, as diagnostic imaging techniques including breast MRI, and ultrasound revealed indications of potential prosthesis rupture and periprosthetic infection.

Outcomes:

Ultimately, en bloc capsulectomy with implant removal was performed, revealing no evidence of implant rupture or infection but rather indicating delayed hematoma formation.

Lessons:

An accurate diagnosis of complications associated with breast prosthesis reconstruction is crucial for effective treatment. The examination and treatment processes employed in this case offer valuable insights toward achieving a more precise diagnosis of prosthesis-related complications, particularly in patients with complex medical histories.
A acute pontine infarction with one-and-a-half syndrome as the manifestation: A case report
Authors: Fu Jing , Yang Hui , Liao Shasha
Published: August 2024

Rationale:

Sudden ocular dyskinesia is usually associated with ophthalmic diseases and rarely with cerebrovascular diseases. This is a rare case of a patient with a sudden onset of ocular dyskinesia due to occlusion of the anterior inferior cerebellar artery and the spiral modiolar artery. This article describes eye movement disorders associated with cerebrovascular disease, aiming to improve our understanding of cerebrovascular diseases and improve the ability of early diagnosis and differential diagnosis.

Patient concerns:

A 52-year-old man presented with acute pontine cerebral infarction 2 days before presentation. The main symptoms were the inability to adduct and abduct the left eyeball, the ability to abduct but not adduct the right eyeball, and horizontal nystagmus during abduction. Cranial computed tomography in our emergency department suggested cerebral infarction, and magnetic resonance imaging examination after admission confirmed the diagnosis of acute pontine cerebral infarction.

Diagnosis:

This patient was ultimately diagnosed with acute pontine cerebral infarction.

Interventions:

He received aspirin, clopidogrel, and butylphthalide, as well as acupuncture and Chinese herbal medicine.

Outcomes:

After 10 days of treatment, the patient’s paralysis of the eye muscles improved significantly.

Lessons:

Eye movement disorders are sometimes an early warning sign of impending vertebrobasilar ischemic stroke. Patients with acute ischemic stroke who have early detection of oculomotor disturbances should be promptly imaged, as missed diagnosis may lead to serious consequences or even death. It provided us with a new diagnostic idea.
Volumetric and textural analysis of PET/CT in patients with diffuse large B-cell lymphoma highlights the importance of novel MTVrate feature
Authors: Czibor Sándor , Csatlós Zselyke , Fábián Krisztián , Piroska Márton , Györke Tamás
Published: August 2024

Objectives

To investigate the prognostic value of clinical, volumetric, and radiomics-based textural parameters in baseline [18F]FDG-PET/CT scans of diffuse large B-cell lymphoma (DLBCL) patients.

Methods

We retrospectively investigated baseline PET/CT scans and collected clinical data of fifty DLBCL patients. PET images were segmented semiautomatically to determine metabolic tumor volume (MTV), then the largest segmented lymphoma volume of interest (VOI) was used to extract first-, second-, and high-order textural features. A novel value, MTVrate was introduced as the quotient of the largest lesion’s volume and total body MTV. Receiver operating characteristics (ROC) analyses were performed and 24-months progression-free survival (PFS) of low- and high-risk cohorts were compared by log-rank analyses. A machine learning algorithm was used to build a prognostic model from the available clinical, volumetric, and textural data based on logistic regression.

Results

The area-under-the-curve (AUC) on ROC analysis was the highest of MTVrate at 0.74, followed by lactate-dehydrogenase, MTV, and skewness, with AUCs of 0.68, 0.63, and 0.55, respectively which parameters were also able to differentiate the PFS. A combined survival analysis including MTV and MTVrate identified a subgroup with particularly low PFS at 38%. In the machine learning-based model had an AUC of 0.83 and the highest relative importance was attributed to three textural features and both MTV and MTVrate as important predictors of PFS.

Conclusion

Individual evaluation of different biomarkers yielded only limited prognostic data, whereas a machine learning-based combined analysis had higher effectivity. MTVrate had the highest prognostic ability on individual analysis and, combined with MTV, it identified a patient group with particularly poor prognosis.
Optical Coherence Tomography Angiography of Macular Microangiopathy in Children With Sickle Cell Disease
Authors: Raffa Enass H. , Raffa Lina , Almadani Samara , Murad Wesal , Alshanti Hawazin
Published: August 2024

In this study, we identified the presence of sickle cell maculopathy and determined correlations between hemolysis indicators and systemic and ocular manifestations in children with sickle cell disease (SCD). Thirty-three patients with SCD 5 to 18 years of age underwent optical coherence tomography angiography (OCTA) as part of a thorough eye examination. The hematological indices and clinical data (hemoglobin, fetal hemoglobin, mean corpuscular volume, and frequency of sickle cell-associated complications and therapy) were collected. The SCD group contained 33 patients (66 eyes), and the control group contained 36 healthy participants (72 eyes). The SCD group had significantly thinner parafoveal thickness (P=0.041) and significantly smaller parafoveal volume (P=0.041) than the controls. The SCD group had lower deep capillary plexus density than the controls (P=0.029). The SCD group had significantly smaller flow areas than the controls (P<0.001). The foveal avascular zone (FAZ) perimeter, foveal density, and FAZ area in the entire retina did not differ significantly between the groups (P>0.05). The platelet level was negatively correlated with parafoveal and perifoveal thickness and density. OCTA detected early macular microvascular changes in children and adolescents with asymptomatic SCD.
Extent of Myometrial Resection With Various Surgical Methods for Endometrial Polypectomy Procedures
Authors: Evans-Hoeker Emily , Millner Adrienne , Lee Grace , Perry Ryan , Kar Ayesha , Swaroop Meyha , Locklear Tonja , Newman Brian , Casey James
Published: August 2024

OBJECTIVE:

To assess whether the frequency and extent of myometrial resection differs among surgical methods commonly used for endometrial polypectomy.

METHODS:

We conducted a retrospective cohort study of pathology samples from polypectomy procedures performed on patients 18–50 years of age. Samples were reevaluated by a blinded pathologist to assess the following primary outcome measures: presence and percentage of myometrium on the pathology sample, prevalence of isolated myometrium, and depth of myometrial resection. Data were evaluated using Fisher exact test and Kruskal-Wallis test, followed by multiple comparisons analysis. To maintain a familywise error rate of 5% across all four primary analyses, the Bonferroni correction method was applied.

RESULTS:

Of 458 pathology samples, 21.8% were obtained using hysteroscopic morcellators, 11.1% were obtained with hysteroscopic scissors, and 67.0% were obtained with hysteroscopy with dilation and curettage (D&C). Hysteroscopic morcellation demonstrated a higher prevalence of myometrium (58.0% vs 9.8% and 15.3%, for hysteroscopic scissors and hysteroscopy with D&C, respectively; P<.001), a larger percentage of pathology samples with more than 25% myometrium (26.0% vs 4.0% and 0.6%, respectively; P<.001), and a higher prevalence of isolated myometrium compared with hysteroscopy with D&C (11.0% vs 0.7%; P<.001).

CONCLUSION:

The presence and proportion of myometrium in polypectomy samples obtained using hysteroscopic morcellators was significantly higher compared with hysteroscopic scissors and hysteroscopy with D&C.
Timing of Antidepressant Use in Pregnancy and Preterm Birth
Authors: Wang Jenny , Roy Debosree , Wang Mary Ying-Fang , Dinh Diana , Lao Ailina , Mendoza Valeria , Xu Gillian , Chatterton Carolyn G. , Ahmadieh Nazanin
Published: August 2024

OBJECTIVE:

To evaluate the implication of timing of antidepressant exposure on preterm birth to better guide clinical counseling.

DATA SOURCES:

A systematic review and meta-analysis was conducted following PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines, using PubMed, MEDLINE Complete, EBSCO, CINAHL Plus, and ClinicalTrials.gov along with a manual search of references in relevant publications. The databases were searched between January 2000 and December 2022 with the following keywords: antidepressants, antidepressant medication, SSRI, selective serotonin reuptake inhibitors, TCA, or SNRI AND pregnancy, pregnant, prenatal, antenatal, perinatal, maternal AND trimester or timing AND preterm or premature.

METHODS OF STUDY SELECTION:

The database search resulted in 162 studies. The 13 studies that met inclusion criteria compared preterm birth rates in pregnant patients exposed to antidepressants at a specified time in pregnancy (early, late, or throughout pregnancy) and a control group. Covidence was used for screening and data extraction. Excel and R were used for tabulation and statistical analysis, respectively.

TABULATION, INTEGRATION, AND RESULTS:

Of the 13 studies, nine measured preterm birth rates with antidepressant use in early pregnancy, 10 in late pregnancy, and four throughout pregnancy. Separate random effects models were used to synthesize the effect sizes from studies that did not adjust for presence of maternal depression in the study sample and those that did. In each model, subgroup analysis was conducted to assess the effect of timing of antidepressant exposure on the odds of preterm birth. In the model unadjusted for depression, pooled odds ratios (ORs) for the association between use of antidepressants and preterm birth were 1.41 (95% CI, 1.10–1.81) in early pregnancy, 1.51 (95% CI, 1.26–1.82) in late pregnancy, and 2.79 (95% CI, 1.27–6.12) throughout pregnancy. After adjusting for depression, the pooled ORs were 1.04 (95% CI, 0.83–1.31) in early pregnancy, 1.26 (95% CI, 0.95–1.66) in late pregnancy, and 1.79 (95% CI, 0.54–5.91) throughout pregnancy. No significant effect of timing was found in either model.

CONCLUSION:

Antidepressant use in pregnancy was not associated with preterm birth, regardless of timing of use. Pregnant patients with an established diagnosis of depression should receive individualized counseling regarding antidepressant use while taking into consideration their risk factors for preterm birth and the implications of untreated depression.

SYSTEMATIC REVIEW REGISTRATION:

PROSPERO, CRD42023390136.
An Evidence-Based Approach to Vaginal Birth
Authors: Tannous Andrew M. , Warffuel Jessica , Van Backle Ann-Sophie , Burgard Iris , Israel Marcella R. , Hartley Sarah , Ramos Jania A. , Stickrath Elaine , Metz Torri , Alston Meredith J.
Published: August 2024

This is a review of evidence-based management of vaginal birth, which is critical to optimizing the outcomes of birthing people and neonates. The current literature supports the use of immediate pushing in the second stage of labor, neuraxial anesthesia administration for vaginal birth for adequate pain control, use of warm compresses in labor to prevent obstetric lacerations, delayed cord clamping for term and preterm neonates, the utility of umbilical cord milking in neonates who require immediate resuscitation, and active management of the third stage of labor with oxytocin administration. In addition, the routine use of episiotomy is shown to increase morbidity without clear evidence of benefit in the setting of spontaneous vaginal delivery or operative vaginal delivery.
Rehabilitation after musculoskeletal injury: an overview of systems in the United States and Canada
Authors: Miclau Theodore A. , Pascual Lisa , Ndoja Silvio , Frazer Abigail , Beaupre Lauren , Schemitsch Emil H.
Published: August 2024

As North America is largely industrialized with a variety of available private transportation options, trauma is a common occurrence, resulting in significant burdens of disability and costs to the health care system. To meet increasing trauma care needs, there is a robust organization of trauma and rehabilitation systems, particularly within the United States and Canada. The American and Canadian health care systems share multiple similarities, including well-equipped Level I trauma centers, specialized inpatient rehabilitation units for polytrauma patients, and thorough evaluations for recovery and post-discharge placement. However, they also have several key differences. In Canada, the criteria for admission to inpatient rehabilitation vary by location, and inpatient rehabilitation is universally accessible, whereas outpatient rehabilitation services are generally not covered by insurance. In the United States, these admission criteria for post-acute inpatient rehabilitation are standardized, and both inpatient and outpatient services are covered by private and government-funded insurance with varying durations. Overall, both health care systems face challenges in post-acute rehabilitation, including benefit limitations and limited provider access in rural areas, and must continue to evolve to meet the rehabilitation needs of injured patients as they reintegrate into their communities.
Rehabilitation after musculoskeletal injury: European perspective
Authors: Kelly Michael , Donovan Richard L. , Dailiana Zoe H. , Pape Hans-Christophe , Chana-Rodríguez Francisco , Pari Carlotta , Ponsen Kornelis Jan , Cattaneo Stefano , Belluati Alberto , Contini Achille , Gómez-Vallejo Jesús , Casallo-Cerezo Marta , Willinge Gijs J.A. , van Veen Ruben N. , Goslings J. Carel , Papadakis Stamatios A.N. , Iliopoulos Efthymios
Published: August 2024

Trauma is one of the main causes of death in younger people and ongoing disability worldwide. In Europe, while there is generally good organization of trauma reception and acute treatment, rehabilitation from major musculoskeletal injuries is less well defined and provided. This article documents the diverse approaches to rehabilitation after major injury in 6 European nations. The recognition of need is universal, but achieving a robust rehabilitation strategy is more elusive across the varying health care systems. Switzerland has the most robust service in the insured population. In the other countries, particularly where there is a reliance on public institutes, this provision is at best patchy. In the Netherlands, innovative patient-empowering strategies have gained traction with notable success, and in the United Kingdom, a recent randomized trial also showed this approach to be reproducible and robust. Overall, there is a clear need for learning across the national systems and implementation of a minimum set of standards.
Comparison between cycloplegic and noncycloplegic refraction in young adult myopes
Authors: Khan Hashim Ali , Tran Huy , Naduvilath Thomas John , Tahhan Nina , Ha Thao , Sankaridurg Padmaja
Published: August 2024

SIGNIFICANCE

This study explores the difference between cycloplegic and noncycloplegic refraction in young adult myopes.

PURPOSE

From the available literature, it is unclear whether cycloplegia is necessary when refracting young adults. This study investigates the agreement between noncycloplegic autorefraction and cycloplegic autorefraction and investigates factors affecting the agreement between the two methods.

METHODS

In total, 125 myopes with ages ranging between 18 and 26 years were included from Australia and Vietnam. Each participant underwent noncycloplegic autorefraction and cycloplegic autorefraction. Cycloplegia was induced with 1% ophthalmic tropicamide.

RESULTS

The mean spherical equivalent difference (95% confidence interval) between noncycloplegic autorefraction and cycloplegic autorefraction was −0.20 D (−0.25 to −0.14 D; t
124 = −7.18, p<0.0001). A mean difference of >0.25 D was seen in 46.8% of eyes. The lower and upper limits of agreement were −0.80 and 0.41 D, respectively. With univariate analysis, factors including age, degree of refractive error, accommodation amplitude, and distance phorias showed no impact on the average difference between cycloplegic autorefraction and noncycloplegic autorefraction. Yet, eyes with near exophoria (F
2,120 = 6.63, p=0.0019) and Caucasian eyes (F
3,121 = 2.85, p=0.040) exhibited the smallest paired differences. However, in the multivariate analysis, only near exophoria was associated with a lower mean difference. A significantly smaller proportion (34.9%) of eyes with near exophoria had a paired difference of −0.25 D or more compared with esophoria (50%) and orthophoria (65%; χ
2 = 6.6, p=0.038).

CONCLUSIONS

Noncycloplegic autorefraction results in more myopic refractive error than cycloplegic autorefraction in young adults.
Current challenges in neurocysticercosis: recent data and where we are heading
Authors: Coyle Christina M. , Bustos Javier A. , Garcia Hector H.
Published: August 2024

Purpose of review

Neurocysticercosis (NCC) is still a significant contributor to neurological disease in vast regions of the world, and increasingly diagnosed in nonendemic countries because of travel and immigration from endemic settings. There is a need for clinicians in endemic and nonendemic regions to understand the complexities of its diagnosis and management.

Recent findings

Recent information on the performance and use of available imaging and immunodiagnostic tools as well as antiparasitic and anti-inflammatory therapeutic regimes were assessed.

Imaging and serology data should be assessed in the context of the specific type of NCC to improve diagnostic precision. In terms of therapeutic approaches, more controlled data is required on the efficacy and safety of combined antiparasitic therapy, and antiseizure and anti-inflammatory regimes should be optimized to minimize perilesional damage and reduce the risk of epilepsy.
Mouse cytomegalovirus lacking sgg1 shows reduced import into the salivary glands
Authors: Ma Jiawei , Bruce Kimberley , Stevenson Philip G. , Farrell Helen E.
Published: August 2024

Cytomegaloviruses (CMVs) transmit via chronic shedding from the salivary glands. How this relates to the broad cell tropism they exhibit in vitro is unclear. Human CMV (HCMV) infection presents only after salivary gland infection is established. Murine CMV (MCMV) is therefore useful to analyse early infection events. It reaches the salivary glands via infected myeloid cells. Three adjacent spliced genes designated as m131/129 (MCK-2), sgg1 and sgg1.1, positional homologues of the HCMV UL128/130/131 tropism determinants, are implicated. We show that a sgg1 null mutant is defective in infected myeloid cell entry into the salivary glands, a phenotype distinct from MCMV lacking MCK-2. These data point to a complex, multi-step process of salivary gland colonization.
Preliminary attempt to inhibit proliferation of NUT carcinoma cell lines using antisense oligonucleotides targeting NUTM1
Authors: Alley Jessica , Vincent Benjamin G. , Rubinsteyn Alexander
Published: August 2024

NUT carcinoma is an aggressive cancer driven by NUTM1 fusion proteins. This study evaluated antisense oligonucleotides (ASOs) targeting NUTM1 as a potential therapeutic approach. Three ASOs targeting NUTM1 and scrambled controls were tested at 10-50 nM doses in three NUT carcinoma cell lines (TC-797, 10-15, 14169) and one control line (293T). ASOs were delivered both gymnotically and using a transfection reagent. Cell viability was assessed at 48 and 72 hours using a luminescence-based assay. No ASOs showed selective inhibition of NUT carcinoma cell viability compared to controls across all conditions tested. Thus, this pilot study did not identify ASOs with activity against NUT carcinoma cells. However, it did establish preliminary protocols and generated data to inform future ASO optimization efforts targeting NUTM1 in NUT carcinoma. Further refinement of ASO design and delivery methods is needed to identify therapeutic candidates.

Graphical Abstract

Hypothesis

This experiment was performed as a pilot experiment to generate data to inform future work, which should include formal hypothesis testing with a reduced number of conditions. The hypothesis of this pilot experiment was that one or more of the non-scrambled antisense oligonucleotides (ASOs) targeting NUTM1 will selectively decrease proliferation and/or viability of NUT carcinoma cells, indicated by a reduction in luminescence (as compared to treated non-NUT carcinoma and untreated NUT carcinoma control cells) using the CellTiter-Glo Luminescent Cell Viability Assay.
Genetic risk score-informed re-evaluation of spirometry quality control to maximise power in epidemiological studies of lung function
Authors: Chen Jing , Shrine Nick , Izquierdo Abril G , Guyatt Anna , Völzke Henry , London Stephanie , Hall Ian P , Dudbridge Frank ,   SpiroMeta Consortium,   CHARGE Consortium, Wain Louise V , Tobin Martin D , John Catherine
Published: August 2024

Background and aim

Epidemiological studies of lung function may discard one-third to one-half of participants due to spirometry measures deemed “low quality” using criteria adapted from clinical practice. We aimed to define new spirometry quality control (QC) criteria that optimise the signal-to-noise ratio in epidemiological studies of lung function.

Material and methods

We proposed a genetic risk score (GRS) informed strategy to categorize spirometer blows according to quality criteria. We constructed three GRSs comprised of SNPs associated with forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC) and the ratio of FEV1to FVC (FEV1/FVC) in individuals from non-UK Biobank cohorts included in prior genome-wide association studies (GWAS). In the UK Biobank, we applied a step-wise testing of the GRS association across groups of spirometry blows stratified by acceptability flags to rank the blow quality. To reassess the QC criteria, we compared the genetic association results between analyses including different acceptability flags and applying different repeatability thresholds for spirometry measurements to determine the trade-off between sample size and measurement error.

Results

We found that including blows previously excluded for cough, hesitation, excessive time to peak flow, or inadequate terminal plateau, and applying a repeatability threshold of 250ml, would maximise the statistical power for GWAS and retain acceptable precision in the UK Biobank. This approach allowed the inclusion of 29% more participants compared to the strictest ATS/ERS guidelines.

Conclusion

Our findings demonstrate the utility of GRS-informed QC to maximise the power of epidemiological studies for lung function traits.
Health Utility Value of Overactive Bladder in Japanese Older Adults
Authors: Yoshioka Takashi , Omae Kenji , Funada Satoshi , Minami Tetsuji , Goto Rei
Published: August 2024

Objectives

To determine the health utility values (HUVs) of overactive bladder (OAB) among adults aged ≥65 years and to assess the HUV decrements (disutilities) of OAB according to its severity.

Methods

This cross-sectional Internet-based study was conducted between 2 and 9 November 2023, with quota sampling with equal probability for each gender and age group (age 65–74 years and ≥75 years). OAB was defined as an urgency score of ≥2 points and a total score of ≥3 points based on the Overactive Bladder Symptom Score. OAB severity was categorized as mild (total score, ≤5 points) or moderate-to-severe (total score, 6–15 points). HUVs were measured using the EuroQol 5-Dimension 5-Level value set for the Japanese population. Multivariable linear regression models were fitted to estimate the covariate-adjusted disutilities of OAB, with eight covariates selected based on previous studies.

Results

Among the 998 participants (51.9% male; mean age, 73.2 years), 158 (15.9%) had OAB, of whom 87 (8.8%) had moderate-to-severe OAB. The mean HUVs for participants with mild and moderate-to-severe OAB were 0.874 and 0.840, respectively, which were lower compared with the HUV for those without OAB (0.913). After adjusting for relevant covariates, disutilities (95% confidence intervals [CIs]) for mild and moderate-to-severe OAB were –0.0334 (–0.0602 to –0.0066) and –0.0591 (–0.0844 to –0.0339), respectively.

Conclusions

This study examined HUVs in older Japanese adults with and without OAB. The results demonstrate that increased OAB severity is associated with greater disutility.
Neutralizing antibodies elicited in sequentially immunized macaques recognize V3 residues on altered conformations of HIV-1 Env trimer
Authors: DeLaitsch Andrew T. , Keeffe Jennifer R. , Gristick Harry B. , Lee Juliet A. , Ding Wenge , Liu Weimin , Skelly Ashwin N. , Shaw George M. , Hahn Beatrice H. , Björkman Pamela J.
Published: August 2024

Eliciting broadly neutralizing antibodies that protect against diverse HIV-1 strains is a primary goal of AIDS vaccine research. We characterized Ab1456 and Ab1271, two heterologously-neutralizing antibodies elicited in non-human primates by priming with an engineered V3-targeting SOSIP Env immunogen and boosting with increasingly native-like SOSIP Envs derived from different strain backgrounds. Structures of Env trimers in complex with these antibodies revealed V3 targeting, but on conformational states of Env distinct from the typical closed, prefusion trimeric SOSIP structure. Env trimers bound by Ab1456 adopted conformations resembling CD4-bound open Env states in the absence of soluble CD4, whereas trimers bound by Ab1271 exhibited a trimer apex-altered conformation to accommodate antibody binding. The finding that elicited antibodies cross-neutralized by targeting altered, non-closed, prefusion Env trimer conformations provides important information about Env dynamics that is relevant for HIV-1 vaccine design aimed at raising antibodies to desired epitopes on closed pre-fusion Env trimers.

Highlights

-

Sequential immunization regimen elicits V3 antibodies targeting non-closed Envs

-

Cryo-EM structures reveal recognition of multiple Env conformational states

-

Neutralization by elicited antibody does not require antibody-virus preincubation

Graphical Abstract
Salidroside Mitigates Malignant Arrhythmias by Restoring Sodium Channel Function During Ultra-Acute Myocardial Infarction
Authors: Wang Gongxin , Zhao Yilin , Zhang Chenchen , Dong Xiuming , Sun Siyu , Wang Xiulong , Li Dongxu , Li Xuefang , Li Huan , Lu Chieh-Ju , Du Yimei , Chen Zhigang , Lin Fei , Hao Guoliang
Published: August 2024

Background

The ultra-acute phase (Phase 1a) of acute myocardial infarction (AMI) is marked by a high incidence of malignant arrhythmias, often occurring during the prehospital period. Currently, there are no effective treatment options available for managing these arrhythmias at this early stage.

Methods and Results

Using dual-channel optical mapping, we simultaneously recorded membrane potentials and calcium transients during acute myocardial infarction. Calcium transient duration maps accurately localized the infarcted region, and action potential activation time maps revealed conduction heterogeneity in the infarcted zone. Patch-clamp recordings showed that Salidroside (Sal) (1 µg/mL) significantly increased sodium current density from -59.27 ± 2.15 pA/pF to -83.46 ± 3.19 pA/pF (P<0.01) and shifted the Nav1.5 activation curve leftward (V1/2 from -37.27 ± 0.5 mV to -44.55 ± 0.7 mV, P<0.01). In rat and rabbit AMI models, Sal pre-treatment reduced conduction heterogeneity and arrhythmia incidence compared to controls. Optical mapping showed improved conduction velocity and uniformity in the Sal group.

Conclusions

Sal restores electrophysiological function in damaged myocardium by modulating sodium currents, reducing conduction heterogeneity, and decreasing malignant arrhythmia incidence during the ultra-acute phase of AMI. These findings suggest a novel therapeutic strategy for AMI, addressing a critical unmet need in antiarrhythmic therapy.

What is New?

This study identifies Salidroside (Sal) as a novel agent that enhances sodium channel currents (Nav1.5), distinguishing it from traditional antiarrhythmic drugs which primarily target potassium channels or β-adrenergic receptors. Sal improves conduction uniformity in the infarcted myocardium by restoring the electrophysiological function of damaged cardiac cells, eliminating slow conduction pathways, and reducing conduction heterogeneity.

This research introduces Sal as a promising candidate for preventing and treating arrhythmias during the critical early stages of MI, potentially improving patient outcomes. Sal administration during the ultra-acute phase (phase 1a) of myocardial infarction (MI) significantly reduces the incidence of malignant arrhythmias, a critical period characterized by high extracellular potassium and increased arrhythmia risk.

Utilizing calcium transient imaging and optical mapping, this study provides precise localization of ischemic regions and detailed electrophysiological characterization, offering a robust methodology for assessing therapeutic efficacy.
Information, certainty, and learning
Authors: Harris Justin A. , Gallistel C. R.
Published: August 2024

More than four decades ago, Gibbon and Balsam (1981) showed that the acquisition of Pavlovian conditioning in pigeons is directly related to the informativeness of the conditioning stimulus (CS) about the unconditioned stimulus (US), where informativeness is defined as the ratio of the US-US interval (C) to the CS-US interval (T). However, the evidence for this relationship in other species has been equivocal. Here, we describe an experiment that measured the acquisition of appetitive Pavlovian conditioning in 14 groups of rats trained with differentC/Tratios (ranging from 1.5 to 300) to establish how learning is related to informativeness. We show that the number of trials required for rats to start responding to the CS is determined by theC/Tratio and, remarkably, the specific scalar relationship between the rate of learning and informativeness aligns very closely to that previously obtained with pigeons. We also found that the response rate after extended conditioning is strongly related toT, with the terminal CS response rate being a scalar function of the CS reinforcement rate (1/T). Moreover, this same scalar relationship extended to the rats’ response rates during the (never-reinforced) inter-trial interval, which was directly proportional to the contextual rate of reinforcement (1/C). The findings establish that animals encode rates of reinforcement, and that conditioning is directly related to how much information the CS provides about the US. The consistency of the data across species, captured by a simple regression function, suggests a universal model of conditioning.
Experience of contraceptive care by midwives for nonpostpartum individuals in the Netherlands: a mixed methods study
Authors: Sprenger Merel , Newton Megan D. , Finkenflügel Renee N.N. , Crone Matty R. , Kiefte-de Jong Jessica C. , Slagboom M. Nienke
Published: August 2024

Since 2015, Dutch midwives have been authorised to prescribe all contraception. Initially providing contraceptive care to postpartum clients, they are increasingly offering it to anyone. It remains unknown how this broader population experiences this care. Therefore, this mixed methods study aims to explore experiences of nonpostpartum individuals receiving contraceptive care from Dutch primary care midwives.

At 13 midwifery practices in the Netherlands, participants were recruited to fill out a survey and participate in an in-depth semi-structured interview, both based on Levesque’s Conceptual Framework of Access to Health. Univariate and multivariate logistic regression analyses were applied to survey data (n = 91) and thematic analysis to interview data (n = 10).

Most survey participants (87.8%) received an intrauterine device during their appointment. A majority (58.2%) rated their care a 10 out of 10. Giving full marks was significantly associated with a higher perceived income (adjusted OR = 3.19, 95% CI = 1.21-8.81, p = 0.021), adjusted for appointment type and time since appointment. Participants reported receiving understandable information, being taken seriously, and having enough time during their appointment. Interviews revealed that participants especially appreciate how midwives make them feel at ease, midwives’ expertise, and the convenience of access.

To conclude, given the positive experiences reported by nonpostpartum individuals with contraceptive care from midwives, efforts should be made to improve task sharing and to increase awareness of midwives as contraception providers. Future research should compare care experiences across all types of providers and include a more representative population.

Statement of significance
Endocytosis of the plasma membrane carboxylate transporter Jen1 inSaccharomyces cerevisiaeunder alkali stress: a mechanism for preventing loss of essential metabolites
Authors: Barata-Antunes Cláudia , de Hulster Erik , Cardoso Clara , Ribeiro Inês P. , Fernandes Vítor , Leite Beatriz , Casal Margarida , Gerós Hernâni , Pronk Jack , Ariño Joaquín , Mans Robert , Paiva Sandra
Published: August 2024

When grown on lactate as a sole carbon source,Saccharomyces cerevisiaecells alkalinize their surroundings. This alkalinization coincides with endocytosis of the Jen1 lactate transporter. Previous studies showed that this process depends on a functional Jen1 transporter and involves Bul1 α-arrestin and an active TORC1 complex. However, it remained unclear whether the internalization of Jen1 triggered by prolonged growth on lactate was exclusively due to the increase in external pH. To further investigate the regulatory mechanisms underlying the alkali stress-induced Jen1 endocytosis,S. cerevisiaecells stably expressing aJEN1-GFPfusion were studied in aerobic carbon-limited continuous cultures subjected to a linear increase of the culture pH. We found that, in these controlled bioreactor cultures, Jen1 internalization is strongly dependent on extracellular pH, showing a sharp transition at pH values of 7.0 to 7.2. This pH threshold coincides with wash-out of the chemostat cultures and with release of pyruvate and acetate. Transcriptome analysis revealed upregulation of genes involved in oxidative phosphorylation around this threshold, which is consistent with higher cellular energy requirements or energy metabolism being compromised. The originality of this study lies in the use of continuous cultures to analyse the endocytosis of a yeast nutrient transporter. This approach allowed the rigorous study of cell responses to a specific alteration in a single environmental condition, such as changes in pH.
Valorisation of spent cultivated meat media for recombinant FGF2 production in GRASLactococcus lactis
Authors: Rizal Juliana , Mainali Prashant , Quek Jun Ping , Lee Ling Tan , Bi Jiawu , Chan Alson Jianchen , Gaffoor Azra Anwar , Ming Chew Lamony Jian , Sugii Shigeki , Ng Say Kong , Ow Dave Siak-Wei , Wong Fong Tian
Published: August 2024

Innovative strategies for sustainable utilization of waste resources are imperative in the pursuit of a circular economy. Recently, the idea of utilizing mammalian spent media as a valuable resource is gaining traction, offering significant opportunities for innovative uses as a food-grade feedstock for microbial fermentation, especially in the production of alternative proteins for research and food purposes.

In this study, we aim to repurpose spent mammalian culture media for production of valuable proteins. Growth factors (GFs) are a family of high-value proteins that naturally stimulate cell proliferation or differentiation. More importantly, these factors also present significant costs for cell culture. Here, we successfully demonstrate the use of spent mammalian culture media for the recombinant production of fibroblast growth factor 2 (FGF2-G3) inLactococcus lactis. Bioreactor fermentation at a 1 L scale confirmed purified yields of 2.6 mg/L of recombinant FGF2-G3 using spent media. Further functional testing indicated that the recombinant FGF2-G3 can promote cell proliferation on anAnguilla japonica(Japanese eel) pre-adipocytic cell line, suggesting its potential for cultivated meat production. Based on the preliminary results of this study, our calculations indicate that fermenting 1 L spent mammalian waste could yield enough growth factors to efficiently grow approximately 52 L of cultivated meat through fermentation. This prediction emphasizes the potential of waste valorisation to sustainably produce protein, thus contributing to environmental preservation and economic viability.

Highlights

Spent mammalian culture media can be repurposed for microbial fermentation.

GRASL. lactiswas used to express FGF2-G3 in an optimized spent media formulation.

Functional FGF2-G3 expression was demonstrated in controlled 1-L bioreactor runs.
Characterizing the dual regulation ofNeisseria gonorrhoeae tdfJin response to zinc and iron
Authors: Padmanabhan Sandhya. , Stoudenmire Julie Lynn , Branch Alexis Hope , Cornelissen Cynthia Nau
Published: August 2024

Gonorrhea is a sexually transmitted infection, caused by the bacterial pathogenNeisseria gonorrhea(Ngo) and affects millions of individuals of all age groups across the globe every year. Infection withNgodoes not result in protection and no effective vaccine has been developed, leaving antibiotics as the only treatment option. With the emergence of strains showing high levels of antibiotic resistance, there is an urgent need for development of novel therapeutics for disease prevention. During pathogenesis the host employs nutritional immunity, to restrict important transition metals such as zinc away fromNgo. This process is counteracted inNgoby the production of highly efficient zinc import TonB-dependent Transporters (TDTs) which are promising vaccine antigens and zinc shuttle ABC transporters found to be important for intracellular survival. InNgozinc homeostasis and transport proteins are regulated by the Zinc uptake regulator (Zur) which represses transcription in the presence of zinc and activates transcription in the absence of zinc. In this study, characterize the promoter elements of the zinc import TDT,tdfJ, which results in dual regulation by zinc and iron. We characterize specificity and binding affinities for regulation oftdfJby a second regulator, Ferric uptake regulator (Fur) in response to iron. The response oftdfJto both iron and zinc and its potential to be an important invasin, makes it an attractive candidate to investigate female genital tract infections. The female genital tract is a conglomerate of these conditions and infections here are often asymptomatic. Taken together, this research provides important knowledge on the regulation of virulence mechanisms in response to zinc, which will aid in the development of therapeutics and an efficacious vaccine against a gonococcal infection.
Assaying Nociception Behaviors inDrosophilaLarvae During Parasitoid Wasp Attacks
Authors: Mauthner Stephanie E. , Borjon Lydia J. , Tracey W. Daniel
Published: August 2024

Nociception in fruit fly (Drosophila melanogaster) larvae is characterized by a stereotyped escape behavior. When a larva encounters a noxious (potentially harmful) stimulus, it responds by curving its body into a c-shape and rolling in a corkscrew-like manner around its long-body axis. This rolling behavior may serve to quickly remove the larva from the source of the noxious stimulus, and is particularly adaptive to escape from a common natural predator of fruit fly larvae: parasitoid wasps (Leptopilina boulardi).L. boulardicompletes its life cycle by using fruit fly larvae as hosts for its offspring. Female wasps sting fly larvae with an ovipositor and lay an egg within the larva. The wasp offspring hatches inside the fly larva, consumes the fly tissues during pupation, and eventually emerges from the pupal case as an adult wasp. Fruit fly larvae respond to oviposition attacks by rolling, which causes the long flexible ovipositor to be wound around the larval body like a spool. This dislodges the wasp and allows the larva to attempt to escape by crawling. Rolling behavior is triggered by the activation of sensory neurons (nociceptors) whose function can inform our understanding of the mechanisms of nociception. In this protocol, we describe a simple behavioral assay to test and measure nociceptive responses inDrosophilalarvae during oviposition attacks by female parasitoid wasps. First, we discuss parasitoid wasp husbandry and culturing methods in the laboratory. We then describe how to perform the wasp nociception assay on third-instar fruit fly larvae.