bluuebunny/crossref_metadata_2025 huggingface dataset:
In the Eye of the Beholder: A Stakeholder Analysis of the Value of the “Promotion in Place” Competency-Based Time-Variable Graduate Medical Education Pilot
Authors: Balmer Dorene F. , Pusic Martin V. , Weinstein Debra F. , Co John Patrick T. , Goldhamer Mary Ellen J.
Published: December 2024

Purpose

Competency-based time-variable (CBTV) graduate medical education (GME) has been implemented in Canada, Europe, and the United States, yet its perceived value has not been explored. Promotion in Place (PIP) is a CBTV GME program in which residents graduating early advance to attending status with “sheltered independence” until the standard graduation date. This study describes perceived value of CBTV GME and PIP at Mass General Brigham by capturing diverse stakeholder perspectives.

Method

In this stakeholder analysis using semistructured interviews (June 2022–August 2023), 49 participants were invited (44 representative members and 5 external stakeholders) from 11 GME programs: PIP eligible residents, program directors (PDs), chairs, service chiefs, and external national medical education organization leaders. Authors’ understanding of value was informed by Harvey and Green’s conceptualization of quality in higher education as “fit for purpose,” “standards monitoring,” “transformation,” and “value for the money.” Deductive codes and inductive subcodes captured diverse perspectives of value.

Results

Of the 49 invited stakeholders, 34 (69%) were interviewed across 5 stakeholder groups. Nearly all groups cited aspects of PIP that are “fit for purpose” as evidence of value; PIP supported “workforce readiness” and provided “sheltered independence” as intended. External stakeholders, PDs, service chiefs, hospital leadership, and faculty cited value aligning with “standards monitoring” (e.g., PIP must maintain or improve patient and resident outcomes). Nearly all groups cited aspects of PIP aligning with “transformation” as evidence of value. PIP promoted “independent decision-making” and enhanced trainee confidence. Chairs cited aspects of PIP aligning with “value for the money” (e.g., “cost neutral” as optimal for sustainability and avoidance of “hidden costs” such as assessment burden).

Conclusions

Understanding perceptions of PIP and CBTV GME value is critical to engaging diverse stakeholders and extending CBTV GME to more programs and specialties. PIP’s transformative nature underscores the added value of CBTV GME.
Isorhynchophylline Inhibits Platelet Activation and Thrombus Formation
Authors: Liu Yun , Zhu Hui , Dai Yue , Zhang Jie , Li Yingying , Jiang Huimin , Sun Yueyue , Qiao Jianlin , Xu Xiaoqi
Published: December 2024

Isorhynchophylline is a Chinese herbal medicine and has multiple effects such as anti-inflammatory and neuroprotective effects. Whether isorhynchophylline has antithrombotic property is unknown. This study aims to evaluate its role in platelet function. Human platelets were incubated with isorhynchophylline (0, 10, 20, and 40 μM) at 37°C for 1 hour to detect platelet aggregation and activation, receptors level, spreading, and calcium mobilization. In addition, isorhynchophylline (5 mg/kg) was injected into mice to measure in vivo hemostasis and thrombosis. Isorhynchophylline dose-dependently reduced platelet aggregation, adenosine triphosphate secretion, P-selectin expression, and αIIbβ3 activation induced by collagen-related peptide or thrombin without affecting surface level of receptors αIIbβ3, GPIbα, and glycoprotein VI. Meanwhile, isorhynchophylline-treated platelets showed reduced spreading. Moreover, isorhynchophylline reduced platelet calcium mobilization, phosphatidylserine exposure, and the phosphorylation of PLCγ2 and PKCα. Furthermore, administration of isorhynchophylline into mice impaired platelet hemostatic function and arterial/venous thrombosis without affecting coagulation. In conclusion, isorhynchophylline impairs platelet function and arterial/venous thrombosis, implying its potential to be a novel agent for treating thrombotic or cardiovascular diseases.
Modeling metabolic-associated steatohepatitis with human pluripotent stem cell-derived liver organoids
Authors: Wu Xiaoshan , Jiang Dacheng , Wang Yuchen , Li Xin , Liu Chenyu , Chen Yanhao , Sun Wei , He Ruikun , Yang Yi , Gu Xiaosong , Jiang Chunping , Ding Qiurong
Published: December 2024

Background:

Metabolic-associated steatohepatitis (MASH) is one of the most prevalent liver diseases worldwide, with a global prevalence estimated between 3% and 5%, posing a significant health burden. Human liver organoids (HLOs) have previously been generated to model steatohepatitis, offering a potential cellular disease model for studying MASH. However, the current HLO model lacks detailed molecular characterizations and requires further improvement.

Methods:

HLOs derived from human pluripotent stem cells were treated with oleic acid and TGFβ to mimic the MASH progression. Treated HLOs were then analyzed using both bulk and single-cell RNA sequencing. Functional characterization was performed through staining with BODIPY, TMRM, CellROX, and Collagen I, as well as terminal deoxynucleotidyl transferase dUTP nick end labeling and ELISA assays. In addition, a test using the MASH HLO model to validate the hepatoprotective effects of several herb extracts was also conducted.

Results:

Both RNA-seq and single-cell RNA sequencing demonstrated a close resemblance of multiple molecular signatures and key intercellular communications in and between hepatocyte-like cells and stellate-like cells in the MASH HLO model, compared to human MASH. Furthermore, functional characterizations revealed progressive features of human MASH in the MASH HLO model, including severe steatosis, oxidative stress, mitochondrial dysfunction, inflammation, and fibrosis. In addition, the Schisandra extracts have been demonstrated to have significant antioxidative, anti-inflammatory, and antifibrotic properties in the context of MASH.

Conclusions:

This study offers an improved HLO disease model of human MASH, which can be potentially applied to facilitate the understanding of the MASH pathogenesis and the discovery of effective treatments.
A 5-day course of repetitive transcranial magnetic stimulation before pain onset ameliorates future pain and increases sensorimotor peak alpha frequency
Authors: Chowdhury Nahian S. , Taseen Khandoker J. , Chiang Alan KI. , Chang Wei-Ju , Millard Samantha K. , Seminowicz David A. , Schabrun Siobhan M.
Published: December 2024

Repetitive transcranial magnetic stimulation (rTMS) has shown promise as an intervention for pain. An unexplored research question is whether the delivery of rTMS prior to pain onset might protect against a future episode of prolonged pain. The present study aimed to determine whether (1) 5 consecutive days of rTMS delivered prior to experimentally induced prolonged jaw pain has a prophylactic effect on future pain intensity and (2) whether these effects were accompanied by increases in corticomotor excitability (CME) and/or sensorimotor peak alpha frequency (PAF). On each day from day 0 to 4, 40 healthy individuals received a single session of active (n = 21) or sham (n = 19) rTMS over the left primary motor cortex. Peak alpha frequency and CME were assessed on day 0 (before rTMS) and day 4 (after rTMS). Prolonged pain was induced via intramuscular injection of nerve growth factor in the right masseter muscle after the final rTMS session. From days 5 to 25, participants completed twice-daily electronic diaries including pain on chewing and yawning (primary outcomes), as well as pain during other activities (eg, talking), functional limitation in jaw function and muscle soreness (secondary outcomes). Compared to sham, individuals who received active rTMS subsequently experienced lower pain on chewing and yawning. Furthermore, active rTMS led to an increase in PAF. This is the first study to show that rTMS delivered prior to prolonged pain onset can protect against future pain. Our findings suggest that rTMS may hold promise as a prophylactic intervention for pain.
Trends in Cervical and Anal Cancer Incidence and Mortality in the United States
Authors: McKinnish Tyler R. , Kuroki Lindsay M. , Schwarz Julie K. , Mazul Angela L.
Published: December 2024

Objectives

This article describe trends in the incidence and mortality of cervical (CC) and anal (AC) cancers by race and neighborhood socioeconomic status.

Methods

The Surveillance, Epidemiology, and End Results (SEER) database was used to construct a cohort of CC and AC cases from 2006 to 2018. Incidence rates and survival were calculated by race and neighborhood socioeconomic status (nSES). Annual percent change (APC) in incidence was calculated using linear regression, and 5-year overall survival (OS) by the Kaplan-Meier method.

Results

Of the cases, 33,487 CC and 16,018 AC cases were identified. Women of low nSES were nearly 4 times more likely to be diagnosed with cervical cancer than those of high nSES. Cervical cancer incidence declined marginally in all groups except for low nSES women who are White (APC 0.0). Women who are Black had lower 5-year OS than their nSES counterparts of other races (most notably for Black women of low nSES 53% vs White 63%). Similarly, the low nSES AC cohort contained nearly 3 times the number of diagnoses as the high nSES cohort. AC incidence increased most in women who are White (APC 1.8 and 2.2 for low and high nSES) and men who are Black and low nSES (APC 3.3). Five-year OS was lowest for men who are Asian American and Pacific Islander (40% and 50% for low and high nSES, respectively).

Conclusions

These data suggest a strong correlation between nSES, race, and their interaction on the incidence and survival trends of HPV-related disease and highlight inconsistent effects between cervical and anal cancers.
Characterizing the Frequency and Severity of Clinical Signs and Architectural Changes in Vulvar Lichen Sclerosus
Authors: Ngo Madeline , Chang Hannah R. , Mauskar Melissa M.
Published: December 2024

Untreated vulvar lichen sclerosus (VLS) can have a significant negative impact on quality of life, increase the risk of neoplastic transformation, and lead to irreversible architectural changes. Early and appropriate management using ultrapotent topical steroids is crucial to alleviate symptoms and prevent long-term complications. This study aimed to characterize clinical signs and architectural changes of 364 VLS patients at a tertiary center. The majority of the patients had sought care from ≥1 provider previously, were referred by a physician, had undergone prior vulvar biopsies, and had previously tried topical steroids. The authors observed predominantly mild clinical signs alongside more frequent severe architectural changes. These findings highlight the increased need for nuanced clinical evaluation, sufficient lifelong maintenance therapy to prevent architectural changes, and improved clinical scoring systems to differentiate between active VLS disease and residual damage.
Oral Capsule FMT Combined With Bezlotoxumab Is a Successful Rescue Protocol Following Failure of FMT Alone in the Treatment of Recurrent C. difficile Infection
Authors: Hoeg Austin , Kuchma Nataliia , Krane Andrew , Graiziger Carolyn , Thomas Juana , Kelly Colleen R. , Khoruts Alexander
Published: December 2024

Goals:

Evaluate the benefit of adding bezlotoxumab to repeat fecal microbiota transplantation (FMT) in patients with recurrent Clostridioides difficile infections after the failure of FMT alone.

Background:

The initial failure of FMT in breaking the cycle of recurrent Clostridium difficile(C. difficile) infections is associated with a greater risk of subsequent failure. Our previous analysis showed that FMT failure is associated with delayed repair of fecal microbiota at 1 week after administration. We hypothesized that increasing the symptom-free interval by adding bezlotoxumab would improve the outcomes of a second FMT.

Study:

A new rescue protocol that combines FMT with bezlotoxumab for patients who previously failed FMT alone was implemented in 2 academic medical centers. The clinical outcomes of a new protocol were captured in a prospective registry. The results were compared in a retrospective analysis of clinical outcomes of prior experience with repeat FMT by itself. All FMT preparations were standardized for dose. Bezlotoxumab administration was synchronized temporally with the second FMT to maximize its duration of action.

Results:

Our historical cure rate of second FMT in treatment of recurrent C. difficile infection was 48% (15/31 patients). Addition of bezlotoxumab to the second FMT resulted in a cure rate of 89% (24/27 patients).

Conclusions:

Addition of bezlotoxumab markedly improved the cure rate of the second FMT following initial FMT failure. The rationale for the protocol design highlights the importance of understanding the pharmacokinetics of both bezlotoxumab and FMT. Similar principles may apply to other live biotherapeutic products that are becoming available for prevention of C. difficile infection recurrence.
Goals of chronic obstructive pulmonary disease management: a focused review for clinicians
Authors: Raghavan Sairam , Hatipoğlu Umur , Aboussouan Loutfi S.
Published: December 2024

Purpose of review

The diagnosis of chronic obstructive pulmonary disease (COPD) encompasses heterogeneous pathophysiological mechanisms which can shape an individual patient's experience. This paper reviews available therapeutic options for the clinician intending to individualize care toward patient goals.

Recent findings

The contemporary targeted interventions for COPD include the novel phosphodiesterase inhibitor ensifentrine, the interleukin-4 receptor (IL4R alpha subunit) antibody dupilumab, augmentation therapy for alpha-1 antitrypsin deficiency. Other interventions promoting physical and mental well being include re-envisioned pulmonary rehabilitation, self-management, targeting of comorbidities such as sarcopenia, and virtual health coaching interventions to expand patient access. Opioids did not relieve dyspnea and did not change total step count.

Advances in precision therapy are complemented by the discovery of novel pathophysiology pathways and behavioral and rehabilitation interventions as a holistic view of COPD management emerges. The management of COPD continues to evolve with new tools including precision medicine and individualized care. Comorbidities remain important determinants of health, yet their prevalence and impact are underestimated.
Preoperative blood tests provide diagnostic and prognostic information about patients with hepatocellular carcinoma
Authors: Kostakis Ioannis D. , Kotelis Nikolaos , Safavi Danial , Iype Satheesh
Published: December 2024

Introduction

Our aim was to assess parameters derived from preoperative blood tests as diagnostic or prognostic markers in patients with operable hepatocellular carcinoma (HCC).

Methods

We included 210 patients who underwent liver resection as the first treatment for suspected hepatocellular adenoma (HCA) or HCC (January 2010–December 2022). Parameters originated from preoperative complete blood count and biochemical blood tests were examined for associations with clinicopathological parameters and survival.

Results

There were 31 cases of HCA and 179 cases of HCC. Fibrosis-4 index (FIB-4)≥0.77 provided the best diagnostic accuracy for differentiating between HCA and HCC [area under the curve: 0.914, P < 0.001, sensitivity: 93.8%, specificity: 82.8%, positive predictive value (PPV): 96.9%, negative predictive value (NPV): 69.9%]. Patients with T2–T4 tumours had higher levels of aspartate aminotransferase to alanine aminotransferase ratio (AST/ALT) (P < 0.001), liver function tests index (P = 0.005), platelets-liver function tests index (PLFTI) (P = 0.011), and α-fetoprotein (AFP) (P < 0.001), but the diagnostic accuracy was mediocre. Patients with moderately or poorly differentiated tumours had higher levels of FIB-4 (P = 0.023), and AFP (P = 0.001), providing high PPV (89.4 and 95.1%, respectively). Albumin to alkaline phosphatase ratio (ALB/ALP)>0.508 [hazard ratio (HR): 0.501, P = 0.009], FIB-4>1.41 (HR: 2.272, P = 0.007), PLFTI>0.087 (HR: 1.849, P = 0.016), and AFP>3.1 (HR: 3.066, P = 0.006) provided statistically significant results in relation to disease-free survival, and ALB/ALP>0.389 (HR: 0.505, P = 0.036) provided statistically significant results in relation to overall survival.

Conclusion

Preoperative blood tests provide useful information in treatment-naive surgical candidates with suspected HCC regarding distinguishing from HCA, tumour differentiation, and risk of disease recurrence and death.
Role of immunotherapy in managing cancers prior to liver transplantation
Authors: Bredin Philip , Galvin Zita , O’Kane Grainne M.
Published: December 2024

Purpose of review

Immune checkpoint inhibitors (ICIs) have transformed the treatment landscape in advanced hepatocellular carcinoma and increasingly are being evaluated in earlier stage disease. Herein we explore the role of ICIs pre-liver transplant for liver cancers.

Recent findings

Given the high response rates with combination approaches including locoregional treatments, more patients with liver confined disease, without vascular invasion, who have received ICIs are now being rendered eligible for potential liver transplant. This opportunity to expand the population who may benefit from liver transplant has also come with challenges recognizing the global shortage of organs. Post-liver transplant immunosuppression potentially competes with the immune-stimulating effects of ICIs and graft rejection has been a concern. ICIs may provide an opportunity to maintain patients on the waiting list but an understanding of who is likely to benefit is needed, to circumvent possible toxicities. In addition, ICIs are now considered standard of care, in combination with chemotherapy, for advanced cholangiocarcinoma, where the role of liver transplant is evolving.

As the eligibility criteria globally for liver transplant in the setting of malignancy continues to expand, the integration of ICIs becomes increasingly important.
Relationship between characteristics of segmental phase angles and walking ability in patients with hemiplegia after stroke and traumatic brain injury in a convalescent rehabilitation ward
Authors: Tsujinaka Ryo , Yoshitani Takahiro , Suzuki Hikari , Tanaka Ryo , Izutani Yumi , Morimoto Kaede
Published: December 2024

This study determined the characteristics of the phase angles (PhAs) of the trunk, affected limb, and unaffected limb at admission and their relationship with walking ability at discharge in patients with stroke and traumatic brain injury in a convalescent rehabilitation ward. Stroke and traumatic brain injury survivors with hemiplegia admitted to a convalescent rehabilitation ward were divided into independent- and dependent-walking groups. The trunk, affected limb, and unaffected limb PhAs were evaluated using bioelectrical impedance analysis and compared between the independent- and dependent-walking groups. Friedman’s test was performed to analyze differences in the trunk, affected limb, and unaffected limb PhAs within each group. Multiple regression was performed to examine the association between walking ability and segmental PhAs. We enrolled 47 patients (independent-walking group: n = 12; dependent-walking group: n = 35). The dependent-walking group had a significantly lower trunk, affected limb, and unaffected limb PhAs. The segmental PhA was higher in the trunk than in the affected and unaffected limbs in the independent-walking group and lower in the affected limb than in the trunk and unaffected limb in the dependent-walking group. Only the trunk PhA at admission was significantly associated with walking ability at discharge (β = 0.367; P = 0.002). The trunk PhA at admission may be related to walking ability at discharge in patients undergoing stroke and traumatic brain injury rehabilitation.
Risk Factors and a Prediction Model for Hemorrhagic Transformation in Acute Ischemic Stroke With Atrial Fibrillation
Authors: Fu Wang , Zhang Jun , Bi Qianqian , Lu Yanqin , Liu Lili , Zhou Xiaoyu , Wang Jue , Wang Feng
Published: December 2024

Objectives:

To identify the risk factors of hemorrhagic transformation (HT) and to establish a prediction model for HT in patients with acute ischemic stroke (AIS) and atrial fibrillation (AF).

Methods:

From January 2015 to December 2018, patients with AIS and AF were enrolled. Demographics, lesion features, and blood test results were collected. Univariate and multivariate logistic regression analyses were used to identify the independent risk factors of HT. The receiver operating curve (ROC) curve was utilized to determine the cutoff values and the efficiency of the variables. A predictive model was subsequently developed based on the identified independent risk factors.

Results:

A total of 259 patients were included. Age [odds ratio (OR): 1.094; 95% CI: 1.048-1.142; P<0.001], LDL-C (OR: 0.633; 95% CI: 0.407-0.983; P=0.042), uric acid (OR: 0.996; 95% CI: 0.991-0.999; P=0.031), Alberta Stroke Program Early CT Score (ASPECTS) (OR: 0.700; 95% CI: 0.563-0.870; P<0.001), cerebral cortex infarction (OR: 0.294; 95% CI: 0.168-0.515; P<0.001), and massive cerebral infarction (OR: 3.683; 95% CI: 3.025-5.378; P<0.001) were independently associated with HT. We have developed a model incorporating these variables. The area under the curve of the predictive model was 0.87 (95% CI: 0.83-0.92), demonstrating satisfactory predictive ability with a sensitivity of 83.5% and a specificity of 76.4%.

Conclusions:

Our predictive model, which integrates age, LDL-C, uric acid, ASPECTS, cerebral cortex infarction, and massive cerebral infarction, can be used to predict HT after AIS in patients with AF, thereby facilitating the mitigation of adverse outcomes.
Psychosocial factors account for a proportion of the difference in cognitive performance between persons with and without HIV
Authors: Dreyer Anna Jane , Le Roux Celine , Thomas Kevin G.F. , Sabin Caroline A. , Winston Alan , Khoo Saye , Joska John A. , Nightingale Sam
Published: December 2024

Objective:

To investigate whether psychosocial factors account for a proportion of the difference in cognitive performance between persons with and without HIV.

Design:

Cross-sectional study of 273 participants (178 persons with HIV) from a low income area of Cape Town, South Africa,

Methods:

Participants completed comprehensive cognitive testing (7 domains) and 12 psychosocial measures (5 current: income, occupation, assets, accommodation, depressive symptoms, 7 from childhood: assets, quality of education, exposure to childhood trauma and violence, primary caregiver occupation and highest level of education), as well as demographic measures standard in cognition studies (age, sex, years of education). We investigated the HIV association with global cognitive performance after adjustment for standard demographic variables, exploratory psychosocial variables, and balancing characteristics of those with and without HIV using propensity score modelling.

Results:

Persons with HIV had significantly lower scores than persons without HIV in 8/12 psychosocial variables. Of these, 7/12 significantly predicted global T-score. In unadjusted regression, HIV status was associated with a reduction in global T-score of 3.72 units. Adjustment for standard variables, reduced the effect of HIV on global T score by 26.9% to 2.72, additional adjustment for psychosocial variables reduced by 40.3% to 2.22, and adjustment for propensity scores by 42.7% to 2.13.

Conclusions:

Persons with HIV in this setting have lower psychosocial indices, both current and in childhood, which are associated with lower cognitive test performance as an adult. This is incompletely mitigated by adjustments for standard demographic variables which risks overestimation of cognitive impairment on a population level.
The Snails: A Simple Technique for Reduction of Frontal Bossing in Children With Scaphocephaly
Authors: Stella Irene , Hayward Richard , Klein Olivier
Published: December 2024

Objective:

Scaphocephaly represents the most frequent single-suture craniosynostosis, with a male prevalence. In many cases, prominent frontal bossing (sphenocephaly) is the major aesthetic concern, typically in school-aged children. This aspect is also usually found in patients with late presentation (after 1 year of age). Several techniques have been described for the correction of frontal bossing in these patients, most involving wide frontal bone exposure and reconstruction. The authors describe a different, less invasive technique, useful in severe sphenocephalic patients, independently from age.

Methods:

Thirteen children aged from 3.5 to 22 months were operated on in our institution between 2016 and 2023 using the snails technique, in addition to the treatment for the craniosynostosis itself. The technique is described, consisting in spiral frontal impacted craniotomies. Transfusional rate and duration of surgery are reported and compared with 15 randomly selected patients treated at the same time without Snails technique. Postoperative follow-up is almost 1 year.

Results:

Cosmetic postoperative results, based on parental and clinician’s satisfaction as well as on radiographic and photographic assessment, showed rapid improvement of frontal bossing, which remains stable during years. Transfusion rate during scaphocephaly repair with Snails technique is not different from control, even if time of procedure is longer.

Conclusion:

Among several techniques described to directly correct frontal bossing, the snail technique is more simple and less invasive, avoiding further craniotomies over the superior sagittal sinus, and does not imply consistent blood loss.
The Impact of Acupuncture on Pain Intensity, Nausea, and Vomiting for Laparoscopic Cholecystectomy: A Meta-analysis Study
Authors: Tang Xi , Qu Shijie
Published: December 2024

Background:

Acupuncture may have some potential in pain relief after laparoscopic cholecystectomy, and this meta-analysis aims to explore the impact of acupuncture on pain intensity, nausea and vomiting for patients undergoing laparoscopic cholecystectomy.

Methods:

PubMed, EMbase, Web of science, EBSCO, Cochrane library databases, CNKI, VIP, and Wangfang were systematically searched, and we included randomized controlled trials (RCTs) assessing the effect of acupuncture on pain control for laparoscopic cholecystectomy.

Results:

Five RCTs and 366 patients were included in the meta-analysis. Overall, compared with control intervention for laparoscopic cholecystectomy, acupuncture was associated with significantly reduced pain scores at 6 hours [mean difference (MD)=−0.86; 95% CI=−1.37 to −0.34; P=0.001, 2 RCTs) and pain scores at 8 to 10 hours (MD=−0.71; 95% CI=−1.13 to −0.28; P=0.001, 2 RCTs), decreased incidence of nausea (odds ratio=0.10; 95% CI=0.03-0.34; P=0.0003, 3 RCTs), and vomiting (odds ratio=0.11; 95% CI=0.01-0.85; P=0.03, 3 RCTs), but demonstrated no obvious impact on pain scores at 12 to 24 hours (MD=−0.38; 95% CI=−1.02 to 0.27; P=0.25, 2 RCTs).

Conclusions:

Acupuncture may be effective to reduce pain intensity, nausea, and vomiting for laparoscopic cholecystectomy.
Pain Following Obstetric Anal Sphincter Injuries: A Prospective Cohort Study
Authors: Fazeli Yasamin , Lua-Mailland Lannah L. , Yao Meng , Wallace Shannon L.
Published: December 2024

Importance

Studies characterizing pain and pain management following obstetric anal sphincter injury (OASI) are limited.

Objectives

Our primary objective was to analyze time to pain resolution following OASI. Secondary objectives included analyzing pain severity, location, triggers, and patterns of pain medication use.

Study Design

This was a prospective cohort study of patients with OASIs seen in a postpartum care clinic at a tertiary referral center between 2017 and 2022. We analyzed data on pain resolution, visual analog scale pain scores, pain triggers, pain location, and pain medications.

Results

A total of 362 patients were included in this study. In the Kaplan-Meier estimator, 58.5% of patients showed resolution of pain by 3 months following their initial postpartum care clinic visit, and 73.3% showed resolution of pain by 6 months. The median months to pain resolution was 2.2 (95% confidence interval: 1.6–3.0) for patients with third-degree lacerations and 2.3 (95% confidence interval: 1.6–6.8) for patients with fourth-degree lacerations. Visual analog scale scores showed the most improvement in the first 2 months. Common pain triggers included sitting and bowel movements in the first few months, as well as intercourse during later recovery. Pain location varied over time; bilateral pain in the levator ani muscles and obturator internus were most prevalent at each time point. Pain appeared to be predominantly managed by acetaminophen and ibuprofen.

Conclusions

Half of patients who experience OASI will have pain resolution by 2-3 months postpartum. Most patients will have resolution of their pain by 6 months postpartum.
Transcutaneous Tibial Nerve Stimulation for Urge Incontinence: A Randomized Clinical Trial
Authors: Shah Nemi M. , Lukacz Emily S. , Ferrante Kimberly L. , Menefee Shawn A.
Published: December 2024

Importance

Overactive bladder is a distressing syndrome that significantly affects quality of life. Transcutaneous tibial nerve stimulation (TTNS) has been proposed as a home-based, patient-centered therapy that could improve access to treatment for this condition.

Objective

We aimed to determine the efficacy of 12 weeks of TTNS versus sham therapy in reducing symptomatic bother in ambulatory women with urgency urinary incontinence.

Study Design

This was a double-masked, sham-controlled randomized trial. The primary outcome was the change in Overactive Bladder Questionnaire scores. Secondary outcomes included those with 50% or greater reduction in urgency incontinence episodes on 3-day voiding diaries and Patient Global Impression of Improvement.

Results

One hundred women were randomized (65 intervention, 35 sham) and included in analysis. Both groups experienced clinically meaningful improvement in Overactive Bladder Questionnaire scores postintervention from baseline, which was not significant between groups (symptom severity: intervention −19.5 ± 20.2 vs sham −19.4 ± 20.4, P = 1.0; health-related quality of life −16.6 ± 18.5 vs −13.8 ± 16.8, P = 0.5). In the TTNS group, 58.8% of women achieved 50% or greater reduction in urgency incontinence episodes versus 41.7% of women in the sham group (P = 0.2), and 25% versus 18% were “much” or “very much improved” (P = 0.2). A sensitivity analysis confirmed these findings.

Conclusions

Clinically meaningful reductions in overactive bladder symptoms were observed in both TTNS and sham therapy without significant differences between groups; however, a trend toward greater reduction in incontinence episodes and overall impression of improvement was noted in the active treatment. The therapeutic benefit from regularly connecting with a clinician should be considered when developing new therapies.
Oceanic and ionospheric tidal magnetic fields extracted from global geomagnetic observatory data
Authors: Tyler Robert H. , Trossman David S.
Published: December 2024

Ocean tide generated magnetic fields contain information about changes in ocean heat content and transport that can potentially be retrieved from remotely sensed magnetic data. To provide an important baseline towards developing this potential, tidal signals are extracted from 288 land geomagnetic observatory records having observations within the 50-year time span 1965–2015. The extraction method uses robust iteratively reweighted least squares for a range of models using different predictant and predictor assumptions. The predictants are the time series of the three vector components at each observatory, with versional variations in data selection and processing. The predictors fall into two categories: one using time-harmonic bases and the other that directly use lunar and solar ephemerides with gravitational theory to describe the tidal forces. The ephemerides predictors are shown to perform better (fitting more variance with fewer predictors) than do the time-harmonic predictors, which include the traditional ‘Chapman–Miller method’. In fitting the oceanic lunar tidal signals, the predictants with the highest signal/noise involve the ‘vertical’ magnetic vector component following principle-component rotation. The best simple semidiurnal predictor is the ephemeris series of lunar azimuth weighted by the inverse-cubed lunar distance. More variance is fitted with predictors representing the lunar tidal potential and gradients calculated for each location/time.

This article is part of the theme issue ‘Magnetometric remote sensing of Earth and planetary oceans’.
Drug combinations targeting FAK and MEK overcomes tumour heterogeneity in glioblastoma
Authors: Furqan Muhammad , Elliott Richard J R , Nagle Peter , Dawson John C. , Masalmeh Roza , Garcia Virginia Alvarez , Munro Alison F. , Drake Camilla , Morrison Gillian M , Pollard Steven M. , Ebner Daniel , Brunton Valerie G. , Frame Margaret C , Carragher Neil O.
Published: December 2024

Glioblastoma (GBM) is an aggressive brain tumour with limited treatment options and poor prognosis, largely due to its heterogeneity and the involvement of multiple intracellular signalling pathways that contribute to drug resistance. Standard therapies have not significantly improved patient outcomes over the past two decades. While recent advancements in targeted drug combination therapies, such as dabrafenib and trametinib, show promise for certain GBM subgroups, identifying drug combinations effective across the broader GBM population remains a challenge. Integrin-mediated signalling, particularly through Focal Adhesion Kinase (FAK), plays a pivotal role in GBM pathogenesis and invasion, making it a potential therapeutic target [1].

In our study, we utilized a chemogenomic screening approach to identify synergistic drug combinations that target FAK in glioblastoma. We initially employed a CRISPR-engineered GBM model to assess the effects of FAK depletion and discovered that combining FAK inhibitors with MEK inhibitors, particularly trametinib, demonstrated synergistic effects. This potent combination was validated through various 2D & 3D assays, including cell viability/apoptotic assessment, synergistic analysis, cellular imaging, and target engagement assays. The combination also effectively inhibited spheroid growth and invasion across a diverse panel of patient derived GBM stem cells. Molecular mechanisms underlying these effects included suppression of multiple kinase signalling pathways and enhanced apoptosis, elucidated using Reverse Phase Protein Array (RPPA) profiling and western blot validation.In vivo, the combination therapy significantly reduced tumour volume in orthotopic transplantation models. These findings suggest that combining FAK and MEK inhibitors represent a promising therapeutic strategy to overcome the challenges of GBM treatment.
fluxTrAM: Integration of tracer-based metabolomics data into atomically resolved genome-scale metabolic networks for metabolic flux analysis
Authors: Huang Luojiao , Preciat German , Alarcon-Gil Jesus , Moreno Edinson L. , Wegrzyn Agnieszka , Thiele Ines , Schymanski Emma L. , Harms Amy , Fleming Ronan M.T. , Hankemeier Thomas
Published: December 2024

Quantitative inference of intracellular reaction rates is essential for characterising metabolic phenotypes. The classical experimental method for measuring metabolic fluxes makes use of stable-isotope tracing of metabolites through the metabolic network, followed by mass spectrometry analysis. The most common13C-based metabolic flux analysis requires multidisciplinary knowledge in analytical chemistry, cell biology, and mathematical modelling, as well as the use of multiple independent tools for handling mass spectrometry data. Besides, flux analysis is usually carried out within a small network to validate a specific biological hypothesis. To overcome interdisciplinary barriers and extend flux interpretation towards a genome-scale level, we developed fluxTrAM, a semi-automated pipeline for processing tracer- based metabolomics data and integrating it with atomically resolved genome-scale metabolic networks to enable flux predictions at genome-scale. fluxTrAM integrates different software packages inside and outside of the COBRA Toolbox v3.4 for the generation of metabolite structure and reaction databases for a genome-scale model, labelled mass spectrometry data processing into standardised mass isotopologue distribution data (MID), and metabolic flux analysis. To demonstrate the utility of this pipeline, we generated13C-labeled metabolomics data on anin vitrohuman induced pluripotent stem cell (iPSC)-derived dopaminergic neuronal culture and processed13C-labeled MID datasets. In parallel, we generated a cheminformatic database of standardised and context-specific metabolite structures, and atom-mapped reactions for a genome-scale dopaminergic neuronal metabolic model. MID data could be exported into established flux inference software for conventional flux inference on a core model scale. It could also be integrated into the atomically resolved metabolic model for flux inference at genome-scale using moiety fluxomics method. The core model flux solution and moiety flux solution were then compared to two additional flux solutions predicted via flux balance analysis and entropic flux balance analysis. The extensive computational flux analysis and comparison helped to better evaluate the obtained flux feasibility of the neuron-specific genome-scale model and suggested new tracer-based metabolomics experiments with novel labeling configurations, such as labelling a moiety within the thymidine metabolite. Overall, fluxTrAM enables the automation of labelled liquid chromatography (LC)-mass spectrometry (MS) data processing into MID datasets and atom mapping for any given genome-scale metabolic model. It contributes to the standardisation and high throughput of metabolic flux analysis at genome- scale.
Label-Free Visualization and Segmentation of Endothelial Cell Mitochondria Using Holotomographic Microscopy and U-Net
Authors: Michael Raul , Modirzadeh Tallah , Issa Tahir Bachar , Jurney Patrick
Published: December 2024

Understanding the physiological processes underlying age-related cardiovascular disease (CVD) requires examination of endothelial cell (EC) mitochondrial networks, because mitochondrial function and adenosine triphosphate production are crucial in EC metabolism, and consequently influence CVD progression. Although current biochemical assays and immunofluorescence microscopy can reveal how mitochondrial function influences cellular metabolism, they cannot achieve live observation and tracking changes in mitochondrial networks through fusion and fission events. Holotomographic microscopy (HTM) has emerged as a promising technique for real-time, label-free visualization of ECs and their organelles, such as mitochondria. This non-destructive, non-interfering live cell imaging method offers unprecedented opportunities to observe mitochondrial network dynamics. However, because existing image processing tools based on immunofluorescence microscopy techniques are incompatible with HTM images, a machine-learning model is required. Here, we developed a model using a U-net learner with a Resnet18 encoder to identify four classes within HTM images: mitochondrial networks, cell borders, ECs, and background. This method accurately identifies mitochondrial structures and positions. With high accuracy and similarity metrics, the output image successfully provides visualization of mitochondrial networks within HTM images of ECs. This approach enables the study of mitochondrial networks and their effects, and holds promise in advancing understanding of CVD mechanisms.
Optical tomography reconstructing 3D motion and structure of multiple-scattering samples under rotational actuation
Authors: Moser Simon , Kvale Lovmo Mia , Strasser Franziska , Hagenbuchner Judith , Ausserlechner Michael J. , Ritsch-Marte Monika
Published: December 2024

Optical Diffraction Tomography (ODT) has emerged as a powerful tool for imaging biological cells in a non-invasive and label-free manner. However, conventional approaches using ODT by varying the illumination are plagued by the missing cone problem, which introduces ambiguity and deteriorates the axial resolution in the reconstruction. Although utilizing object rotation has the potential to yield isotropic resolution, experimental control or prior retrieval of the rotational parameters is challenging. In this work, we demonstrate ODT of multiple-scattering samples undergoing variable rotational motion, unlocking the potential for isotropic resolution in non-contact systems. We introduce a comprehensive reconstruction method to jointly retrieve both sample and rotational motion in 3D. An interferometric setup enables the recording of amplitude and phase data while the object is rotated in a non-contact manner around one or more chosen axes in an acoustofluidic device. We evaluate the tomographic reconstruction performance of the method for clusters of micro-beads and highlight its suitability for biomedical application beyond single cells, demonstrating high-resolution reconstruction of dense cancer spheroids containing more than 100 cells.
Evolution of thermal tolerance in marine diatoms: Metabolic strategies under heat stress
Authors: Aranguren-Gassis María , Diz Angel P. , Huete-Ortega María , Allen Andrew , Litchman Elena
Published: December 2024

In the last decade, numerous laboratory experiments have demonstrated that when marine phytoplankton are exposed to thermal stress, they can evolve high temperature tolerance in a short time (weeks to months). This evolutionary potential may ensure the persistence of marine phytoplankton species under current and future global warming. However, the effect of such adaptation on the phytoplankton interaction with the environment and other organisms depends on how cellular metabolism shifts during the evolutionary process. In order to elucidate which cellular strategies allow the emergence of thermo-tolerant populations, we analyzed the proteomics response of a marine diatom (Chaetoceros simplex) to both thermal acclimation and evolutionary adaptation. We found that high temperature-tolerant populations exhibit a conservative cellular strategy when acclimated to high, above-optimal temperature, where recycling and reallocation is favored at the expense of new structures’ biosynthesis. While this strategy gives the populations that evolved high temperature tolerance an advantage under thermal stress, the shift to resource reallocation may explain the absence of high-temperature adaptation when cells are exposed to low nitrate availability.
Genome-scale prediction of gene ontology from mass fingerprints reveals new metabolic gene functions
Authors: Vavricka Christopher J. , Mochizuki Masao , Yuzawa Satoshi , Murata Masahiro , Yoshida Takanobu , Watanabe Naoki , Nakatsui Masahiko , Ishii Jun , Hara Kiyotaka , Alper Hal S. , Hasunuma Tomohisa , Kondo Akihiko , Araki Michihiro
Published: December 2024

Mass-based fingerprinting can characterize unknown strains, however expansion of these methods to predict specific gene functions is lacking. Therefore, rapid mass fingerprinting was developed to functionally profile a comprehensive yeast knockout library. Matrix assisted laser desorption ionization (MALDI)-time of flight (TOF) mass fingerprints of 3,238 Saccharomyces cerevisiae knockouts were digitized for correlation with gene ontology (GO) annotations. Random forests and support vector machine (SVM) algorithms precisely assigned GO accessions with AUC scores all above 0.83. SVM was the best predictor with average true positive and true negative rates of 0.975 and 0.991, respectively. The SVM model suggested new functions for 28 uncharacterized yeast genes. Metabolomics analysis of two knockouts (YDR215C and YLR122C) of uncharacterized genes predicted to be involved in methylation-related metabolism, showed altered intracellular contents of methionine-related metabolites. Increased S-adenosylmethionine in YDR215C highlights potential for enhancement of methylation pathways. These results demonstrate that MALDI-TOF fingerprints can be rapidly digitized, resulting in datasets that enable prediction of microbial genotypes and even the function of specific genes. This fingerprinting method can inform optimal bioproduction chassis selection.
Alevin-fry-atac enables rapid and memory frugal mapping of single-cell ATAC-seq data using virtual colors for accurate genomic pseudoalignment
Authors: Singh Noor Pratap , Khan Jamshed , Patro Rob
Published: December 2024

Ultrafast mapping of short reads via lightweight mapping techniques such as pseudoalignment has significantly accelerated transcriptomic and metagenomic analyses, often with minimal accuracy loss compared to alignment-based methods. However, applying pseudoalignment to large genomic references, like chromosomes, is challenging due to their size and repetitive sequences.

We introduce a new and modified pseudoalignment scheme that partitions each reference into “virtual colors…. These are essentially overlapping bins of fixed maximal extent on the reference sequences that are treated as distinct “colors” from the perspective of the pseudoalignment algorithm.

We apply this modified pseudoalignment procedure to process and map single-cell ATAC-seq data in our new toolalevin-fry-atac. We comparealevin-fry-atacto bothChromapandCell Ranger ATAC.Alevin-fry-atacis highly scalable and, when using 32 threads, is approximately 2.8 times faster thanChromap(the second fastest approach) while using approximately one third of the memory and mapping slightly more reads.

The resulting peaks and clusters generated fromalevin-fry-atacshow high concordance with those obtained from bothChromapand theCell Ranger ATACpipeline, demonstrating that virtual colorenhanced pseudoalignment directly to the genome provides a fast, memory-frugal, and accurate alternative to existing approaches for single-cell ATAC-seq processing. The development ofalevin-fry-atacbrings single-cell ATAC-seq processing into a unified ecosystem with single-cell RNA-seq processing (viaalevin-fry) to work toward providing a truly open alternative to many of the varied capabilities ofCellRanger. Furthermore, our modified pseudoalignment approach should be easily applicable and extendable to other genome-centric mapping-based tasks and modalities such as standard DNA-seq, DNase-seq, Chip-seq and Hi-C.
Genetic determinants of gene expression noise and its role in complex trait variation
Authors: Long Yuexuan , Ni Xiaolin , Chen Tingwei , Hong Qiyang , Wang Jixin , Wang Cong , Huang Zigeng , Xu Haiqing , Sun Mengyi , Pang Junling , Choi Jiyeon , Zhang Tongwu , Long Erping
Published: December 2024

Even genetically identical cells in a homogeneous environment can exhibit heterogeneous mRNA abundance because of widely unavoidable random fluctuations, typically referred to as ‘gene expression noise’. Recent studies showed that noise, not just a nuisance, is indeed involved in cellular activities (e.g., immune response), evolutionary processes, and diseases mechanisms. However, determinants of the gene expression noise and its functional role in variations of human complex traits remain largely unexplored. Here, we established an atlas of gene expression noise from 1.23 million human peripheral blood cells of 981 individuals, identifying its age- and gender-dependent pattern. We then identified 10,770 independent expression noise quantitative trait loci (enQTLs) for 6,743 unique enGenes (genetically driven gene expression noise) across 7 immune cell types. Most enQTLs were distinct from expression quantitative trait loci (eQTLs) and showed differential enrichment of functional elements across the genome. Colocalization of enQTLs with trait-associated genetic loci interpreted previously unexplained loci and pinpointed novel putative genes underlying hematopoietic traits and autoimmune diseases. Overall, this study unravels the genetic determinants of gene expression noise and implicates as a previously underappreciated mechanism underlying variation of human complex traits and diseases.