bluuebunny/crossref_metadata_2025 huggingface dataset:
A cross-sectional review of contact allergens in popular self-tanning products
Authors: Newton Jazmin , Ogunremi Oluwafunke , Paulsen Riley T. , Lien Molly , Sievers Meaghan , Greenway Bietz Mandi
Published: February 2024

Background:

In recent years, self-tanners have become a well-liked alternative to sun tanning and tanning bed usage, as strikingly similar results can be achieved without the harmful side effects of ultraviolet exposure.

Objective:

The aim of this study is to investigate the presence and prevalence of potential allergens in the most popular self-tanning products.

Methods:

Five major retailers in the United States were evaluated, from which 17 different brands and 44 unique self-tanning products were analyzed. The ingredients in each self-tanning product were compared with 80 and 36 notable contact allergens taken from the North American Contact Dermatitis Group and Food and Drug Administration–approved T.R.U.E (Thin-Layer Rapid Use Epicutaneous Patch Test), respectively.

Results:

We found that contact allergens are frequently present in self-tanning products; allergens especially common are propylene glycol, linalool, polysorbate, d-limonene, benzyl alcohol, tocopherol (vitamin E), fragrances, and other scented botanicals. On average, each self-tanner we analyzed contained 11.86 allergens.

Limitations:

The limitation is that commercial names could not be eliminated from the analysis, introducing potential bias.

Conclusion:

While self-tanning products are a safer alternative to tanning bed use or sunbathing, consumers and clinicians alike must be aware that they may cause an allergic reaction of the skin for some users.
Enhancing foot care education and support strategies in adults with type 2 diabetes
Authors: Ju Hsiao-Hui , Ottosen Madelene , Alford Jeffery , Jularbal Jed , Johnson Constance
Published: February 2024

Background:

People with diabetes are susceptible to serious and disabling foot complications, which increase their morbidity and mortality rates. Examining the perspectives of people with diabetes on their foot care routines could help elucidate their beliefs and offer practical ways to prevent foot problems.

Purpose:

We explored the perspectives of adults with diabetes on their foot care practices to identify and enhance foot care education and support strategies.

Methodology:

Using the Zoom platform, 29 adults with diabetes completed a 3-month telehealth educational program, during which interviews were conducted. This article reports the results of thematic content analysis of the qualitative data. Coded participant statements were organized into categories and reexamined to identify emergent themes.

Results:

Analysis of participants' perceptions revealed four main themes of influences that facilitated and/or hindered their foot care practices. Foot care behaviors were facilitated by patients' personal knowledge of others with diabetes-related foot consequences (theme 1). Foot care practices were hindered by the emotional impact of living with diabetes (theme 2), and the physical, social, and lifestyle limitations associated with foot care (theme 3). Finally, patients noted that interactions with family could be either a facilitator or hindrance to their foot care routines (theme 4).

Conclusions:

These findings highlight multiple patient-centered factors related to personal, physical, psychosocial, and cultural influences that affect foot care behaviors.

Implications:

An understanding of how patients manage diabetes-related foot care can help nurse practitioners enhance foot care education and support strategies in this population.
Ethical considerations and decision making in opioid prescribing for chronic pain: A case study in rheumatology practice
Authors: Carnago Lisa , Knisely Mitchell R. , Malek Janet
Published: February 2024

Dilemmas regarding opioid prescribing for chronic pain frequently occur within health care settings. The ethical principles of autonomy, beneficence, nonmaleficence, and justice, as well as the principles of care ethics, can assist in addressing these opioid-related dilemmas. The purpose of this clinical case study is to provide a case study highlighting an opioid prescribing dilemma and then identify opioid-related transition considerations; address ethical questions that nurse practitioners (NPs) may encounter in clinical practice when providing care for individuals living with chronic pain who may need or use a prescribed opioid medication; and draw on the ethical principles and care ethics to provide guidance for NPs who face these challenging issues.
Relation between frailty and adverse outcomes in elderly patients with gastric cancer: a scoping review
Authors: Tan Zheng-Ke-Ke , Tang Wen-Zhen , Jia Kui , Li Dan-Ni , Qiu Li-Yan , Chen Xin , Yang Li
Published: February 2024

Background:

Playing an exemplary role, frailty have crucial effect on the preoperative evaluation of elderly patients. Previous studies have shown that frailty is associated with complications and mortality in patients with gastric cancer (GC). However, with the development of the concept of “patient-centered”, the range of health-related outcomes is broad. The differences in relation between frailty and various adverse outcomes will be further explored.

Method:

The PubMed, Embase, Web of Science, Cochrane Library, China National Knowledge Infrastructure, Wan Fang, and Chinese Biomedical Literature databases were searched for keywords, including frailty (such as frail) and gastric cancer (such as stomach neoplasms or stomach cancer or gastrectomy or gastric surgery). The search period is until August 2023. The included studies were observational or cohort studies with postoperative related adverse outcomes as primary or secondary outcome measures. Valid assessment tools were used. The Quality Assessment Tool for Observational Cohort and Cross-sectional Studies was used to assess methodological quality in the included literature.

Result:

15 studies were included, including 4 cross-sectional studies, 8 retrospective cohort studies, and 3 prospective cohort studies. Among them, 6 studies were rated as “Good” and 9 studies were rated as “Fair,” indicating that the quality of the literature was high. Then, 10 frailty assessment tools were summarized and classified into two broad categories in accordance with frailty models. Results of the included studies indicated that frailty in elderly patients with GC was associated with postoperative complications, mortality, hospital days, readmissions, quality of life, nonhome discharge, and admission to the intensive care unit.

Conclusion:

This scoping review concludes that high levels of preoperative frailty increase the risk of adverse outcomes in elderly patients with GC. Frailty will be widely used in the future clinical evaluation of elderly gastric cancer patients, precise risk stratification should be implemented for patients, and frailty management should be implemented well to reduce the occurrence of adverse treatment outcomes.
Papillary Renal Cell Carcinoma: Evolving Classification by Combined Morphologic and Molecular Means
Authors: Przybycin Christopher G.
Published: February 2024

Papillary renal cell carcinoma classification has evolved as a result of attentive morphologic observations by pathologists coupled with specific immunohistochemical, molecular, and clinical data. Refinement of this relatively common diagnostic category of renal neoplasia has resulted in the parsing out of specific renal cell carcinoma subtypes that no longer belong in the papillary renal cell carcinoma category and can have distinct familial and prognostic implications (eg, fumarate hydratase (FH)-deficient renal cell carcinomas). In addition, evolving classification has enabled more accurate diagnosis by surgical pathologists (through the description of recognizable morphologic variants). In many cases, molecular findings have aided and confirmed morphologic categorization. The combination of morphologic and molecular findings continues to provide important prognostic information for patients and their clinicians.
Nudging During Pediatric Intensive Care Conferences With Family Members: Retrospective Analysis of Transcripts From a Single-Center, 2015–2019*
Authors: Olive Aliza M. , Finnsdottir Wagner Asdis , Mulhall Daniel T. , October Tessie W. , Hart Joanna L. , Sherman Ashley K. , Wallisch Jessica S. , Miller-Smith Laura
Published: February 2024

OBJECTIVES:

Nudging, a behavioral economics concept, subtly influences decision-making without coercion or limiting choice. Despite its frequent use, the specific application of nudging techniques by clinicians in shared decision-making (SDM) is understudied. Our aim was to analyze clinicians’ use of nudging in a curated dataset of family care conferences in the PICU.

DESIGN:

Between 2019 and 2020, we retrospectively studied and coded 70 previously recorded care conference transcripts that involved physicians and families from 2015 to 2019. We focused on decision-making discussions examining instances of nudging, namely salience, framing, options, default, endowment, commission, omission, recommend, expert opinion, certainty, and social norms. Nudging instances were categorized by decision type, including tracheostomy, goals of care, or procedures.

SETTING:

Single-center quaternary pediatric facility with general and cardiac ICUs.

PATIENTS:

None.

INTERVENTIONS:

None.

MEASUREMENTS:

We assessed the pattern and frequency of nudges in each transcript.

MAIN RESULTS:

Sixty-three of the 70 transcripts contained SDM episodes. These episodes represented a total of 11 decision categories based on the subject matter of nudging instances, with 308 decision episodes across all transcripts (median [interquartile range] 5 [4–6] per conference). Tracheostomy was the most frequently discussed decision. A total of 1096 nudging instances were identified across the conferences, with 8 (6–10) nudge types per conference. The most frequent nudging strategy used was gain frame (203/1096 [18.5%]), followed by loss frame (150/1096 [13.7%]).

CONCLUSIONS:

Nudging is routinely employed by clinicians to guide decision-making, primarily through gain or loss framing. This retrospective analysis aids in understanding nudging in care conferences: it offers insight into potential risks and benefits of these techniques; it highlights ways in which their application has been used by caregivers; and it may be a resource for future trainee curriculum development.
Comparing the Quality of Domain-Specific Versus General Language Models for Artificial Intelligence-Generated Differential Diagnoses in PICU Patients*
Authors: Akhondi-Asl Alireza , Yang Youyang , Luchette Matthew , Burns Jeffrey P. , Mehta Nilesh M. , Geva Alon
Published: February 2024

OBJECTIVES:

Generative language models (LMs) are being evaluated in a variety of tasks in healthcare, but pediatric critical care studies are scant. Our objective was to evaluate the utility of generative LMs in the pediatric critical care setting and to determine whether domain-adapted LMs can outperform much larger general-domain LMs in generating a differential diagnosis from the admission notes of PICU patients.

DESIGN:

Single-center retrospective cohort study.

SETTING:

Quaternary 40-bed PICU.

PATIENTS:

Notes from all patients admitted to the PICU between January 2012 and April 2023 were used for model development. One hundred thirty randomly selected admission notes were used for evaluation.

INTERVENTIONS:

None.

MEASUREMENTS AND MAIN RESULTS:

Five experts in critical care used a 5-point Likert scale to independently evaluate the overall quality of differential diagnoses: 1) written by the clinician in the original notes, 2) generated by two general LMs (BioGPT-Large and LLaMa-65B), and 3) generated by two fine-tuned models (fine-tuned BioGPT-Large and fine-tuned LLaMa-7B). Differences among differential diagnoses were compared using mixed methods regression models. We used 1,916,538 notes from 32,454 unique patients for model development and validation. The mean quality scores of the differential diagnoses generated by the clinicians and fine-tuned LLaMa-7B, the best-performing LM, were 3.43 and 2.88, respectively (absolute difference 0.54 units [95% CI, 0.37–0.72], p < 0.001). Fine-tuned LLaMa-7B performed better than LLaMa-65B (absolute difference 0.23 unit [95% CI, 0.06–0.41], p = 0.009) and BioGPT-Large (absolute difference 0.86 unit [95% CI, 0.69–1.0], p < 0.001). The differential diagnosis generated by clinicians and fine-tuned LLaMa-7B were ranked as the highest quality in 144 (55%) and 74 cases (29%), respectively.

CONCLUSIONS:

A smaller LM fine-tuned using notes of PICU patients outperformed much larger models trained on general-domain data. Currently, LMs remain inferior but may serve as an adjunct to human clinicians in real-world tasks using real-world data.
Well-differentiated Squamous Cell Carcinoma With Sarcomatous Differentiation in Patient With a History of Recurrent Verrucous Carcinoma
Authors: Ijaz Komal , Johannesen Eric , Nguyen T Van
Published: February 2024

Human papillomavirus–independent vulvar squamous cell carcinoma has a peak incidence in about the eighth decade of life. A variable portion of the vulvar squamous cell carcinoma are human papillomavirus–independent comprising 20% to 80% of all cases. Verrucous carcinoma (VC) is part of the spectrum of human papillomavirus–independent carcinomas and its combination with well-differentiated squamous cell carcinoma with sarcomatous differentiation is an extremely unusual neoplasm. The available literature on VC is currently limited to case reports and small single-institution studies. Here, we present a case concerning an 81-year-old woman with a history of chronic itching, swelling, and lichen sclerosis with variable-sized multiple white-pink plaques of the vulva. The pathologic diagnosis of VC was made. The patient later on developed multiple lesions of biopsy proved VC and most recent biopsy shows well-differentiated squamous cell carcinoma with abrupt sarcomatous differentiation. A review of the literature shows the rarity of this lesion of the female genital tract. Clinicians and patients should be aware of the aggressive behavior of cancers and adjust their surgical management together with the follow-up strategy. To the best of our knowledge, this is the first description of a VC and well-differentiated squamous cell carcinoma with abrupt sarcomatous differentiation occurring in the vulva.
Benefits, Challenges, and Opportunities in Addressing Medicaid Beneficiaries' Non-Medical Risks to Health: A Qualitative Analysis
Authors: LaPoint Myklynn , Vu Maihan B. , Ricks Katharine , Flower Kori B. , Domino Marisa Elena , Dave Gaurav , Berkowitz Seth A.
Published: February 2024

Context:

North Carolina's Healthy Opportunities Pilots (HOP) is a Medicaid 1115 Waiver program that seeks to address nonmedical risks to health for Medicaid beneficiaries through multisector collaboration. Among other stakeholders, HOP involves collaboration between human services organizations that deliver interventions, network leads, which establish and oversee the human services organizations within a region of the state.

Objective:

To understand how employees at human services organizations and network leads prepared to deliver HOP services.

Design:

Qualitative analysis of semistructured interviews. Interviews were conducted between April and June 2022. Interviews were recorded, transcribed verbatim, coded thematically, and analyzed using a conceptual model derived from the consolidated framework for implementation research.

Setting:

Organizations within North Carolina counties participating in HOP.

Participants:

Employees of human services and network lead organizations across all 3 HOP regions of North Carolina.

Results:

The researchers interviewed 37 participants. Overall, organizations experienced benefits from HOP participation, including capacity-building resources, flexibility in allocating resources, and creating community-wide enthusiasm for addressing nonmedical risks to health. There were also key challenges. These included the time needed to build capacity, adjustments to the work processes and regulations inherent to multisector collaboration, geographic variation in availability of services to offer, and the difficulty of addressing different needs. Finally, participants recognized substantial opportunities that HOP presented, including membership in a more extensive network, exposure to a learning community, and a more sustainable funding source.

Conclusions:

The perspectives of individuals preparing to deliver HOP services offer important lessons for those developing and implementing large-scale programs that can address nonmedical threats to health.
Charting the Advocacy Landscape: A Qualitative Content Analysis of Syllabi in Public Health Graduate Education
Authors: Schneider Glenn E. , DiOrio Alexandra , Asada Yuka , Hearne Shelley A.
Published: February 2024

Context:

Addressing public health challenges necessitates policy approaches, but concerns persist about public health graduates' preparedness to advocate.

Objective:

This qualitative study sought to assess advocacy content and skills taught to Master of Public Health students enrolled in US accredited schools and programs of public health (SPPHs) by analyzing 98 course syllabi submitted to the Council on Education for Public Health (CEPH) between 2019 and 2021. Syllabi were submitted by SPPHs during their (re)accreditation process to demonstrate compliance with CEPH's advocacy competency requirement.

Design:

Qualitative content analysis study. Syllabi were analyzed using MAXQDA Qualitative Data Analysis Software using a 2-coder approach.

Setting:

SPPHs accredited by CEPH.

Participants:

Ninety-eight syllabi submitted to CEPH by 22 schools of public health and 54 programs of public health.

Main Outcome Measures:

Exemplary language from advocacy courses and assignments and aggregate frequency of syllabi advocacy content and skills.

Results:

Most advocacy courses (61%) were survey, health policy, or health care delivery courses, covering policy (66%), policy communication (46%), coalition-building (45%), lobbying (36%), community organizing (33%), and media advocacy (24%) skills. Only 7% prioritized advocacy skill instruction, and 10% addressed how to advocate in an equitable way.

Conclusions:

Defining public health advocacy and essential skills is crucial. Issuing competency guidelines, supporting advocacy faculty, offering standardized training, and expanding experiential learning are important first steps. More research is needed on how academic institutions are incorporating equity skill training into courses, whether separate from or combined with advocacy skills.
Superiority of a Silk Surgical Site Wound Closure Device over Synthetic Dressings
Authors: Rouhani Daniel S. , Singh Navin K. , Chao James J. , Almutairi Adah , Seradj Mehran H. , Badowski-Platz Rebecca , Toranto Jason D. , Mofid M. Mark
Published: February 2024

Background:

Silk fibroin is an emerging biomaterial with enhanced properties of cellular regeneration, growth, and proliferation. The use of a silk fibroin wound dressing has the potential to decrease the incidence of wound-healing complications and to improve patient outcomes compared with synthetic dressing alternatives.

Methods:

A randomized, single-blind clinical trial was conducted on 50 patients who were dressed with a silk fibroin dressing on 1 side of their body and 3M Steri-Strips on the contralateral side after abdominoplasty, reduction mammaplasty, or brachioplasty procedures. Data were collected over 5 postoperative visits using photographs and an investigator-administered questionnaire to monitor erythema, skin irritation, skin discomfort, need for pharmaceutical intervention, wound dehiscence, and mechanical skin injury. A comprehensive 75-patient statistical analysis was conducted, combining the results with a previously published study comparing Dermabond Prineo with the silk dressing.

Results:

A total of 20.8% of patients (10 of 48) were assessed by surgeons as having skin erythema (7 to 10) on the Steri-Strip control side, with 0% (0 of 48) on the silk dressing side (P = 0.002). The frequency of breast triple-point separation in 43 cases was 30.2% (13 of 43) on the Steri-Strip side and 9.3% (4 of 43) on the silk side (P = 0.012). A total of 75% of patients (36 of 48) had partial or total detachment of Steri-Strips, 0% (0 of 48) had total detachment of the silk dressing, and 18.8% (9 of 48) had partial detachment of the silk dressing within the first 2 weeks (P < 0.001).

Conclusion:

A silk fibroin wound dressing significantly reduces the incidence of wound-healing complications throughout the postoperative period.

CLINICAL QUESTION/LEVEL OF EVIDENCE:

Therapeutic, II.

Clinical Relevance Statement:

The adoption of a silk fibroin wound dressing into clinical practice has the potential to improve patient outcomes, decrease medical adhesive–related skin injuries, and reduce the rate of wound-healing complications.
Examining incidence of diabetes in people with HIV: tracking the shift in traditional and HIV-related risk factors
Authors: Mohammad Pritom Gazi Sakir , Yang Xueying , Gao Haoyuan , Chen Shujie , Zhang Jiajia , Olatosi Bankole , Li Xiaoming
Published: February 2024

Background and objective:

The risk factors of diabetes mellitus (DM) in people with HIV (PWH) may be dynamic in a life course manner. This study aimed to describe incidence of DM and investigate the trajectory of changes in risk factor associated with DM incidence over around 15 years among a statewide cohort of PWH in South Carolina (SC).

Design:

This is a population-based cohort study.

Methods:

Data were retrieved from the integrated statewide electronic health records between 2006 and 2020 in SC. Separate subgroup analysis was conducted according to the patients’ different follow up duration (i.e., 5, 10, and 15 years) to observe the evolving risk factors of DM development, using multivariable logistic regressions.

Results:

The DM incidence among a total of 9115 PWH was 8.9 per 1000 person-years. In the overall model, being >60 years old, hypertension, and obesity were positively associated with DM while alcohol consumption, years of HIV diagnosis and high percentage days of viral suppression were negatively associated with the outcome. In the subgroup analyses, similar risk factors were observed. The odds of DM increased in a graded fashion with age. Hypertension was positively associated with DM in all groups and retention to care was negatively associated with the outcome in groups 1 and 3.

Conclusion:

This large-scale population-based study has revealed a relatively lower incidence of DM among PWH than some other US States. The evolving risk factors over time underline the need for maintaining retention to care to prevent the occurrence of DM.
Effect of Lower Extremity Nerve Decompression in Patients with Painful Diabetic Peripheral Neuropathy
Authors: Rozen Shai M. , Wolfe Gil I. , Vernino Steven , Raskin Philip , Hynan Linda S. , Wyne Kathleen , Fulmer Rita , Pandian Geetha , Sharma Shiv K. , Mohanty Ahneesh J. , Sanchez Cristina V. , Hembd Austin , Gorman April
Published: February 2024

Objective:

Evaluate the effect of nerve decompression on pain in patients with lower extremity painful Diabetic Peripheral Neuropathy (DPN).

Summary Background Data:

Currently, no treatment provides lasting relief for patients with DPN. Benefits of nerve decompression remain inconclusive.

Methods:

This double-blinded, observation- and same-patient sham surgery-controlled randomized trial enrolled patients aged 18-80 years with lower extremity painful DPN who failed one-year of medical treatment. Patients were randomized to nerve decompression- or observation-group (2:1). Decompression-group patients were further randomized and blinded to nerve decompression in either right or left leg and sham surgery in the opposite leg. Pain (11-point Likert score) was compared between decompression and observation groups and between decompressed versus sham legs at 12 and 56 months.

Results:

Of 2987 screened patients, 78 were randomized. At 12 months, compared with controls (n=37), both right-decompression-group (n=22) and left-decompression-group (n=18) reported lower pain (mean difference for both, −4.46; [95% CI, −6.34 to −2.58 and −6.48 to −2.45 respectively]; P<0.0001). Decompressed and sham legs equally improved. At 56 months, compared with controls (n=14), pain was lower in both the right-decompression-group (n=20) (mean difference, −7.65; [95% CI, −9.87 to −5.44]; P<0.0001) and left-decompression-group (n=16) (mean difference, −7.26; [95% CI, −9.60 to −4.91]; P<0.0001). Mean pain score was lower in decompressed versus sham legs (mean difference, 1.57 [95% CI, 0.46 to 2.67]; P=0.0002).

Conclusion:

Although nerve decompression was associated with reduced pain, the benefit of surgical decompression needs further investigation since a placebo effect may be responsible for part or all of these effects.
Ambulatory seizure detection
Authors: Bernini Adriano , Dan Jonathan , Ryvlin Philippe
Published: February 2024

Purpose of review

To review recent advances in the field of seizure detection in ambulatory patients with epilepsy.

Recent findings

Recent studies have shown that wrist or arm wearable sensors, using 3D-accelerometry, electrodermal activity or photoplethysmography, in isolation or in combination, can reliably detect focal-to-bilateral and generalized tonic-clonic seizures (GTCS), with a sensitivity over 90%, and false alarm rates varying from 0.1 to 1.2 per day. A headband EEG has also demonstrated a high sensitivity for detecting and help monitoring generalized absence seizures. In contrast, no appropriate solution is yet available to detect focal seizures, though some promising findings were reported using ECG-based heart rate variability biomarkers and subcutaneous EEG.

Several FDA and/or EU-certified solutions are available to detect GTCS and trigger an alarm with acceptable rates of false alarms. However, data are still missing regarding the impact of such intervention on patients’ safety. Noninvasive solutions to reliably detect focal seizures in ambulatory patients, based on either EEG or non-EEG biosignals, remain to be developed. To this end, a number of challenges need to be addressed, including the performance, but also the transparency and interpretability of machine learning algorithms.
Challenging fungal infections in cystic fibrosis: a case of mixed Aspergillus species infection and antifungal combination testing
Authors: Pontes Laís , Reichert-Lima Franqueline , Perini Leme Giordano Ana Luisa , Moretti Maria Luiza , Zaninelli Schreiber Angélica
Published: February 2024

Aspergillus stands as the predominant fungal genus in the airways of cystic fibrosis (CF) patients, significantly contributing to their morbidity and mortality. Aspergillus fumigatus represents the primary causative species for infections, though the emergence of rare species within the Aspergillus section Fumigati has become noteworthy. Among these, Aspergillus lentulus is particularly significant due to its frequent misidentification and intrinsic resistance to azole antifungal agents. In the invasive aspergillosis and resistant infections, combination antifungal therapy has proven to be an effective approach. This report documents a case involving the death of a CF patient due to a pulmonary exacerbation linked to the colonization of multiple Aspergillus species, including A. lentulus, A. fumigatus, and A. terreus, and treated with Itraconazole (ITC) monotherapy. We delineated the procedures used to characterize the Aspergillus isolates in clinical settings and simulated in vitro the impact of the combination antifungal therapy on the isolates obtained from the patient. We evaluated three different combinations: Amphotericin B (AMB) + Voriconazole (VRC), AMB + Anidulafungin (AND), and VRC + AND. Notably, all strains isolated from the patient exhibited a significant decrease in their minimum inhibitory concentration (MIC) or minimum effective concentration (MEC) values when treated with all combinations. The VRC + AMB combination demonstrated the most synergistic effects. This case report emphasizes the importance of susceptibility testing and precise identification of Aspergillus species to enhance patient prognosis. It also underscores the potential benefits of combined antifungal treatment, which, in this case, could have led to a more favorable patient outcome.
Intermittent energy restriction inhibits tumor growth and enhances paclitaxel response in a transgenic mouse model of endometrial cancer
Authors: Zhao Ziyi , Wang Jiandong , Kong Weimin , Fang Ziwei , Coleman Michael , Milne Ginger , Burkett Wesley C. , Newton Meredith A. , Lee Douglas , Deng Beor , Shen Xiaochang , Suo Hongyan , Sun Wenchuan , Hursting Stephen , Zhou Chunxiao , Bae-Jump Victoria L
Published: February 2024

Objective

Overweight/obesity is the strongest risk factor for endometrial cancer (EC), and weight management can reduce that risk and improve survival. We aimed to establish the differential abilities of intermittent energy restriction (IER) and low-fat diet (LFD), alone and in combination with paclitaxel, to reverse the procancer effects of high-fat diet (HFD)-induced obesity in a mouse model of EC.

Methods

Lkb1fl/flp53fl/flmice were fed high-fat diet (HFD) or LFD to generate obese and lean phenotypes, respectively. Obese mice were maintained on HFD or switched to LFD (HFD-LFD) or IER (HFD-IER). Ten weeks after induction of endometrial tumor, mice in each group received paclitaxel or placebo for 4 weeks. Body and tumor weights; tumoral transcriptomic, metabolomic and oxylipin profiles; and serum metabolic hormones and chemocytokines were assessed.

Results

HFD-IER and HFD-LFD, relative to HFD, reduced body weight; reversed obesity-induced alterations in serum insulin, leptin and inflammatory factors; and decreased tumor incidence and mass, often to levels emulating those associated with continuous LFD. Concurrent paclitaxel, versus placebo, enhanced tumor suppression in each group, with greatest benefit in HFD-IER. The diets produced distinct tumoral gene expression and metabolic profiles, with HFD-IER associated with a more favorable (antitumor) metabolic and inflammatory environment.

Conclusion

InLkb1fl/flp53fl/flmice, IER is generally more effective than LFD in promoting weight loss, inhibiting obesity-related endometrial tumor growth (particularly in combination with paclitaxel), and reversing detrimental obesity-related metabolic effects. These findings lay the foundation for further investigations of IER as a EC prevention strategy in women with overweight/obesity.
Sterol-lipids enable large-scale, liquid-liquid phase separation in bilayer membranes of only 2 components
Authors: Wilson Kent J. , Nguyen Huy Q. , Gervay-Hague Jacquelyn , Keller Sarah L.
Published: February 2024

Despite longstanding excitement and progress toward understanding liquid-liquid phase separation in natural and artificial membranes, fundamental questions have persisted about which molecules are required for this phenomenon. Except in extraordinary circumstances, the smallest number of components that has produced large-scale, liquid-liquid phase separation in bilayers has stubbornly remained at three: a sterol, a phospholipid with ordered chains, and a phospholipid with disordered chains. This requirement of three components is puzzling because only two components are required for liquid-liquid phase separation in lipid monolayers, which resemble half of a bilayer. Inspired by reports that sterols interact closely with lipids with ordered chains, we tested whether phase separation would occur in bilayers in which a sterol and lipid were replaced by a single, joined sterol-lipid. By evaluating a panel of sterol-lipids, some of which are found in bacteria, we discovered a minimal bilayer of only two components (PChemsPC and diPhyPC) that robustly demixes into micron-scale, liquid phases. It suggests a new role for sterol-lipids in nature, and it reveals a membrane in which tie-lines (and, therefore, the lipid composition of each phase) are straightforward to determine and will be consistent across multiple laboratories.

Significance Statement

A wide diversity of bilayer membranes, from those with hundreds of lipids (e.g., vacuoles of living yeast cells) to those with very few (e.g., artificial vesicles) phase separate into micron-scale liquid domains. The number of components required for liquid-liquid phase separation has been perplexing: only two should be necessary, but more are required except in extraordinary circumstances. What minimal set of molecular characteristics leads to liquid-liquid phase separation in bilayer membranes? This question inspired us to search for single, joined “sterol-lipid” molecules to replace both a sterol and a phospholipid in membranes undergoing liquid-liquid phase separation. By producing phase-separating membranes with only two components, we mitigate experimental challenges in determining tie-lines and in maintaining constant chemical potentials of lipids.
Topo-Net: Retinal Image Analysis with Topological Deep Learning
Authors: Ahmed Faisal , Coskunuzer Baris
Published: February 2024

The analysis of fundus images for the early screening of eye diseases is of great clinical importance. Traditional methods for such analysis are time-consuming and expensive as they require a trained clinician. Therefore, the need for a comprehensive and automated clinical decision support system to diagnose and grade retinal diseases has long been recognized. In the past decade, with the substantial developments in computer vision and deep learning, machine learning methods have become highly effective in this field to address this need. However, most of these algorithms face challenges like computational feasibility, reliability, and interpretability.

In this paper, our contributions are two-fold. First, we introduce a very powerful feature extraction method for fundus images by employing the latest topological data analysis methods. Through our experiments, we observe that our topological feature vectors are highly effective in distinguishing normal and abnormal classes for the most common retinal diseases, i.e., Diabetic Retinopathy (DR), Glaucoma, and Age-related Macular Degeneration (AMD). Furthermore, these topological features are interpretable, computationally feasible, and can be seamlessly integrated into any forthcoming ML model in the domain. Secondly, we move forward in this direction, constructing a topological deep learning model by integrating our topological features with several deep learning models. Empirical analysis shows a notable enhancement in performance aided by the use of topological features. Remarkably, our model surpasses all existing models, demonstrating superior performance across several benchmark datasets pertaining to two of these three retinal diseases.
SREBP-dependent regulation of lipid homeostasis is required for progression and growth of pancreatic ductal adenocarcinoma
Authors: Ishida Chiaki T. , Myers Stephanie L. , Shao Wei , McGuire Meredith R. , Liu Chune , Kubota Casie S. , Ewachiw Theodore E. , Mukhopadhyay Debaditya , Ke Suqi , Wang Hao , Rasheed Zeshaan A. , Anders Robert A. , Espenshade Peter J.
Published: February 2024

Metabolic reprogramming is a necessary component of oncogenesis and cancer progression that solid tumors undergo when their growth outstrips local nutrient supply. The supply of lipids such as cholesterol and fatty acids is required for continued tumor cell proliferation, and oncogenic mutations stimulate de novo lipogenesis to support tumor growth. Sterol regulatory element-binding protein (SREBP) transcription factors control cellular lipid homeostasis by activating genes required for lipid synthesis and uptake. SREBPs have been implicated in the progression of multiple cancers, including brain, breast, colon, liver, and prostate. However, the role the SREBP pathway and its central regulator SREBP cleavage activating protein (SCAP) in pancreatic ductal adenocarcinoma (PDAC) has not been studied in detail. Here, we demonstrated that pancreas-specific knockout ofScaphas no effect on mouse pancreas development or function, allowing for examination of the role forScapin the murine KPC model of PDAC. Notably, heterozygous loss ofScapprolonged survival in KPC mice, and homozygous loss ofScapimpaired PDAC tumor progression. Using subcutaneous and orthotopic xenograft models, we showed that SCAPis required for human PDAC tumor growth. Mechanistically, chemical or genetic inhibition of the SREBP pathway prevented PDAC cell growth under low serum conditions due to a lack of lipid supply. Highlighting the clinical importance of this pathway, the SREBP pathway is broadly required for cancer cell growth, SREBP target genes are upregulated in human PDAC tumors, and increased expression of SREBP targets genes is associated with poor survival in PDAC patients. Collectively, these results demonstrate that SCAP and the SREBP pathway activity are essential for PDAC cell and tumor growthin vitroandin vivo, identifying SCAP as a potential therapeutic target for PDAC.

SIGNIFICANCE

Our findings demonstrate that SREBP pathway activation is a critical part of the metabolic reprogramming that occurs in PDAC development and progression. Therefore, targeting the SREBP pathway has significant therapeutic potential.
Elastohydrodynamic mechanisms govern beat pattern transitions in eukaryotic flagella
Authors: Veeraragavan Shibani , Parast Farin Yazdan , Nosrati Reza , Prabhakar Ranganathan
Published: February 2024

Eukaryotic cilia and flagella exhibit complex beating patterns that vary depending on environmental conditions such as fluid viscosity1. These transitions are thought to arise from changes in the internal forcing provided by the axoneme, although the mechanism remains unclear2,3. We demonstrate with simulations of Kirchhoff rods driven internally by active bending moments that a single elastohydrodynamic instability universally explains transitions between planar, quasiplanar, helical, and complex beating patterns due to changes in either the internal forcing, flagellar stiffness and length, or due to changes in the hydrodynamic resistance, either due to the viscosity of the ambient medium or the presence of a plane wall. The beat patterns and transitions are comparable to those exhibited by bull sperm and sea urchin sperm in our experiments and elsewhere3–5. Our results point to a general model that can describe flagellar and ciliary beating across all species. We further show that internal dynein forces can be estimated by comparing simulation results with experimental observations of transitional viscosities. This can potentially lead to diagnostic assays to measure the health of sperm cells based on their beating pattern.
Quantifying the IUCN Red List: Using historical assessments to calculate future extinction risk
Authors: Bates Ryan , Taylor Elizabeth , Sun Yuheng , Gumbs Rikki , Böhm Monika , Gray Claudia , Rosindell James
Published: February 2024

The IUCN Red List of Threatened Species assigns species to discrete categories based on a common set of criteria to capture relative extinction risk. Some quantitative analyses require a continuous probability of extinction not provided by discrete categories. Furthermore, the criteria may not translate to extinction risk in a universal way across species, because some species’ attributes are not incorporated into the criteria. Here we calculate extinction risk using Markov Models parameterised with historical IUCN Red List assessment data, and we provide quantitative extinction risk for use in downstream analyses. We find that taxonomy, body size, and habitat specialism interact with extinction risk in ways not fully captured by the existing categories. For example, an Endangered habitat specialist appears equally at risk compared to a Critically Endangered habitat generalist. We hope our findings will support more accurate quantitative biodiversity analyses of species extinctions and declines using Red List data.
𝛀-Loop mutations control the dynamics of the active site by modulating a network of hydrogen bonds in PDC-3 β-lactamase
Authors: Chen Shuang , Mack Andrew R , Hujer Andrea M , Bethel Christopher R. , Bonomo Robert A , Haider Shozeb
Published: February 2024

The expression of antibiotic-inactivating enzymes, such as Pseudomonas-derived cephalosporinase-3 (PDC-3), is a major mechanism of intrinsic resistance in bacteria. To explore the relationships between structural dynamics and altered substrate specificity as a result of amino acid substitutions in PDC-3, innovative computational methods like machine learning driven adaptive bandit molecular dynamics simulations and markov state modeling of the wild-type PDC-3 and nine clinically identified variants were conducted. Our analysis reveals that structural changes in the Ω-loop controls the dynamics of the active site. The E219K and Y221A substitutions have the most pronounced effects. The modulation of three key hydrogen bonds K67(sc)-G220(bb), Y150(bb)-A292(bb) and N287(sc)-N314(sc) were found to result in an expansion of the active site, which could have implications for the binding and inactivation of cephalosporins. Overall, the findings highlight the importance of understanding the structural dynamics of PDC-3 in the development of new treatments for antibiotic-resistant infections.
A self-adaptive and versatile tool for eliminating multiple undesirable variations from transcriptome
Authors: Zhang Mengji , Yan Lei , Wang Xinbo , Yuan Yi , Zou Shimin , Yao Sichao , Wang Xinyu , Xu Tian , Chen Bin , Yang Dong
Published: February 2024

Accurate identification of true biological signals from diverse undesirable variations in large-scale transcriptomes is essential for downstream discoveries. Herein, we develop a universal deep neural network, called DeepAdapter, to eliminate various undesirable variations from transcriptomic data. The innovation of our approach lies in automatic learning of the corresponding denoising strategies to adapt to different situations. The data-driven strategies are flexible and highly attuned to the transcriptomic data that requires denoising, yielding significant improvement in reducing undesirable variation originating from batches, sequencing platforms, and bio-samples with varied purity beyond manually designed schemes. Comprehensive evaluations across multiple batches, different RNA measurement technologies and heterogeneous bio-samples demonstrate that DeepAdapter can robustly correct diverse undesirable variations and accurately preserve biological signals. Our findings indicate that DeepAdapter can act as a versatile tool for the comprehensive denoising of the large and heterogeneous transcriptome across a wide variety of application scenarios.
Impact of a team-based versus individual clinician-focused training approach on primary healthcare professionals’ intention to have serious illness conversations with patients: a theory informed process evaluation of a cluster randomized trial
Authors: Souza Lucas Gomes , Archambault Patrick , Asmaou Bouba Dalil , Dofara Suélène Georgina , Guay-Bélanger Sabrina , Cortez Ghio Sergio , Gadio Souleymane , Michaels LeAnn , Paquette Jean-Sébastien , Izumi Shigeko (Seiko) , Totten Annette M. , Légaré France ,   The Meta-LARC ACP Cluster Randomized Trial team
Published: February 2024

Background

Cluster Randomized Trials (cRTs) conducted in real-world settings face complex challenges due to diverse practices and populations. Process evaluations alongside cRTs can help explain their results by exploring possible causal mechanisms as the trial proceeds.

Objective

To conduct a process evaluation alongside a cRT that compared the impact of team-based vs. individual clinician-focused SICP training on primary healthcare professionals’ (PHCPs) intention to have serious illness conversations with patients.

Methods

The cRT involved 45 primary care practices randomized into a team-based (intervention) or individual clinician-focused training program (comparator) and measured primary outcomes at the patient level: days at home and goal of care. Our theory-informed mixed-methods process evaluation alongside the cRT measured intention to have serious illness conversations with patients among the trained PHCPs using the CPD-Reaction tool. Barriers and facilitators to implementing serious illness conversations were identified through open-ended questions and analyzed using the Theoretical Domains Framework. We used the COM-B framework to perform triangulation of data. We reported results using the CONSORT and GRAMMS reporting guidelines.

Results

Of 535 PHCPs from 45 practices, 373 (69.7%) fully completed CPD-Reaction (30.8% between 25-34 years old; 78.0% women; 54.2% had a doctoral degree; 50.1% were primary care physicians). Mean intention scores for the team-based (n=223) and individual clinician-focused arms (n=150) were 5.97 (Standard Error: 0.11) and 6.42 (Standard Error: 0.13), respectively. Mean difference between arms was 0.0 (95% CI −0.30;0.29; p=0.99) after adjusting for age, education and profession. The team-based arm reported barriers with communication, workflow, and more discomfort in having serious illness conversations with patients.

Conclusions

Team-based training did not outperform individual clinician-focused in influencing PHCPs’ intention to have serious illness conversations. Future team-based interventions could foster behaviour adoption by focusing on interprofessional communication, better organized workflows, and better support and training for non-clinician team members.

Registration

ClinicalTrials.gov(ID:NCT03577002).
Localization of Human UBE3A Isoform 3 is Highly Sensitive to Amino Acid Substitutions at p.Met21 Position
Authors: van Esbroeck Annelot C. M. , Verhagen Rob F. M. , Biagioni Martina , Fossati Matteo , Distel Ben , Elgersma Ype
Published: February 2024

UBE3A encodes three isoforms of Ubiquitin E3 ligase A, which differ in their N-terminal sequence, abundance, and localization. Recently, three individuals diagnosed with Angelman Syndrome have been described who carry a variant that abrogates the start codon of the predominant nuclear isoform 1 (hUBE3A-Iso1p.Met1Thr) and concomitantly results in a missense variant in isoform 3 (hUBE3A-Iso1p.Met21Thr), which we previously reported to be nuclear enriched as well.

Here, we studied the effect of the p.Met21Thr variant on hUBE3A-Iso3 localization. Recombinant expression of hUBE3A-Iso3p.Met21Thrin U2-OS and mouse neurons revealed similar UBE3A labelling in the nucleus and cytosol, indicating hUBE3A-Iso3 localization is sensitive to amino acid changes at this position. This finding prompted us to revisit hUBE3A-Iso3 localization, since we previously introduced a p.Met21Ala/p.Met22Ala amino acid substitution in hUBE3A-Iso3 and its mouse orthologue mUBE3A-Iso2 to prevent translation of the shorter hUBE3A-Iso1 and mUBE3A-Iso3 nuclear isoforms. Introduction of silent mutations to disfavour translation of the short UBE3A isoforms enabled us to determine the localization hUBE3A-Iso3 and mUBE3A-Iso2 in the absence of amino acid changes at the p.Met21/p.Met22 position, respectively. Surprisingly, hUBE3A-Iso3 localization shifted from predominant nuclear localization for hUBE3A-Iso3p.Met21Alato a predominant cytosolic localization of the Kozak optimized hUBE3A-Iso3KOZAK, while their mouse orthologues mUBE3A-Iso2p.Met22Alaand mUBE3A-Iso2KOZAKboth localized predominantly to the cytosol.

Taken together, these experiments indicate that the localization of human UBE3A-Iso3 is highly sensitive to amino acid substitutions at the p.Met21 position and that variants at this position not only abrogate the translation of hUBE3A-Iso1, but can also change the localization of hUBE3A-Iso3.