bluuebunny/crossref_metadata_2025 huggingface dataset:
High-fat/high-sucrose diet results in a high rate of MASH with HCC in a mouse model of human-like bile acid composition
Authors: Ueda Hajime , Honda Akira , Miyazaki Teruo , Morishita Yukio , Hirayama Takeshi , Iwamoto Junichi , Ikegami Tadashi
Published: December 2024

Background:

Wild-type (WT) mice fed a conventional high-fat/high-sucrose diet (HFHSD) rarely develop metabolic dysfunction–associated steatohepatitis (MASH) with HCC. Because mouse bile acid (BA) is highly hydrophilic, we hypothesized that making it hydrophobic would lead to MASH with HCC.

Methods:

Eleven-week-old WT and Cyp2a12/Cyp2c70 double knockout (DKO) mice were divided into two groups, including one which was fed a normal chow diet, and one which was fed an HFHSD. Samples were collected after 15, 30, 47, and 58 weeks for histological, biochemical, and immunological analyses.

Results:

In the HFHSD group, body weight gain did not differ in WT versus DKO mice, although HFHSD-fed DKO mice exhibited markedly accelerated liver inflammation, fibrosis, and carcinogenesis. HFHSD upregulated lipogenesis and downregulated fatty acid oxidation in both WT and DKO mice, which increased liver lipid accumulation and lipotoxicity. However, the increase in reactive oxygen species production and carcinogenesis observed in DKO mice could not be explained by abnormal lipid metabolism alone. Regarding BA metabolism, DKO mice had a higher hydrophobicity index. They exhibited an age-associated increase in chenodeoxycholic acid (CDCA) levels because of CYP8B1 activity inhibition due to the farnesoid X receptor activation. HFHSD further downregulated CYP8B1, presumably by activating the Liver X receptor. Liver CDCA accumulation was associated with increased inflammation, reactive oxygen species production, and hepatocyte FGF15 induction. Moreover, in noncancerous liver tissues, HFHSD appeared to activate STAT3, an oncogenic transcription factor, which was enhanced by a CDCA-rich environment.

Conclusions:

Here, we developed a new model of MASH with HCC using mice with human-like BA composition and found that HFHSD and elevated hepatic CDCA synergistically increased the risk of MASH with HCC.
Clinical utility of two-step hepatitis E virus IgM antibody testing in a low-prevalence setting: A 10-year retrospective multicenter study
Authors: Chiu Chia-Yu , Razonable Raymund R. , Yao Joseph D. , Watt Kymberly D. , Chesdachai Supavit
Published: December 2024

Background:

Diagnostic uncertainty caused by the low positive predictive value of HEV-specific IgM antibody (Ab) testing in a low-prevalence setting. We investigated the utility of a two-step HEV IgM Ab testing approach for diagnosing HEV infection.

Methods:

We retrospectively reviewed all adults who underwent HEV IgM Ab and/or HEV RNA testing from July 2013 through June 2023 at Mayo Clinic. Two-step HEV IgM testing involved initial testing using recomWell HEV IgM ELISA (Mikrogen, Neuried, Germany), with reflex to recomLine HEV IgM Strip (Mikrogen, Neuried, Germany) on all recomWell HEV IgM-reactive or IgM-equivocal specimens, as recomLine HEV IgM has higher specificity than recomWell HEV IgM but is more labor-intensive.

Results:

A total of 1640 patients had HEV IgM Ab or HEV RNA testing, including 1293 (79%) with only HEV IgM Ab testing, 213 (13%) with only HEV RNA testing, and 134 (8%) with both HEV IgM Ab and HEV RNA testing. Eighteen HEV infections were diagnosed with acute (N=16) and chronic (N=2) infections. Two-step IgM Ab testing did not identify 2 solid organ transplant recipients with chronic HEV infection. In acute HEV infection with HEV viremia, 3 out of 4 patients (2 solid organ transplant recipients and 1 patient with Guillain-Barre syndrome) were treated with ribavirin.

Conclusions:

A two-step HEV IgM Ab test may accurately diagnose acute HEV infection in immunocompetent persons. However, this approach fails to identify chronic HEV infection in immunocompromised individuals who need HEV RNA testing to establish the diagnosis.
Topical Losartan for Corneal Fibrosis: A Case Series With Densitometry Analysis
Authors: Burgos-Blasco Barbara , Moloney Gregory
Published: December 2024

Purpose:

To present the clinical, topographic, and densitometry outcomes of patients with corneal fibrosis treated with topical losartan.

Methods:

In this case series, patients with corneal scars treated with topical losartan 0.8 mg/mL 4 times a day for 6 months were included. Age, sex, cause of corneal opacity, months with corneal opacity, and previous topical treatment were recorded. Patients were examined at baseline and 1, 3, and 6 months after starting treatment. At each visit, uncorrected and best-corrected visual acuity, subjective refraction, intraocular pressure, slit-lamp examination, corneal tomography, and densitometry were performed. Patients were asked about drop comfort and possible side effects on a 0 to 10 self-reported scale.

Results:

Eight eyes of 7 patients (4 males, 3 females, mean age 45.1 ± 12.0 years) were included. Best-corrected visual acuity logMAR was 0.28 ± 0.17 pretreatment and 0.17 ± 0.11 after 6 months of topical losartan (P = 0.358). The visual acuity of 5 eyes improved, 1 eye remained unchanged, and the vision of 2 eyes declined. No changes in topographic and densitometry parameters were noted within the cohort analyzed as a group (all P > 0.05). No systemic side effects were reported, and tolerance was from very good to excellent (all 2/10 or better).

Conclusions:

No significant improvements in visual acuity and densitometry values were noted with topical losartan in this series analyzed as a group. Further research to assess the full scope of clinical applications in corneal fibrosis is needed, particularly randomized clinical trials to address the effect of time and unequivocally prove its beneficial effects.
Effectiveness and Safety of Resident-Performed Same-Day Bilateral 360-Degree Selective Laser Trabeculoplasty in Patients with Open-Angle Glaucoma
Authors: Xiao Jason , Si Zhuangjun , Qiu Mary
Published: December 2024

Précis

Resident-performed same-day bilateral selective laser trabeculoplasty are safe and effective for patients with primary open-angle glaucoma or ocular hypertension.

Purpose:

To assess the efficacy and safety of resident-performed same-day bilateral 360-degree selective laser trabeculoplasty (SLT).

Patients and Methods:

Retrospective chart review was performed for patients who received bilateral, resident-performed SLT at the University of Chicago from January 1, 2020 to December 31, 2022 under the supervision of one glaucoma surgeon (MQ). Patients were included in this analysis if they underwent same-day bilateral 360-degree SLT and had at least 6 months follow-up available. Data were collected on visual acuity, intraocular pressure (IOP), number of IOP-lowering medications, and complications for up to 2 years after the procedure.

Results:

There were 48 patients included in this analysis, and the diagnosis was either primary open-angle glaucoma (85.4%) or ocular hypertension (14.6%). For patients whose SLT goal was to lower IOP (n=38), the mean baseline IOP in right eyes (OD) was 19.2 mmHg on 2.1 medications, and in left eyes (OS) was 19.5 mmHg on 2.1 medications. At final follow-up (mean 519 days), the mean IOP in right eyes was 15.8 mmHg on 2.0 medications, and in left eyes was 15.8 mmHg OS on 2.2 medications, resulting in an IOP reduction of 17.6% OD and of 18.8% OS. For patients whose SLT goal was to lower medication number (n=10), the mean baseline IOP in right eyes was 16.7 mmHg on 2.3 medications, and in left eyes was 16.4 mmHg OS on 2.3 medications. At final follow-up (mean 528 days), the mean IOP in right eyes was 17.6 mmHg on 1.1 medications, and in left eyes was 16.3 mmHg OS on 1.1 medications, resulting in a medication reduction of 1.1 fewer medications OD and 1.1 fewer medications OS. One patient experienced a 6 mmHg IOP rise above baseline 4 weeks after SLT, and another developed 2 small, focal areas of peripheral anterior synechiae. Six (12.5%) patients underwent additional IOP-lowering surgery during the chart review period.

Conclusions:

Resident-performed same-day bilateral 360-degree SLT is effective and associated with minimal complications, with rates comparable to those of attending-performed SLT in the literature. SLT can be individualized to patients’ goals of IOP-lowering or medication reduction. Teaching institutions can consider incorporating this method of education for appropriate patients with primary open angle glaucoma or ocular hypertension.
Gunsight suture with subcutaneous vacuum drainage during enterostomy decreased the surgical site infection rate in obese rectal cancer patients: A retrospective study
Authors: Zhang Lei , Xiao Zhi-Qiang , San Chang-Ling , Miao Tong-Lin
Published: December 2024

Background

Surgical site infection (SSI) is the most common complication after stoma closure and is particularly common in obese patients. To reduce the incidence of SSI, various skin closure techniques have been proposed; however, the best technique is still under debate. The purpose of this study was to explore the effectiveness of subcutaneous vacuum drains (SVDs) after two surgical suture techniques following stoma reversal in obese patients.

Methods

Data from 190 obese patients with rectal cancer who underwent stoma reversal for enterostomy between February 2012 and April 2023 at Jinxiang Hospital Affiliated to Jining Medical University were retrospectively analyzed. These patients were divided into two groups: gunsight suture (GS) with SVD and primary linear suture (PLS) with SVD. The GS group and PLS group included 90 and 100 patients, respectively. The clinical characteristics and short-term outcomes were compared between the two groups. Postoperative pain scores were analyzed using a generalized estimation equation.

Results

Surgery was successfully performed in both groups. The rate of SSI in the GS group was significantly lower than that in the PLS group (2.2% vs 9.0%, P = 0.046). Patients in the GS group had a significantly shorter wound healing time than did patients in the PLS group, as well as a significantly shorter postoperative fasting time (P < 0.05). No significant differences were found between the groups in terms of the postoperative hospital stay, operative time, and estimated blood loss (P > 0.05). The results of the generalized estimation equation analysis showed that the GS group had significantly lower pain scores at 12, 24, 48, and 72 h after surgery than the PLS group (P < 0.05). Moreover, the GS group showed significantly better alleviation of wound pain between 12 and 72 h after surgery (P < 0.05).

Conclusions

The GS technique with SVD may be recommended for wound closure of a nonfunctioning stoma in obese patients.
Preliminary validation of Global Leadership Initiative on Malnutrition criteria in cancer patients: A cross-sectional study
Authors: Huang Zhe-Yu , Zhang Rui , Yin Rui-Kang , Wang Shi-Jie , Han Jiang-Long , Wang Qi-Lan , Fu Zhen-Ming
Published: December 2024

Background

The Global Leadership Initiative on Malnutrition (GLIM) has been used in China since 2019. This study aimed to test the use of the GLIM criteria in Chinese cancer patients and to compare the diagnostic performance of the GLIM criteria with the Patient-Generated Subjective Global Assessment (PG-SGA) and modified PG-SGA (mPG-SGA).

Methods

A total of 2,000 cancer patients were consecutively screened using the Nutritional Risk Screening 2002 instrument on admission. Patients at nutritional risk (Nutritional Risk Screening 2002 score ≥ 3) were enrolled to obtain the complete GLIM, PG-SGA, and mPG-SGA criteria. To evaluate the convergent validity, Spearman correlation analysis was used to compare the test-retest reliability of the GLIM criteria and its results with the scores of various nutritional tools and objective parameters. Kruskal-Wallis tests and χ
2 tests were used to test the discriminant validity among groups with different nutritional status. We calculated the sensitivity, specificity, positive predictive value, and negative predictive value for the various tools.

Results

There were 562 patients found to be at nutritional risk, accounting for 28.1% of all patients. One hundred seventy-four patients (8.7%) were diagnosed as moderately malnourished, and 333 patients (16.6%) were severely malnourished based on the PG-SGA. When assessed using the GLIM criteria, 185 patients (9.3%) were diagnosed as moderately malnourished and 311 patients (15.5%) were severely malnourished. The content validity of the GLIM criteria was 95%, evaluated by 60 medical staff members. The test-retest reliability was good. For the diagnosis of malnutrition versus the PG-SGA, the sensitivity of the GLIM was “good” (90.5%; 95% confidence interval [95% CI] = 88.0%–93.1%), with a positive predictive value of 92.5% (95% CI = 90.2%–94.9%), but the specificity and negative predictive value were “poor.” Similar results were obtained when the mPG-SGA was used as the criterion.

Conclusions

Overall, this cross-sectional study suggests that the GLIM criteria comprise a valid and reliable tool to assess the nutritional status of Chinese cancer patients.
Comparison of outcomes of community-acquired sepsis and hospital-acquired sepsis in critically ill patients: a systematic review and meta-analysis
Authors: Lamichhane Pratik , Kalansuriya Imesha , Manhalattummal Muhammed Faris , Khanal Kapil , Agrawal Anushka , Pasam Tejaswi , Pandit Pukar
Published: December 2024

Background:

Subgrouping sepsis by the location of onset, such as hospital-acquired sepsis or community-acquired sepsis, aids in clinical management, planning future interventional studies, and the formulation of healthcare policies. The aim of our study is to describe differences in clinical outcomes between hospital and community-acquired sepsis admitted to critical care units.

Patients and methods:

PubMed, Embase, and Google Scholar were systematically searched from inception to February 2024. Any observational studies comparing the outcomes of adult patients (≥18 years) admitted to the intensive care unit (ICU) with community-acquired sepsis and hospital-acquired sepsis were included in the analysis. The primary outcome assessed by our study was the risk of mortality in the patients, calculated as a pooled odd’s ratio with a 95% confidence interval (CI). Other secondary outcomes, like length of stay in the ICU, and length of overall hospital stay, were also extracted and studied.

Results:

The risk of death in patients with hospital-acquired sepsis was significantly higher than that in patients with community-acquired sepsis (OR = 2.19, 95% CI = 1.82-2.63, P < 0.001) (Fig. 1). Likewise, patients admitted due to hospital-acquired sepsis were likely to have a longer length of stay in the ICU than patients with community-acquired sepsis (Hedge’s g = 1.27, 95% CI = 0.67-1.87, P < 0.001). The length of total hospital stay was also significantly higher in patients with hospital-acquired sepsis (Hedge’s g = 0.71, 95% CI = 0.20–1.13, P < 0.001).

Conclusions:

The risk of mortality, the length of ICU stay and overall hospital stay was significantly higher in hospital-acquired sepsis compared to community-acquired sepsis.
Progress to Implement the National Strategy on Hunger, Nutrition, and Health at the US Department of Agriculture
Authors: Fleischhacker Sheila , Chandran Kumar , Cotwright Caree , Winters Marian , Abley Melanie , Chester Deirdra , Jacobs-Young Chavonda , Long Cindy
Published: December 2024

Poor nutrition is the leading cause of chronic illness, which 6 of every 10 adults in the United States face. Caring for these conditions necessitates ongoing, expensive medical care, with 85% to 90% of healthcare costs attributable to chronic diseases. Recognizing this nutrition crisis, the Biden-Harris Administration hosted a historic White House Conference on Hunger, Nutrition, and Health that took place in September 2022. This conference was the first of its kind in more than 50 years and developed an agenda around a bold goal to end hunger and increase healthy eating and physical activity by 2030. The day before the 2022 conference, the Biden-Harris Administration released a National Strategy with actions the federal government would take across 5 pillars in addition to a fact sheet detailing more than $8 billion in new commitments from nongovernmental entities. Across the 5 pillars, this article summarizes the US Department of Agriculture accomplishments during the first 2 years of implementation and concludes with ways nutrition professionals can help accelerate progress.
Tele-Pulmonary Rehabilitation in Hybrid Form Compared With Conventional Pulmonary Rehabilitation
Authors: Racodon Michaël , Sergeant David , Mucci Patrick , Fabre Claudine
Published: December 2024

Objective

The aim of the study is to study the noninferiority of functional capacity and quality of life between hybrid tele-pulmonary rehabilitation and pulmonary rehabilitation in patients with chronic respiratory diseases.

Design

Sixty-four participants underwent a 5-wk pulmonary rehabilitation program and were divided into two groups: a pulmonary rehabilitation group and a hybrid tele-pulmonary rehabilitation group.

The 6-Minute Walk Test, a time limit test, the Single-Leg Stance Test, and the Sit-to-Stand Test were used to evaluate functional capacity, whereas quality of life was self-evaluated using the VQ11 questionnaire.

Results

Both groups had improved their performances in the 6-Minute Walk Test and time limit test, their strength capacity in the Sit-to-Stand Test, and their balance in the Single-Leg Stance Test to a similar extent (P < 0.001) after the 5-wk program. For the quality of life, a more pronounced improvement for the hybrid tele-pulmonary rehabilitation group was observed (P < 0.001) 7 wks and 1 yr after the end of the program.

Conclusions

The effectiveness hybrid tele-pulmonary rehabilitation protocol seems to be comparable to that of the conventional model. Hybrid tele-pulmonary rehabilitation is not inferior with improvements in functional capacity and quality of life.
Prospective Intervention Study Using Immediate-Fit, Adjustable Prostheses for Persons With Lower Limb Loss in Botswana—A Feasibility and Patient Acceptance Trial
Authors: Kebaetse Maikutlo , Mogorosi Ntsatsi , Kenia Jessica , Shofer Frances , Dillingham Timothy
Published: December 2024

Objective

The aim of the study is to test the feasibility of an immediate-fit, adjustable prosthesis (iFIT Prosthesis) for persons with limb loss in Botswana.

Design

As part of the University of Pennsylvania and University of Botswana’s long-term partnership, 18 persons with limb loss were fit at four different locations in Botswana. Patients were followed for 4–9 mos after fitting with an interview and Prosthetic Comfort and Utility questionnaire.

Results

Out of 18 participants, 13 were located and provided follow-up feedback. Seven of the original 13 were still wearing the adjustable socket, while three reverted to their old socket and three did not use any socket. The highest positive rated question was the ability of the socket to accommodate changes in volume. Twelve (92%) of the participants said that they would recommend the system, yet cited that bulk and lack of cosmetic cover as major issues. For participants who had a conventional prosthesis, it took over a year to get their device through prosthetists using conventional fabrication techniques.

Conclusions

This socket system seems to be a feasible option for persons with lower limb loss in Botswana. To address the issues raised by participants and enhance user acceptance, the immediate-fit, adjustable system should become less bulky and include a cosmetic cover.
Genomic insights into two new subspecies of Herbaspirillum huttiense strains isolated from diseased foliage in Florida
Authors: Poudel Mousami , Sharma Anuj , Minsavage Gerald V. , Fullem Kiersten , Huguet-Tapia Jose , Norman David J. , Goss Erica M. , Harmon Carrie L. , Jones Jeffrey B.
Published: December 2024

The genus Herbaspirillum comprises 13 species, the majority of which are plant colonizers. However, some species are occasionally isolated from environmental sources, including water and polluted soil, while others are opportunistic human pathogens. Four novel bacterial strains were isolated from diseased foliage of tomato and Boston fern in Florida, USA. Phylogenetic analysis based on the 16S rRNA gene sequence placed all strains into the genus Herbaspirillum. The Gram-negative strains produced opaque, creamy white, mucoid colonies, which is typical of the genus Herbaspirillum. Biolog biochemical profiling also identified those strains as members of Herbaspirillum. The strains were subjected to whole-genome sequencing, and their genomes were compared with those of reference strains of Herbaspirillum spp. using average nucleotide identity (ANI). The two strains isolated from Boston fern shared 99% pairwise ANI, as did the two strains isolated from tomato. Among all reference genomes tested, the novel strains shared the highest ANI to Herbaspirillum huttiense subsp. huttiense (G21-1742 and NC 40101, 96.76%; SE1, 97.23%; F1, 97.16%) and to H. huttiense subsp. putei. These values are above the established 95% threshold for species delineation based on ANI. As the ANI between members of the two currently described subspecies of H. huttiense, i.e. huttiense and putei, is also ~97%, it can be inferred that the two groups of novel strains described in this study should be considered as candidates for classification as two new subspecies of H. huttiense, given that the current H. huttiense subspecies also have ~97% with the fern and tomato strains. In silico DNA–DNA hybridization results were consistent with those of ANI; comparison of G21-1742 and NC 40101 with H. huttiense subsp. putei IAM 15032Tand H. huttiense subsp. huttiense LMG 2199T produced DNA–DNA hybridization (DDH) values of 66.1 and 73.6 %, respectively. Similarly, SE1 and F1 had DDH values of 68.9 and 68.8% with H. huttiense subsp. putei IAM 15032T and 77.1 and 76.7% with H. huttiense subsp. huttiense LMG 2199T, respectively. The genomes of all novel isolates carry genes involved in plant pathogenesis, including those of the type III secretion system, which are not present in other H. huttiense strains. Based on genomic and phenotypic data, we conclude that these strains represent the first phytopathogenic subspecies within H. huttiense and the names proposed are H. huttiense subsp. nephrolepidis for the two strains isolated from Nephrolepis exaltata (designated strain, G21−1742=LMG 33362=NCPPB 4765) and H. huttiense subsp. lycopersici (designated strain, SE1=LMG 3361=NCPPB 4764) for the two strains isolated from Solanum lycopersicum.
Prevalence of visual impairment and its causes in adults aged 50 years and older: Estimates from the National Eye Surveys in Malaysia
Authors: Salowi Mohamad Aziz , Naing Nyi Nyi , Mustafa Norasyikin , Wan Nawang Wan Radziah , Sharudin Siti Nurhuda , Ngah Nor Fariza
Published: December 2024

Background

Population surveys are necessary to measure a community’s eye care needs. We conducted simultaneous surveys in two regions in Malaysia in 2023 to estimate the prevalence of visual impairment (VI), identify its main causes, and compare the results with the survey in 2014.

Methods

The surveys were simultaneously done in Eastern and Sarawak administrative regions using the Rapid Assessment of Avoidable Blindness (RAAB) technique. It involved a multistage cluster sampling method, each cluster comprising 50 residents aged 50 years and older. The prevalence of VI (blindness, severeness, moderate, and early) and its primary cause were determined through a visual acuity check and eye examination with a hand-held ophthalmoscope. Results were compared with the previous survey in 2014.

Results

A total of 10,184 subjects were enumerated, and 9,709 were examined (94.5% and 96.2% responses for Eastern and Sarawak, respectively). The prevalence of blindness and severe VI appeared to decrease. For blindness: Eastern 1.4%, 95%CI (0.9, 1.9) to 0.8%, 95%CI (0.5, 1.1) and Sarawak: 1.6% 95%CI (1.0, 2.1) to 0.6%, 95%CI (0.3, 0.9). For severe VI: Eastern 1.2%, 95%CI (0.8, 1.7) to 0.9%, 95%CI (0.6, 1.1) and Sarawak 1.1% 95%CI (0.6, 1.6) to 0.9%, 95% CI(0.6, 1.2). The main cause of blindness was untreated cataracts: 77.3% (Eastern) and 75.0% (Sarawak). Diabetic retinopathy was the 2ndmain cause of blindness for Eastern at 9.1%, but it only caused early to severe VI in Sarawak.

Conclusion

The prevalence of blindness and severe VI were reduced. The reduction could have been attributed to a community cataract program implemented soon after the survey in 2014. However, more efforts are needed to address the high percentage of avoidable blindness within both regions.
Mental illness stigma in England: What happened after the Time to Change Programme to reduce stigma and discrimination?
Authors: Ronaldson Amy , Henderson Claire
Published: December 2024

Background

We investigated the extent to which positive changes in stigma outcomes reported over the course of Time to Change were sustained by 2023, two years after the programme’s end in 2021.

Methods

We used regression analyses to evaluate trends in outcomes. Measures were of stigma-related knowledge (Mental Health Knowledge Schedule (MAKS)), attitudes (Community Attitudes to the Mentally Ill scale (CAMI)), and desire for social distance (Reported and Intended Behaviour Scale (RIBS)). We also examined willingness to interact with people based on vignettes of depression and schizophrenia, and attitudes towards workplace discrimination against people with these conditions, using data from the British Social Attitudes Survey (BSAS) 2015 for comparison.

Findings

Reported in standard deviation units (95% confidence intervals (CI)), attitudes towards mental illness improved between 2008 and 2023 (SD=0.24, 95% CI=0.16 to 0.31), but following an increase of 9.9% between 2008-19, scores decreased by 3.3% (p=0.015). After improvements to 2019, 2023 MAKS and RIBS scores no longer differed from 2009 scores, indicating decreases since 2019 in stigma-related knowledge (MAKS scores declined 7.8% since 2019, p<0.001) and willingness to interact (RIBS scores declined by 10.2% since 2019, p<0.001). Conversely, comparison with BSAS 2015 data indicated that in 2023 respondents were more willing to interact with people with depression (β=-2.69, p<0.001) and schizophrenia (β=-2.70, p<0.001); and more likely to agree that people with either condition are just as likely to be promoted, and to disagree that their medical history should influence this. This change was most pronounced for schizophrenia (OR=2.52, 95% CI=2.02 to 3.14).

Conclusions

The lasting positive changes reflect support for non-discrimination and willingness to interact with someone after a sense of familiarity is evoked. Besides the end of Time to Change, interpretations for declines in other outcomes include the impacts of the covid-19 pandemic; economic stress; and reduced access to healthcare.
Summer heat, historic redlining, and neighborhood walking among older adults: 2017 National Household Travel Survey
Authors: Mitsova Diana , Besser Lilah M. , Le Elaine T.
Published: December 2024

No known studies have examined the relationships between urban heat islands, historic redlining, and neighborhood walking in older adults. We assessed whether: 1) individual and neighborhood characteristics (including redlining score) differ by neighborhood summer land surface temperature (LST); 2) higher LST is associated with less neighborhood walking, and whether associations differ by historic redlining score; and 3) neighborhoods with discriminatory redlining scores have greater LSTs. We used data on 3,982 ≥65-year olds from the 2017 National Household Travel Survey. Multivariable negative binomial and linear regressions tested associations between LST z-score (comparing participant’s neighborhood LST to surrounding region’s LST) and self-reported neighborhood walking, and the association between living in neighborhoods redlined as “definitely declining” or “hazardous” (versus “still desirable”/“best”) and LST z-score. LSTs were higher for those in neighborhoods with higher area deprivation scores and more African American/Black residents. Older adults living in neighborhoods with higher summer LST z-scores had fewer minutes of neighborhood walking/day. This association seemed limited to individuals with neighborhood redlining scores of “still desirable”/“best”. Neighborhood redlining scores of “definitely declining” or “hazardous” (versus “still desirable” and “best”) were associated with greater neighborhood summer LSTs. Overall, these findings suggest that historically redlined neighborhoods may more often experience urban heat island effects, and older adults living in hotter neighborhoods may less often engage in neighborhood walking. Future work is needed to elucidate the impact of extreme heat on health promoting behaviors such as walking and the types of interventions that can successfully counteract negative impacts to historically disadvantaged communities.
Disentangling the shared genetics of ADHD, cannabis use disorder and cannabis use and prediction of cannabis use disorder in ADHD
Authors: Nielsen Trine Tollerup , Duan Jinjie , Levey Daniel F. , Bragi Walters G. , Johnson Emma C. , Thorgeirsson Thorgeir ,   VA Million Veteran Program, Werge Thomas , Mortensen Preben Bo , Stefansson Hreinn , Stefansson Kari , Hougaard David M. , Agrawal Arpana , Gelernter Joel , Grove Jakob , Børglum Anders D. , Demontis Ditte
Published: December 2024

Cannabis use disorder (CUD) and cannabis use (CU) are prevalent conditions cooccurring with ADHD, but not much is known about the underlying shared genetics. Here we perform cross-disorder GWAS meta-analyses of ADHD and CUD or CU to identify pleiotropic risk loci and evaluate differences in the genetics of ADHD-CUD and ADHD-CU, and subsequently we dissect the polygenic architecture of CUD comorbidity in ADHD in the iPSYCH cohort.

There was a higher genetic overlap of ADHD and CUD than observed for ADHD and CU and we found a significant direct effect of ADHD genetic risk on CUD with only a minor part (12%) mediated by the genetics of CU. We identified 36 genome-wide significant loci for ADHD-CUD and 10 loci for ADHD-CU, with concordant direction of effect on the phenotypes. Three different approaches identifiedDRD2, which encodes the dopamine 2 receptor, as a risk gene for ADHD-CUD and, overall, ADHD-CUD risk genes were associated with high expression across several brain tissues and brain developmental stages, which was not observed for ADHD-CU genes. ADHD-CUD and ADHD-CU demonstrated similar genetic correlations with substance use phenotypes, while they differed significantly with respect to substance use disorder (SUD) phenotypes. ADHD-CUD individuals had significantly increased polygenic score (PGS) for psychiatric disorders compared to ADHD without CUD and increased burden of rare deleterious variants. Stratifying individuals with ADHD by their CUD-PGS revealed an absolute risk of 22% for comorbid CUD among the 20% of cases with the highest CUD-PGS, which was strikingly higher than the absolute risk of 1.6% observed among the 20% of controls with the highest CUD-PGS. Sex-specific analyses identified substantial differences in the absolute risk of comorbid CUD between males and females with ADHD, with a ∼10% higher CUD risk among males than females in the high-risk CUD-PGS group (24% risk for males and 14% risk for females).
Concurrent mapping of Electrical, Chemical, and Functional Neuroactivity
Authors: Wu Zhifang , Gu Yameng , Cao Jianbo , Liu Sha , Hu Lingzhi , Li Yang , Liang Meng , Song Hao , Yang Shuai , Yuan Jianmin , Xie Jun , Xu Jun , Li Xiaomeng , Zheng Rong , Wei Hua , Liu Haiyan , Wang Hongliang , Hao Xinzhong , Hu Yujie , Liu Zhifen , Yang Lijun , Zhang Yanbo , Sun Xishan , Xu Ruokun , Lian Shizhong , Zhu Quan , Xie Weiwei , Xie Chunxia , Zhang Di , Li Sijin
Published: December 2024

Understanding the complex mechanism of human brain function requires innovative approaches that capture the intricate interplay of electrical, chemical, and hemodynamic activities. We developed the PMEEN system, named for its concurrent integration of PET, MRI, EEG, Eye Tracking, and fNIRS modalities by successfully addressing the electromagnetic and gamma ray interference among these modalities and incorporation of centralized clock control to allow simultaneous spatial registration and temporal synchronization. Here we show that PMEEN enables the concurrent acquisition of metabolic, structural, electrical, hemodynamic, and behavioral data, providing a comprehensive view of brain function that was previously inaccessible. By successfully validating the system in healthy volunteers and clinical cases involving patients with major depressive disorder, Alzheimer's disease, and epilepsy, we demonstrate its potential for advancing both research and clinical diagnostics. These findings represent a significant technological step forward in neuroimaging, allowing for a holistic understanding of the neural mechanisms underlying cognition and neurological disorders, and setting the stage for future breakthroughs in brain research and therapy.
Hybrid Neural Differential Equations to Model Unknown Mechanisms and States in Biology
Authors: Whipple Benjamin , Hernandez-Vargas Esteban A.
Published: December 2024

Efforts to model complex biological systems increasingly face challenges from ambiguous relationships within the model, such as through partially unknown mechanisms or unmodelled intermediate states. Hybrid neural differential equations are a recent modeling framework which has been previously shown to enable identification and prediction of complex phenomena, especially in the context of partially unknown mechanisms. We extend the application of hybrid neural differential equations to enable incorporation of theorized but unmodelled states within differential equation models. We find that beyond their capability to incorporate partially unknown mechanisms, hybrid neural differential equations provide an effective method to include knowledge of unmeasured states into differential equation models.
Addressing algorithmic bias in precision well-being for medical education: A socially fair approach for clustering
Authors: Alluri Priyanshu , Chen Zequn , Marrero Wesley J. , Jacobson Nicholas C. , Thesen Thomas
Published: December 2024

Background

Medical students frequently experience heightened levels of anxiety, depression, and burnout. These challenges are disproportionately borne by students from underrepresented backgrounds, who are exposed to systemic inequities, discrimination, and reduced access to supportive resources. While precision well-being approaches, characterized by identifying distinct well-being phenotypes for personalized interventions, hold promise, standard machine learning clustering algorithms such as K-Means may inadvertently exacerbate these disparities. Furthermore, the underlying factors contributing to poorer mental health outcomes among underrepresented students remain insufficiently understood.

Objective

We aim to identify well-being phenotypes that achieve an equitable distribution of clustering costs across racial groups, identify conditions under which fair and standard clustering solutions converge, and investigate the demographic and socioeconomic factors that shape mental health patterns in students underrepresented in medicine.

Methods

Drawing on a diverse sample of 4161 medical students from multiple U.S. institutions participating in the Healthy Minds Survey (2016–2021), we compared the outcomes of socially fair and standard k-Means clustering algorithms using Patient Health Questionnaire-9, General Anxiety Disorder-7, and Flourishing scores. We then employed average treatment effect analyses to identify factors that exacerbate mental health challenges and those that enhance resilience, with a particular emphasis on underrepresented populations.

Results

The socially fair clustering algorithm significantly reduced the disproportionate burden on minority populations, aligning with standard clustering outcomes when student groups were racially and socioeconomically homogeneous. Perceived discrimination emerged as a key factor driving poorer mental health, while stable financial conditions, robust social engagement, and involvement in culturally or ethnically oriented organizations were linked to greater resilience and improved well-being.

Conclusions

Incorporating fairness objectives into clustering algorithms substantially reduced the disproportionate burden on minority students and yielded a more equitable understanding of their mental health patterns. By identifying factors that influence mental health outcomes, our socially-fair precision well-being approach allows for more personalized well-being interventions. These insights equip educators and policymakers with actionable targets for developing culturally responsive, data-driven interventions that not only alleviate distress but also support resilience, ultimately advancing more inclusive, effective precision well-being strategies for all medical students.
Alignment-Free Viral Sequence Classification at Scale
Authors: van Zyl Daniel J. , Dunaiski Marcel , Tegally Houriiyah , Baxter Cheryl ,   The INFORM Africa research study group, de Oliveira Tulio , Xavier Joicymara S.
Published: December 2024

Background

The rapid increase in nucleotide sequence data generated by next-generation sequencing (NGS) technologies demands efficient computational tools for sequence comparison. Alignment-based methods, such as BLAST, are increasingly overwhelmed by the scale of contemporary datasets due to their high computational demands for classification. This study evaluates alignment-free (AF) methods as scalable and rapid alternatives for viral sequence classification, focusing on identifying techniques that maintain high accuracy and efficiency when applied to extremely large datasets.

Results

We employed six established AF techniques to extract feature vectors from viral genomes, which were subsequently used to train Random Forest classifiers. Our primary dataset comprises 297,186 SARS-CoV-2 nucleotide sequences, categorized into 3502 distinct lineages. Furthermore, we validated our models using dengue and HIV sequences to demonstrate robustness across different viral datasets. Our AF classifiers achieved 97.8% accuracy on the SARS-CoV-2 test set, and 99.8% and 89.1% accuracy on dengue and HIV test sets, respectively.

Conclusion

Despite the high-class dimensionality, we show that word-based AF methods effectively represent viral sequences. Our study highlights the practical advantages of AF techniques, including significantly faster processing compared to alignment-based methods and the ability to classify sequences using modest computational resources.
Multiscale Single-Cell Assessment of the Fibrotic Niche in Idiopathic Pulmonary Fibrosis
Authors: Liu Bin , Stewart Iain , May James , Zarcone Maria Concetta , Lopez-Jimenez Elena , Lambie Nathalie , Matthews Nik , Johnson Simon R , Tatler Amanda L. , Hewitt Richard , Wain Louise V , Clifford Rachel L , Renzoni Elisabetta A. , George Peter M. , Wells Athol U. , Reed Anna K. , Jenkins R. Gisli , John Alison E.
Published: December 2024

Background

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and fatal disease characterized by excessive extracellular matrix deposition within the lung. Recent advances in single-cell RNA sequencing have identified unique populations of epithelial cells lacking KRT5 while expressing KRT17; fibroblasts characterized by high collagen production, and the expression of CTHRC1; as well as a distinct subset of SPP1 positive macrophages. However, the precise interactions among these and potentially other cells that lead to the formation of fibrotic niche remain unclear.

Methods

Using spatial transcriptomics and Hyperion imaging mass cytometry we compared the cellular populations in formalin fixed paraffin embedded fibrotic lesions (n=9 patients) with control lung (n=9), and using CellChat we investigated the cellular interactions.

Results

Spatial transcriptomic analysis identified 180,067 cells which demonstrated three unique fibrotic niches enriched for KRT5-/KRT17+ epithelial cells, SPP1+ macrophages and collagen producing fibroblasts as well as a unique DCN+ expressing plasma B cell. Ligand receptor analysis inferred that most fibrotic cells interacted with ATII cells, with the exception of KRT5-/KRT17+ epithelial cells which interacted primarily with macrophages. Hyperion Mass Cytometry identified 55,979 cells, which identified similar cell populations clustered into two unique fibrotic niches: a stromal fibrotic niche characterized by CTHRC1+ fibroblasts interacting with fibrotic associated plasma cells, and a second niche containing KRT5-/KRT17+ cells and SPP1+ macrophages. This latter niche appeared likely to originate from the control bronchial niche with progressive loss of KRT5.

Conclusion

These findings describe the characteristics of the fibrotic niche, support the hypothesis that basal cells can also contribute to the origin of the fibrotic epithelium and describe a novel fibrotic plasma cell population, shedding light on the complex cellular dynamics within fibrotic human lung tissues.
Structural and Antigenic Characterization of Novel and DiverseHenipavirusGlycoproteins
Authors: May Aaron J. , Lella Muralikrishna , Lindenberger Jared , Berkman Alex , Kumar Ujjwal , Dutta Moumita , Barr Maggie , Parks Rob , Newman Amanda , Huang Xiao , Song Kijun , Ilevbare Victor , Sammour Salam , Park Chan Soo , Adhikari Radha Devkota , Devkota Priyanka , Janowska Katarzyna , Liu Yanshun , Scapellato Garrett , Spence Taylor N. , Mansouri Katayoun , Edwards Robert J , Saunders Kevin O. , Haynes Barton F. , Acharya Priyamvada
Published: December 2024

Henipaviruses, a genus within theParamyxoviridaefamily, include the highly virulent Nipah and Hendra viruses that cause reoccurring outbreaks of deadly disease1. Recent discoveries of several newParamyxoviridaespecies, including the zoonotic Langya virus2, have revealed much higher antigenic diversity than currently characterized and prompted the reorganization of these viruses into theHenipavirusandParahenipavirusgenera3. Here, to explore the limits of structural and antigenic variation in both genera, collectively referred to here as HNVs, we constructed an expanded, antigenically diverse panel of HNV fusion and attachment glycoproteins from 56 unique HNV strains that better reflects global HNV diversity. We expressed and purified the fusion protein ectodomains and the attachment protein head domains and characterized their biochemical, biophysical and structural properties. We performed immunization experiments in mice leading to the elicitation of antibodies reactive to multiple HNV fusion proteins. Cryo-electron microscopy structures of diverse fusion proteins elucidated molecular determinants of differential pre-fusion state metastability and higher order contacts. A crystal structure of the Gamak virus attachment head domain revealed an additional domain added to the conserved 6-bladed, β-propeller fold. Taken together, these studies expand the known structural and antigenic limits of the HNVs, reveal new cross-reactive epitopes within both genera and provide foundational data for the development of broadly reactive countermeasures.
Rational molecular design for improved ZHD101 thermal stability based on the introduction of disulfide bonds at the dimer interface and B-factor analysis
Authors: Ding Weiqiu , Huang Yujie , Zhang Haiyi , Zheng Shaoyan , Xie Chunfang , Yao Dongsheng
Published: December 2024

Abstract

Zearalenone hydrolase 101 (ZHD101), derived fromClonostachys rosea, is known to effectively degrade the main contaminant (zearalenone) in animal feed, but the thermal instability of ZHD101 limits its industrial application. In this study, we successfully enhanced the thermal stability of ZHD101 through two iterative rounds of rational molecular design. First, after the prediction of disulfide bond sites, ZHD101T229Cwas obtained, and a new disulfide bond was formed between two single ZHD101 subunits to construct a dimer ZHD101. Then, based on ZHD101T229C, two high-vibration hotspot amino acids N137 and D170 were selected by analyzing atomic position fluctuations and dynamic information A small and precise mutant library containing three mutants (ZHD101T229C/N137L, ZHD101T229C/D170L, and ZHD101T229C/D170C) was obtained by saturation mutagenesis and calculation of binding energy in silico. Compared with the wild type, the thermal half-inactivation temperature (T50) of ZHD101T229C/D170Cincreased by 7°C, its half-life (t1/2) increased by 200% at 50°C, and its melting temperature (Tm) increased by 18.1°C. Molecular docking suggested that new covalent bond formation and shorter bond distance may contribute to the improved thermal stability of ZHD101. The rational design strategy proposed in this work can provide a reference for the thermal stability modification and optimization of other proteins.

Importance

Zearalenone (ZEN) is a nonsteroidal estrogenic mycotoxin that poses a significant threat to animal feed safety. ZEN hydrolase 101 (ZHD101) catalyzes the conversion of ZEN into a nontoxic product, offering a promising detoxification strategy. However, the thermal instability of ZHD101 severely limits its industrial application. In this study, the thermal stability of ZHD101 was significantly improved through two rounds of rational design, resulting in the ZHD101T229C/D170Cmutant. ZHD101T229C/D170Cexhibited the improved half-inactivation temperature (T50), half-life (t1/2) and the highest melting temperature (Tm) reported thus far. Overall, the iterative combinatiorial mutation strategy involved the introduction of a disulfide bond between two single subunits and the application of B-factor analysis to identify hotspot amino acids residues. This approach effectively enhanced the enzyme’s structural stability, paving the way for its industrial application. ZHD101T229C/D170Cand the rational design strategy presented in this work provide a robust framework for the thermal stability optimization of similar biocatalysts, advancing the practical use of ZHD101 in the feed industry.
An NAMPT Inhibitor Decreases NAMPT Capture by an Antibody Directed against the 5-Phosphoribosyl-1-Pyrophosphate-Binding Loop: A Rational for an NAMPT Occupancy Assay
Authors: Shomali Maysoun , Hilairet Sandrine , Duhamel Marianne , Nardi Frederico , Bertrand Thomas , Mathieu Magali , Arrebola Rosalia , Penarier Geraldine , Jegham Samir , Arigon Jerome , Cosnier Sylvie , Bouaboula Monsif
Published: December 2024

Nicotinamide phosphoribosyltransferase (NAMPT) catalyzes the rate-limiting step of nicotinamide adenine dinucleotide (NAD) biosynthesis. NAMPT inhibitors (NAMPTi) have been shown to be NAMPT substrates. The resulting NAMPTi-phosphoribose (RP) adduct binds tightly to NAMPT and inhibits the enzyme. Using new NAMPTi, SAR154782, structural analyses performed in this study unveiled a close proximity of the SAR154782-RP complex to the 5-phosphoribosyl-1-pyrophosphate-binding (PRPP-binding) loop within the NAMPT catalytic site. The PRPP-binding loop of NAMPT is subject to conformational flexibility. Interestingly, the PRPP-binding loop domain is oriented to the outer side of the NAMPT dimer and can potentially serve as an antigen-binding site for antibodies. Here we report for the first time that the NAMPTi-RP adduct bound to NAMPT decreases NAMPT capture by an antibody directed against the c-terminal PRPP-binding loop in NAMPT. This finding was then used to explore cellular NAMPT occupancy. The NAMPTi-RP complex displays a sustained, cellular NAMPT occupancy that correlates with the inhibition of NAMPT activity. Moreover, a good correlation between NAMPT occupancy, NAD decrease, and NAMPTi efficacy was observedin-vivoin a NCI-H82 small cell lung cancer (SCLC) xenograft model. NAMPT-occupancy assay can be used in clinical settings to better define the optimal dose levels and dose regimen for effective NAMPT inhibition.