bluuebunny/crossref_metadata_2025 huggingface dataset:
Volumetric analysis: Rethinking brain metastases response assessment
Authors: Ocaña-Tienda Beatriz , Pérez-Beteta Julián , Romero-Rosales José Antonio , Asenjo Beatriz , Ortiz de Mendivil Ana , Pérez Romasanta Luis Alberto , Albillo Labarra Jose David , Nagib Fátima , Vidal Denis María , Luque Belén , Arana Estanislao , Pérez-García Víctor M
Published: December 2023

Background

The Response Assessment in Neuro-Oncology for Brain Metastases (RANO-BM) criteria are the gold standard for assessing brain metastases (BMs) treatment response. However, they are limited by their reliance on 1D, despite the routine use of high-resolution T1-weighted MRI scans for BMs, which allows for 3D measurements. Our study aimed to investigate whether volumetric measurements could improve the response assessment in patients with BMs.

Methods

We retrospectively evaluated a dataset comprising 783 BMs and analyzed the response of 185 of them from 132 patients who underwent stereotactic radiotherapy between 2007 and 2021 at 5 hospitals. We used T1-weighted MRIs to compute the volume of the lesions. For the volumetric criteria, progressive disease was defined as at least a 30% increase in volume, and partial response was characterized by a 20% volume reduction.

Results

Our study showed that the proposed volumetric criteria outperformed the RANO-BM criteria in several aspects: (1) Evaluating every lesion, while RANO-BM failed to evaluate 9.2% of them. (2) Classifying response effectively in 140 lesions, compared to only 72 lesions classified by RANO-BM. (3) Identifying BM recurrences a median of 3.3 months earlier than RANO-BM criteria.

Conclusions

Our study demonstrates the superiority of volumetric criteria in improving the response assessment of BMs compared to the RANO-BM criteria. Our proposed criteria allow for evaluation of every lesion, regardless of its size or shape, better classification, and enable earlier identification of progressive disease. Volumetric criteria provide a standardized, reliable, and objective tool for assessing treatment response.
Comparative Effectiveness of Fidaxomicin vs Vancomycin in Populations With Immunocompromising Conditions for the Treatment of Clostridioides difficile Infection: A Single-Center Study
Authors: Alsoubani Majd , Chow Jennifer K , Rodday Angie Mae , Kent David , Snydman David R
Published: December 2023

Background

Clostridioides difficile infection (CDI) is a leading cause of morbidity in immunocompromised hosts with increased risk of complications and recurrences. In this study, we examined the clinical effectiveness of fidaxomicin vs vancomycin in treating CDI in this patient population.

Methods

This single-center retrospective study evaluated patients with CDI between 2011 and 2021. The primary outcome was a composite of clinical failure, relapse at 30 days, or CDI-related death. A multivariable cause-specific Cox proportional hazards model was used to test the relationship between treatment and the composite outcome, adjusting for confounders and treating death from other causes as a competing risk.

Results

This study analyzed 238 patients who were immunocompromised and treated for CDI with oral fidaxomicin (n = 38) or vancomycin (n = 200). There were 42 composite outcomes: 4 (10.5%) in the fidaxomicin arm and 38 (19.0%) in the vancomycin arm. After adjustment for sex, number of antecedent antibiotics, CDI severity and type of immunosuppression, fidaxomicin use significantly decreased the risk of the composite outcome as compared with vancomycin (10.5% vs 19.0%; hazard ratio, 0.28; 95% CI, .08–.93). Furthermore, fidaxomicin was associated with 70% reduction in the combined risk of 30- and 90-day relapse following adjustment (hazard ratio, 0.27; 95% CI, .08–.91).

Conclusions

The findings of this study suggest that the use of fidaxomicin for treatment of CDI reduces poor outcomes in patients who are immunocompromised.
A competency framework on simulation modelling-supported decision-making for Master of Public Health graduates
Authors: Hrzic Rok , Cade Maria Vitoria , Wong Brian Li Han , McCreesh Nicky , Simon Judit , Czabanowska Katarzyna
Published: December 2023

Background

Simulation models are increasingly important for supporting decision-making in public health. However, due to lack of training, many public health professionals remain unfamiliar with constructing simulation models and using their outputs for decision-making. This study contributes to filling this gap by developing a competency framework on simulation model-supported decision-making targeting Master of Public Health education.

Methods

The study combined a literature review, a two-stage online Delphi survey and an online consensus workshop. A draft competency framework was developed based on 28 peer-reviewed publications. A two-stage online Delphi survey involving 15 experts was conducted to refine the framework. Finally, an online consensus workshop, including six experts, evaluated the competency framework and discussed its implementation.

Results

The competency framework identified 20 competencies related to stakeholder engagement, problem definition, evidence identification, participatory system mapping, model creation and calibration and the interpretation and dissemination of model results. The expert evaluation recommended differentiating professional profiles and levels of expertise and synergizing with existing course contents to support its implementation.

Conclusions

The competency framework developed in this study is instrumental to including simulation model-supported decision-making in public health training. Future research is required to differentiate expertise levels and develop implementation strategies.
Is gender equality associated with a longer healthier life? Ecological evidence from 27 European countries
Authors: Leão Teresa , Doetsch Julia , Henriques Ana , Fraga Sílvia
Published: December 2023

Background

The association between gender equality and higher life expectancies has been described. Yet, little is known about its association with healthy life expectancy (HLE), or which domains are consistently associated with longer and healthier lives. We aimed to study the association between country-level gender equality, its domains and subdomains, with life expectancy and HLE in Europe, from 2013 to 2019.

Methods

We combined life and HLE estimates from Eurostat with the Gender Equality Index and its ‘work’, ‘knowledge’, ‘money’, ‘time’ and ‘power’ domains and respective subdomains, for 27 European countries. Associations were estimated using panel data regression analyses adjusted for Gross Domestic Product, healthcare expenditure and Gini coefficient.

Results

Higher life and healthy life expectancies were found in country years with higher gender equality, both for men and women. Associations were particularly consistent for the ‘work’ (βHLE-men = 0.59; βHLE-women = 0.59; P < 0.05) and ‘power’ domains (βHLE-men = 0.09; βHLE-women = 0.12, P < 0.01), especially for the ‘work participation’, ‘political’ and ‘economic power’ subdomains.

Conclusion

These results point to a country-level association between gender equality and life and healthy life expectancies, suggesting that gender disparities in ‘work participation’ and ‘political’ and ‘economic power’ play a role in the health of women and men through their aging course.
Suicide in individuals with no psychiatric disorders: what makes you vulnerable?
Authors: Sher L
Published: December 2023

Globally, hundreds of thousands of people die by suicide every year. Suicides are usually associated with psychiatric illness. However, considerable evidence suggests that a significant number of individuals who die by suicide do not have diagnosable psychiatric disorders. The goal of this article is to attract attention to an overlooked issue of suicide in persons with no psychiatric disorders and to discuss some aspects of this issue. Research on identification and prevention of suicidal behavior in people with no psychiatric disorders is very limited. The available data indicate that suicides in individuals without psychiatric disorders are related to life stressors, lack of social support, and certain personality traits such as impulsivity. Suicide risk may be increased in military veterans with no psychiatric disorders. Many physical disorders, especially conditions associated with pain increase suicide risk in individuals with no diagnosable psychiatric disorders. Developmental, genetic and physical factors may play a role in the psychobiology of suicide in people with no psychiatric conditions. Promoting resilience may reduce suicide risk in the general population. Clinicians who work with medical or surgical patients need to have sufficient training in suicide prevention. Possibly, shifting some suicide prevention resources from individuals who are regarded as high-risk suicide patients to the general population may reduce suicide rates. Public education and better awareness about suicide may reduce suicide deaths among people with no psychiatric disorders.
Cost-of-illness changes before and after the diagnosis of systemic lupus erythematosus: a nationwide, population-based observational study in Korea
Authors: Kim Hyoungyoung , Jang Eun Jin , Cho Soo-Kyung , Han Jung-Yong , Jeon Yena , Jung Sun-Young , Sung Yoon-Kyoung
Published: December 2023

Objectives

To estimate the direct healthcare cost progression from before to after systemic lupus erythematosus (SLE) diagnosis and to compare healthcare costs by disease severity.

Methods

Patients with incident SLE diagnosed between 2008 and 2018 were identified from the Korean National Health Insurance database. Annual direct healthcare costs for 5 years before and after SLE were estimated and compared with those of age-, sex- and calendar month-matched (1:4) controls, without SLE. Direct healthcare costs were compared by disease severity of SLE using regression analysis.

Results

Among 11 173 patients with SLE and 45 500 subjects without SLE, annual direct healthcare costs per person increased in the year before SLE diagnosis and peaked in the first year after diagnosis. They were 7.7-fold greater in the SLE patients than in the subjects without SLE ($5871 vs $759). Severe SLE was associated with 3.284-fold (95% CI: 3.075, 3.507) higher annual costs than mild SLE during the year after diagnosis. Older age (age 60–79 years), lupus nephritis, interstitial lung diseases, and comorbidities such as avascular necrosis and chronic kidney disease were associated with higher annual direct healthcare costs (times [95% CI]) in the first year after diagnosis: age 60–69: 1.119 (1.034, 1.211); age 70–79: 1.470 (1.342, 1.611); lupus nephritis: 1.794 (1.711, 1.881); interstitial lung diseases: 1.435 (1.258, 1.638); avascular necrosis: 6.208 (4.541, 8.487); and chronic kidney disease: 1.858 (1.673, 2.064).

Conclusion

Patients with SLE incurred significantly higher direct healthcare costs than subjects without SLE during the first year after diagnosis. Disease severity, older age, major organ involvements and comorbidities were associated with increased healthcare costs.
Attribute misreporting and appraisal bias
Authors: Eriksen Michael D , Kuang Chun , Zhu Wenyu
Published: December 2023

We assemble a property-level panel of appraiser-reported attributes associated with 4.6 million loan applications from 2013 to 2017 to test whether attributes were consistently reported. Appraisers have an incentive to misreport property attributes to justify higher appraised values to ensure that associated mortgage loans are approved. We focus on property transactions with multiple sets of attributes reported by the same appraiser within four quarters and find evidence consistent with an intent to inflate valuations through attribute misreporting. We find that strategic misreporting of attributes is prevalent across markets, and that highly leveraged borrowers whose appraisals had inconsistently reported attributes were 9.8 percent more likely to become seriously delinquent in their loan payments.
Efficacy of DIY Cast Covers: An In Vivo Study
Authors: Udall Dallyn , Zimmerman Remy , Bast Nicholas , Schlechter John
Published: December 2023

Background:

Casting is routinely used in orthopaedics. Preventing a wet cast is crucial for maintaining structural integrity and reducing unwanted complications like unnecessary skin irritation/ulceration, bacterial overgrowth, and unnecessary emergency department visits. Using experimental models, studies have tested various contemporary methods to prevent a wet cast. One such study found that in comparison the most effective and cost-conscious approach was to use a Do-It-Yourself cast cover using a double-bag technique sealed with tape. There is a paucity of literature on the utility of this technique in vivo. The purpose of this study was to investigate the efficacy of the Do-It-Yourself cast cover on human test subjects.

Methods:

Ten volunteers for the study were obtained. Each received one short arm cast and one short leg cast. Each cast was removed after they were deemed dry. These casts were subsequently weighed until they achieved a stable weight. Each cast was then reapplied to the subject’s arm and held together with Scotch tape. A trash bag was then applied around the cast and then secured with Duct tape to the skin. This was repeated to create a double seal. These covered, reapplied casts were submerged under water for 2 minutes. After submersion, the cover was removed, and the cast was reweighed. The casts were then submerged completely without any protection for 2 minutes and their fully saturated weight was recorded. Efficacy was determined by comparing the postsubmersion and full-submersion weights. Data was analyzed using the Mann-Whitney test.

Results:

The percentage of water absorption prevention ranged from 96.8% to 99.9%, with an average of 99.6% across the entire study sample (P<0.0001). No adverse effects were reported.

Conclusion:

Our findings conclude that the double-bag with Duct-tape method is effective at preventing external water absorption. This in vivo study demonstrates that almost all external water absorption can be prevented using this simple and inexpensive technique.

Level of Evidence:

Level II, prospective comparative study.
Histopathologic Characterization of Incidental Lesions Encountered During Mohs Micrographic Surgery With MART-1 Immunohistochemistry
Authors: Hirotsu Kelsey E. , Kibbi Nour , Rieger Kerri E. , Aasi Sumaira Z.
Published: December 2023

BACKGROUND

As the use of melanoma antigen recognized by T cells (MART-1) immunohistochemistry (IHC) with Mohs surgery increases for the treatment of melanoma in situ and invasive melanoma, surgeons should be aware of MART-1 staining patterns of incidental lesions often encountered on frozen sections. Lack of this knowledge can lead to unnecessary additional surgery, increased health care costs, and loss of valuable laboratory staff time and resources.

OBJECTIVE

To characterize the histopathologic features of incidental lesions encountered during Mohs surgery for melanoma. To review key diagnostic and differentiating features on hematoxylin and eosin staining (H&E) and MART-1 IHC of these lesions.

METHODS

A comprehensive review of frozen-section histopathology slides from Mohs cases with MART-1 IHC at our institution was conducted from 2021 to 2023.

RESULTS

Incidental benign and malignant lesions were identified and characterized on H&E frozen sections and MART-1 IHC. Although such entities can share MART-1 staining characteristics with melanoma in situ or melanoma, distinguishing characteristics on H&E and lack of histopathologic criteria for melanoma on MART-1 IHC can be used to distinguish these incidental lesions from melanoma.

CONCLUSION

Staining of frozen sections for Mohs micrographic surgery with H&E and MART-1 IHC together can differentiate common incidental benign and malignant cutaneous lesions from melanoma.
Five-year visual outcome of treatment for retinopathy of prematurity in infants weighing less than 500 g at birth: A multicenter cohort study from J-CREST
Authors: Tomioka Mizuki , Murakami Tomoya , Okamoto Fumiki , Kinoshita Takamasa , Shinomiya Kayo , Nishi Tomo , Jujo Tatsuya , Obata Shumpei , Tsukitome Hideyuki , Ogura Shuntaro , Ueda Kaori , Ishii Ryota , Oshika Tetsuro
Published: December 2023

Purpose:

To investigate the 5-year treatment outcomes of retinopathy of prematurity (ROP) in infants <500 g birth weight and compare laser and anti-vascular endothelial growth factor (VEGF) therapies.

Methods:

A multicenter retrospective study comprised 24 eyes of 13 patients treated for type 1 ROP, followed for 5 years. Initial treatment was laser and anti-VEGF in 13 and 11 eyes, respectively. Data collected included sex, birth characteristics, ROP characteristics at the time of treatment, best-corrected visual acuity (BCVA), spherical equivalent (SE), and astigmatism at 5 years post-treatment.

Results:

Median BCVA was 0.15 logMAR (IQR, 0.0–0.5). Snellen BCVA was ≥20/40 in 73% and ≥20/20 in 27% of eyes. Median SE was -2.37 (IQR, -6.1–-0.1); 75% had myopia (≤ -0.5 D), and 25% had high myopia (≤ -6.0 D). Median astigmatism was 1.25 (IQR, 0.9–3.0); 46% had ≥1.5 D. Anti-VEGF treated eyes showed less myopia (p<0.009), with no BCVA or astigmatism difference (p=0.997, p=0.271) compared to laser-treated eyes.

Conclusion:

One-quarter of the eyes exhibited good visual acuity (Snellen BCVA of 20/20 or better) 5 years post-ROP treatment. Refractive errors were common. Anti-VEGF therapy may be superior to laser therapy in terms of myopic refractive error.
Pan-valvulitis in Children With Kawasaki Disease: A Case Report and Review of the Literature
Authors: Leon-Jimenez Pelayo , Lorenzo-Martin Maria , Tomatis-Souverbielle Cristiana , Akoghlanian Shoghik , Cripe Linda , Ramilo Octavio , Mejias Asuncion
Published: December 2023

We present a rare case of pan-valvular involvement in a 5-month-old female with Kawasaki disease shock syndrome despite early treatment with intravenous immunoglobulin and corticosteroids. She experienced a favorable outcome after the addition of infliximab, which was guided based on clinical, laboratory and echocardiogram findings, rather than recrudescence of fever, the most common indicator of intravenous immunoglobulin resistance.
Resilience of Patients With Brain Tumor While Awaiting Surgery
Authors: Maneekrong Supawadee , Tankumpuan Thitipong , Danaidutsadeekul Suporn , Siwanuwatn Rungsak
Published: December 2023

BACKGROUND:Resilience is the ability of patients to adapt effectively when given a diagnosis of an illness. While awaiting brain tumor surgery, patients often experience uncertainty from brain tumor–related symptoms resulting in inducing depressive symptoms, having physical disability, and reducing quality of life. Resilience studies have been widely conducted in the postoperative phase with a limited knowledge on the preoperative phase. This study aimed to identify predictors of resilience while awaiting brain tumor surgery.METHODS:This cross-sectional predictive study includes 100 participants 18 years and older, with diagnosis of brain tumors, and waiting for brain tumor surgery at the outpatient department of 1 tertiary hospital in Bangkok between August 2022 and February 2023. Multiple linear regression was used to examine the predictors of resilience.RESULTS:Most of the sample (77%) were female with a mean age of 52.71 (13.17) years. The most common type of brain tumor was meningioma (38%). The median waiting time since brain tumor diagnosis until the date of preadmission for operation was 18 (3-1464) days. Symptom severity, social support, and treatment plan were able to explain 37.3% of the variance of resilience in patients awaiting brain tumor surgery (F= 19.077,P< .01,R2= 0.373, adjustedR2= 0.354).CONCLUSION:Resilience is an important skill for patients with brain tumor to manage uncertainty events that occur in their lives. The preoperation phase needs to assess both physical and mental tumor-related symptoms, and include caregivers as part of the care, to promote resilience skill for patients awaiting brain tumor surgery.
Effect of Azilsartan on clinical blood pressure reduction compared to other angiotensin receptor blockers: a systematic review and meta-analysis
Authors: Khan Qaisar Ali , Sharma Shalini , Mulk Ittehad ul , Li David , Belay Naod F. , Afzal Muhammad , Farrukh Ameer Mustafa , Asad Muhammad , Baqi Abdul , Semakieh Bader
Published: December 2023

Background:

Hypertension has significantly contributed to morbidity and mortality, necessitating effective management. Angiotensin receptor blockers (ARBs) have emerged as a cornerstone in hypertension treatment. Azilsartan, a relatively recent addition to the ARB family, offers unique characteristics, including prodrug activation. This systematic review and meta-analysis aimed to evaluate Azilsartan’s role in reducing clinical blood pressure compared to other ARBs and determine the most effective dosage.

Methods:

Following PRISMA guidelines, a comprehensive literature search was conducted in Medline, Web of Science, Cochrane Library, and clinicaltrials.gov. Eligible studies included adult hypertensive patients receiving Azilsartan compared to other ARBs, with clinical systolic blood pressure (SBP) and diastolic blood pressure (DBP) outcomes. Data extraction and quality assessment were performed, and statistical analysis employed comprehensive meta-analysis (CMA) software.

Results:

Eleven randomized controlled trials encompassing 18 studies involving 6024 patients were included. Azilsartan demonstrated significant reductions in clinical SBP (mean difference=−2.85 mmHg) and DBP (mean difference=−2.095 mmHg) compared to other ARBs. Higher doses of Azilsartan showed greater efficacy, with 80 mg exhibiting the most substantial reduction in SBP. The analysis emphasized the need for more studies investigating lower Azilsartan doses (10 and 20 mg).

Conclusion:

This systematic review and meta-analysis underscore Azilsartan’s effectiveness in reducing SBP and DBP. Dose-dependent effects emphasize the importance of optimal dosing when prescribing Azilsartan. These findings provide valuable insights for clinicians in managing hypertension effectively and call for further research, primarily focusing on lower Azilsartan doses and a more diverse patient population.
Relationship Between Immunophenotypes, Genetic Profiles, and Clinicopathologic Characteristics in Small Bowel Adenocarcinoma
Authors: Hoshimoto Aitoshi , Tatsuguchi Atsushi , Yamada Takeshi , Kuriyama Sho , Hamakubo Ryohei , Nishimoto Takayoshi , Omori Jun , Akimoto Naohiko , Gudis Katya , Mitsui Keigo , Tanaka Shu , Fujimori Shunji , Hatori Tsutomu , Shimizu Akira , Iwakiri Katsuhiko
Published: December 2023

Small bowel adenocarcinoma (SBA) is rare, and scant data exist regarding its molecular and clinicopathologic characteristics. This study aimed to clarify the correlation between immunophenotypes, DNA mismatch repair status, genomic profiling, and clinicopathologic characteristics in patients with SBA. We examined 68 surgical resections from patients with primary SBA for immunohistochemical analyses of CK7, CK20, CD10, CDX2, MUC1, MUC2, MUC4, MUC5AC, and MUC6 expression as well as mismatch repair status. Genomic profiling was performed on 30 cases using targeted next-generation sequencing. Tumor mucin phenotypes were classified as gastric, intestinal, gastrointestinal, or null based on MUC2, MUC5AC, MUC6, and CD10 immunostaining. The expression of these proteins was categorized into 3 classifications according to their relationship to: (1) tumor location: CK7/CK20, MUC4, and MUC6; (2) histologic type: mucinous adenocarcinoma was positive for MUC2 and negative for MUC6; and (3) TNM stage: CD10 was downregulated, whereas MUC1 was upregulated in advanced TNM stages. CDX2 was a specific marker for SBA generally expressed in the small intestine. MUC1 and MUC4 expression was significantly associated with worse prognosis. MUC2 expression correlated with better prognosis, except for mucinous adenocarcinoma. Although the difference was not statistically significant, gastric-type tumors were more frequently located in the duodenum and were absent in the ileum. APC and CTNNB1 mutations were not found in the gastric-type tumors. The SBA immunophenotype correlated with tumor location, biological behavior, and genomic alterations. Our results suggest that the molecular pathway involved in carcinogenesis of gastric-type SBA differs from that of intestinal-type SBA.
Specific Pathology Features Enrich Selection of Endometrial Carcinomas for POLE Testing
Authors: Keyhanian Kianoosh , Han Lucy , Howitt Brooke E. , Longacre Teri
Published: December 2023

Identification of ultramutated/POLE-mutated endometrial carcinomas (POLE
M ECs) has important implications given its association with better prognosis. However, POLE mutation testing is not widely available. Our objective was to evaluate POLE
M ECs versus POLE wild-type (POLE
WT) ECs, within a cohort of consultation cases with features suggestive of an ultramutated phenotype. Consultation cases of EC that had undergone POLE hotspot mutation testing over a 3.5-year period were included. Tumor morphology and immunohistochemistry were reviewed for both groups. Chi-square test and t test were used for statistical analysis. Of 25 consultation cases, 12 harbored a POLE mutation (48%) and 13 were wild-type (52%). Patients with POLE
M ECs were younger (59 vs. 71.3 y; P=0.01). Ambiguous histomorphology (5/12 vs. 1/13; P=0.04) and the presence of more than rare bizarre nuclei (8/12 vs. 2/12; P=0.01) differed significantly between POLE
M and POLE
WT ECs, respectively. In the POLE
M group, one case (1/12) demonstrated PMS2 loss, and one (1/12) showed subclonal MLH1/PMS2 loss. Among POLE
WT ECs, 3/13 (23%) showed MLH1/PMS2 loss. p53 was subclonally overexpressed in 4/10 POLE
M and 1/13 POLE
WT cases (P=0.06). Mutant p53 patterns were seen in 1/10 POLE
M versus 6/13 of POLE
WT ECs, respectively (P=0.06). Within our cohort, the specificity of ambiguous histomorphology, bizarre nuclei, subclonal biomarker expression, and marked tumor-infiltrating lymphocytes for POLE
M EC was 83%, 80%, 80%, and 71%, respectively. Where universal POLE testing is not available, these data suggest that morphologic screening (particularly ambiguous histomorphology and the presence of more than rare bizarre nuclei) can be useful for selective enrichment of ECs for POLE testing.
Employment of time-varying sensory evidence to test the mechanisms underlying flexible decision-making
Authors: Kumano Hironori , Uka Takanori
Published: December 2023

To make flexible decisions in dynamic environments, the brain must integrate behaviorally relevant information while simultaneously discarding irrelevant information. This study aimed to investigate the mechanisms responsible for discarding irrelevant information during context-dependent decision-making. We trained two macaque monkeys to switch between direction and depth discrimination tasks in successive trials. During decision-making, the strength of the motion or depth signal changes transiently at various times, introducing a brief pulse. We assessed the effects of pulse on behavioral choices. Consistent with previous findings, early relevant pulses, such as motion pulses during direction discrimination, had a significantly larger effect compared to late pulses. Critically, the effects of irrelevant pulses, such as motion pulses during depth discrimination, exhibited an initial minimal effect, followed by an increase and subsequent decrease as a function of pulse timing. Gating mechanisms alone, aimed at discarding irrelevant information, did not account for the observed time course of pulse effects. Instead, the observed increase in the effects of irrelevant pulses with time suggested the involvement of a leaky integration mechanism. The results suggested that the brain controls the amount of disposal in accumulating sensory evidence during flexible decision-making.
Whole genome sequencing and genotyping Klebsiella pneumoniae multi-drug resistant hospital isolates from Western Kenya
Authors: Dinda Victor , Kimang’a Andrew Nyerere , Kariuki Daniel , Sifuna Anthony Wawire , O’Brien Thomas James , Welch Martin , Reva Oleg N
Published: December 2023

Klebsiella pneumoniae are a frequent cause of nosocomial infections worldwide. Sequence type 147 (ST147) has been reported as a major circulating high-risk lineage in many countries, and appears to be a formidable platform for the dissemination of antimicrobial resistance (AMR) determinants. However, the distribution of this pathogen in Western African hospitals has been scarcely studied. The main objective of this work was to perform whole genome sequencing of K. pneumoniae isolates from a referral hospital in Kakamega (Kenya) for genotyping and identification of AMR and virulence determinants.
Transcriptomic profiling reveals host-specific evolutionary pathways promoting enhanced fitness in the plant pathogen Ralstonia pseudosolanacearum
Authors: Gopalan-Nair Rekha , Jardinaud Marie-Françoise , Legrand Ludovic , Lopez-Roques Céline , Bouchez Olivier , Genin Stéphane , Guidot Alice
Published: December 2023

The impact of host diversity on the genotypic and phenotypic evolution of broad-spectrum pathogens is an open issue. Here, we used populations of the plant pathogen

Ralstonia pseudosolanacearum

that were experimentally evolved on five types of host plants, either belonging to different botanical families or differing in their susceptibility or resistance to the pathogen. We investigated whether changes in transcriptomic profiles, associated with or independent of genetic changes, could occur during the process of host adaptation, and whether transcriptomic reprogramming was dependent on host type. Genomic and transcriptomic variations were established for 31 evolved clones that showed better fitness in their experimental host than the ancestral clone. Few genomic polymorphisms were detected in these clones, but significant transcriptomic variations were observed, with a large number of differentially expressed genes (DEGs). In a very clear way, a group of genes belonging to the network of regulation of the bacterial virulence such as efpR, efpH or hrpB, among others, were deregulated in several independent evolutionary lineages and appeared to play a key role in the transcriptomic rewiring observed in evolved clones. A double hierarchical clustering based on the 400 top DEGs for each clone revealed 2 major patterns of gene deregulation that depend on host genotype, but not on host susceptibility or resistance to the pathogen. This work therefore highlights the existence of two major evolutionary paths that result in a significant reorganization of gene expression during adaptive evolution and underscore clusters of co-regulated genes associated with bacterial adaptation on different host lines.
‘Shaking the Ladder’ reveals how analytic choices can influence associations in nutrition epidemiology: beef intake and coronary heart disease as a case study
Authors: Vorland Colby J. , O’Connor Lauren E. , Henschel Beate , Huo Cuiqiong , Shikany James M. , Serrano Carlos A. , Henschel Robert , Dickinson Stephanie L. , Ejima Keisuke , Bidulescu Aurelian , Allison David B. , Brown Andrew W.
Published: December 2023

Background

Many analytic decisions are made when analyzing an observational dataset, such as how to define an exposure or which covariates to include and how to configure them. Modelling the distribution of results for many analytic decisions may illuminate how instrumental decisions are on conclusions in nutrition epidemiology.

Objective

We explored how associations between self-reported dietary intake and a health outcome depend on different analytical decisions, using self-reported beef intake from a food frequency questionnaire and incident coronary heart disease as a case study.

Design

We used REasons for Geographic and Racial Differences in Stroke (REGARDS) data, and various selected covariates and their configurations from published literature to recapitulate common models used to assess associations between meat intake and health outcomes. We designed three model sets: in the first and second sets (self-reported beef intake modeled as continuous and quintile-defined, respectively), we randomly sampled 1,000,000 model specifications informed by choices used in the published literature, all sharing a consistent covariate base set. The third model set directly emulated existing covariate combinations.

Results

Few models (<1%) were statistically significant at p<0.05. More hazard ratio (HR) point estimates were >1 when beef was polychotomized via quintiles (95% of models) vs. continuous intake (79% of models). When covariates related to race or multivitamin use were included in models, HRs tended to be shifted towards the null with similar confidence interval widths compared to when they were not included. Models emulating existing published associations were all above HR of 1.

Conclusions

We quantitatively illustrated the impact that analytical decisions can have on HR distribution of nutrition-related exposure/outcome associations. For our case study, exposure configuration resulted in substantially different HR distributions, with inclusion or exclusion of some covariates being associated with higher or lower HRs.

This project was registered at OSF:https://doi.org/10.17605/OSF.IO/UE457
Interplay between environmental yielding and dynamic forcing regulates bacterial growth
Authors: Hancock Anna M. , Datta Sujit S.
Published: December 2023

Many bacterial habitats—ranging from gels and tissues in the body to cell-secreted exopolysaccharides in biofilms—are rheologically complex, undergo dynamic external forcing, and have unevenly-distributed nutrients. How do these features jointly influence how the resident cells grow and proliferate? Here, we address this question by studying the growth ofEscherichia colidispersed in granular hydrogel matrices with defined and highly-tunable structural and rheological properties, under different amounts of external forcing imposed by mechanical shaking, and in both aerobic and anaerobic conditions. Our experiments establish a general principle: that the balance between the yield stress of the environment that the cells inhabitσyand the external stress imposed on the environmentσregulates bacterial growth by modulating transport of essential nutrients to the cells. In particular, whenσy< σ, the environment is easily fluidized and mixed over large scales, providing nutrients to the cells and sustaining complete cellular growth. By contrast, whenσy> σ, the elasticity of the environment suppresses large-scale fluid mixing, limiting nutrient availability and arresting cellular growth. Our work thus reveals a new mechanism, beyond effects that change cellular behavior via local forcing, by which the rheology of the environment may regulate microbial physiology in diverse natural and industrial settings.
Comparative analysis of HPV-Human Protein Interaction Networks in Oropharyngeal and Oral Squamous cell carcinomas
Authors: Riaz Arsalan , Khan Faisal F.
Published: December 2023

Oral Squamous Cell Carcinoma (OSCC) accounts for more than 90% of reported head and neck cancers which is the sixth leading cancer worldwide. Oropharyngeal squamous cell carcinoma (OPSCC) cases, a closely located but a different sub-type of head and neck cancer, are also rising worldwide specifically among young individuals with risk factors including viral infection, smoking and alcohol. HPV infection specifically the subtype HPV16 is a significant risk factor in the initiation and progression of OPSCC, but has not been reported to play a role in OSCC. This study sets out to decipher mechanistic differences at the molecular level by comparing the viral-human protein-protein interaction (PPI) networks both in oropharyngeal squamous cell carcinoma (OPSCC) and oral squamous cell carcinoma (OSCC). We found that the unbiased HPV16-Human network consisted of 479 nodes, including 7 HPV16 proteins and 472 human proteins. Enrichment analysis revealed significant involvement of the identified human proteins in ubiquitination, protein degradation, and cancer-related pathways. A subset of 37 genes showed differential expression in HPV-positive OPSCC and OSCC, with TP53 over-expressed and ENDOD1 under-expressed in both cancers. Six genes (NUTM1, MYC, SCN9A, COL27A1, ITGB4, and GNB2) exhibited distinct changes in HPV-positive OPSCC compared to the other groups, where NUTM1 was the most over-expressed in OPSCC HPV+. The identified genes and pathways could serve as potential targets for precision medicine and therapeutic interventions in HPV-associated cancers. Further investigations are required to validate their clinical implication inin vitroandin vivomodels.
Therapeutic validation of MMR-associated genetic modifiers in a humanex vivomodel of Huntington’s disease
Authors: Ferguson Ross , Goold Robert , Coupland Lucy , Flower Michael , Tabrizi Sarah J
Published: December 2023

The pathological huntingtin (HTT) trinucleotide repeat underlying Huntington’s disease (HD) continues to expand throughout life. Repeat length correlates both with earlier age at onset (AaO) and faster progression, making slowing its expansion an attractive therapeutic approach. Genome-wide association studies have identified candidate variants associated with altered AaO and progression, with many found in DNA mismatch repair (MMR) associated genes.

We examine whether lowering expression of these genes affects the rate of somatic expansion in humanex vivomodels using HD iPSCs and HD iPSC-derived striatal neurons. We have generated a stable CRISPR interference HD iPSC line in which we can specifically and efficiently lower gene expression from a donor carrying over 125 CAG repeats.

Lowering expression of each member of the MMR complexes MutS (MSH2, MSH3 & MSH6), MutL (MLH1, PMS1, PMS2 & MLH3) and LIG1 resulted in characteristic MMR deficiencies. Reduced MSH2, MSH3 and MLH1 slowed repeat expansion to the largest degree, while lowering either PMS1, PMS2 and MLH3 slowed it to a lesser degree. These effects were recapitulated in iPSC derived striatal cultures where MutL factor expression was lowered.

Here, reducing the expression of MMR factors by CRISPRi to levels typically reached by current therapeutics effectively slows the pathogenic expansion of the HTT CAG repeat tract. We highlight members of the MutL family as potential therapeutic targets to slow repeat expansion with the aim to delay onset and progression of HD, and potentially other repeat expansion disorders exhibiting somatic instability.

GRAPHICAL ABSTRACT
Cue-Invariant Geometric Structure of the Population Codes in Macaque V1 and V2
Authors: Massot Corentin , Zhang Xiaoqi , Wang Zitong , Rockwell Harold , Papandreou George , Yuille Alan , Lee Tai-Sing
Published: December 2023

Abstract

We investigated the cue-invariant representation of visual patterns associated with surface boundaries in V1 and V2. We found that individual neurons exhibited a modest degree of tuning invariance in their responses to these patterns. This tuning invariance is stronger in V1 than in V2. At a population activity level, we studied the performance of a decoder trained with one cue in decoding patterns defined in another cue. We found that cue-transfer decoding is greatly enhanced when a geometric transform is first performed to align the population activities across cues. With this geometric transform, transfer decoding can be successful even when the tuning invariance of the individual neurons are destroyed by shuffling and when the neurons are from distinct populations. These findings suggest that abstract representation of these boundary-related patterns in V1 and V2 might be primarily encoded in the geometric structures of the population codes, rather than the cue-invariant tuning properties of the individual neurons.
Ras Activation by Hydrostatic Pressure is Enhanced by GAP and GEFin vitro
Authors: Matsuda Teruhiko , Chang Minki , Furukawa Katsuko , Ushida Takashi , Uyeda Taro Q.P.
Published: December 2023

Hydrostatic pressure (HP) is a necessary stimulus for cell differentiation and growth in cultured chondrocytes. Assuming that Ras activation is involved in HP-induced reactions, if cellular Ras activity is increased by HP, Ras itself, Raf, Ras regulators including GTPase activating proteins (GAP) and guanine nucleotide exchange factors (GEF), then the upstream receptor and/or interactions between them should have HP sensitivity. Based on this hypothesis, we first attempted to examine whether Ras is activated by HP, and in the affirmative, identify which factors displayed HP sensitivity using anin vitrosystem to measure Ras activity. Thisin vitrosystem included mRaichu, a FRET-based Ras activity probe, to which two-point mutations were introduced to reduce Ras-independent signals. This improved Raichu was used to investigate the HP sensitivity of two components, the GAP domain (GAPd) derived from p120GAP and the GEF domain (GEFd) derived from hSOS-1. It was found that HP weakly activated Ras activity in the absence of GAPd and GEFd, presumably by facilitating GDP dissociation from Ras. A low concentration of GAPd enhanced HP-induced Ras activation by 16.3% whereas high concentrations of GAPd removed HP sensitivity, suggesting that HP partially dissociates GAPd from the GAPd-Ras-GDP complex and reduces the fraction of inactive Ras. Moreover, a broad concentration range of GEFd also enhanced HP-induced Ras activation. Given that HP also increased Ras activity under a condition mimicking cellular Ras activity, we propose that Ras activation is involved in the differentiation and growth stimulation of chondrocytes by HP.

Statement of Significance

The Ras-cycle has been implicated in the regulation of growth and differentiation of eukaryotic cells. Here, we investigated the relationship between hydrostatic pressure (HP) and components of the Ras-cycle: Ras-Raf, the GAP domain, and the GEF domain. Generally, HP tends to weaken protein-protein and protein-ligand interactions, but in this study, a seemingly positive response was observed: HP-induced Ras activation. Additionally, this response was enhanced by the GEF domain and the GAP domain. Thus, given the multiple cellular functions of Ras and the responses of the Ras-cycle to HP, this study will help clarify the molecular mechanism by which HP modulates cellular functions, particularly in chondrocytes, which are subjected to repetitive HP stimuliin vivo.
Inhibition of the melanocortin-3 receptor (MC3R) causes generalized sensitization to anorectic agents
Authors: Dahir Naima S. , Gui Yijun , Wu Yanan , Sweeney Patrick R. , Williams Savannah Y. , Gimenez Luis E. , Sawyer Tomi K. , Joy Stephen T. , Mapp Anna K. , Cone Roger D.
Published: December 2023

The melanocortin-3 receptor (MC3R) acts presynaptically to regulate GABA release from agouti-related protein (AgRP) nerve terminals and thus may be a negative regulator of multiple circuits involved in feeding behavior and energy homeostasis. Here, we examined the role of MC3R in regulating the response to various anorexigenic agents. Our findings reveal that genetic deletion or pharmacological inhibition of MC3R improves the dose responsiveness to Glucagon-like peptide 1 (GLP1) agonists, as assayed by inhibition of food intake and weight loss. An enhanced anorectic response to other agents, including the acute satiety factors peptide YY (PYY3-36) and cholecystokinin (CCK) and the long-term adipostatic factor, leptin, demonstrated that increased sensitivity to anorectic agents is a generalized result of MC3R antagonism. Enhanced neuronal activation in multiple nuclei, including ARH, VMH, and DMH, was observed using Fos immunohistochemistry following low-dose liraglutide in MC3R knockout mice (Mc3r-/-), supporting the hypothesis that the MC3R is a negative regulator of circuits regulating multiple aspects of feeding behavior. The enhanced anorectic response inMc3r-/-mice after administration of GLP1 analogs was also independent of the incretin effects and malaise induced by GLP1R analogs, suggesting that MC3R antagonists may have value in enhancing the dose-response range of obesity therapeutics.
Axon guidance genes are regulated by TDP-43 and RGNEF through the rate of long-intron processing
Authors: Abbassi Yasmine , Cappelli Sara , Spagnolo Eugenio , Gennari Alice , Visani Giulia , Barattucci Simone , Paron Francesca , Stuani Cristiana , Droppelmann Cristian A. , Strong Michael J. , Buratti Emanuele
Published: December 2023

Rho guanine nucleotide exchange factor (RGNEF) is a guanine nucleotide exchange factor (GEF) mainly involved in regulating the activity of Rho-family GTPases. Previous work has shown that RGNEF inclusions in the spinal motor neurons of ALS patients co-localise with TDP-43, the major RNA binding protein aggregating in the brain and spinal cord of ALS patients. To further characterise their relationship, we have compared the transcriptomic profiles of neuronal-like cells depleted of TDP-43 and RGNEF and show that these two factors predominantly act in an antagonistic manner when regulating the expression of axon guidance genes. From a mechanistic point of view, our experiments show that the effect of these factors on the processivity of long introns can explain their mode of action. Our findings highlight that neurodegenerative processes at the RNA level can often represent the result of combinatorial interactions between different RNA binding factors, leading to a better understanding of pathogenic mechanisms occurring in patients where more than one specific protein may be aggregating in their neurons.
Noninvasive Injectable Optical Nanosensor-Hydrogel Hybrids Detect Doxorubicin in Living Mice
Authors: Cohen Zachary , Alpert Dave J. , Weisel Adam C. , Roach Arantxa , Rahman Syeda , Gaikwad Pooja V. , Nicoll Steven B. , Williams Ryan M.
Published: December 2023

While the tissue-transparent fluorescence of single-walled carbon nanotubes (SWCNTs) imparts substantial potential for use in non-invasive biosensors, development of non-invasive systems is yet to be realized. Here, we investigated the functionality of a SWCNT-based nanosensor in several injectable SWCNT-hydrogel systems, ultimately finding SWCNT encapsulation in a sulfonated methylcellulose hydrogel optimal for detection of ions, small molecules, and proteins. We found that the hydrogel system and nanosensor signal were stable for several weeks in live mice. We then found that this system successfully detects local injections of the chemotherapeutic agent doxorubicin in mice. We anticipate future studies to adapt this device for detection of other analytes in animals and, ultimately, patients.