bluuebunny/crossref_metadata_2025 huggingface dataset:
Sterile Draping of Operative Microscopes in Breast Free Flaps and Surgical Site Infections
Authors: Marable Julian K. , Spoer Daisy L. , Harish Varsha , Berger Lauren E. , Song David H. , Fan Kenneth L.
Published: August 2024

Background

Operative microscopes are traditionally draped in single-use plastic to prevent infection theoretically. The necessity of this routine in breast free flap surgery is unclear. Alternatively, sterile wrapping of microscope handles would reduce operating room waste and provide a more cost-effective and environmentally sustainable approach to sterility. This study aimed to determine whether the draping technique used during abdominally based free flaps (Ab-FF) influenced the rate of surgical site infections.

Methods

We conducted a retrospective review of Ab-FF performed consecutively between March 2017 and August 2022. Patient demographics, comorbidities, perioperative data, and postoperative complications were collected. The primary outcomes included postoperative surgical site infections and environmental impact.

Results

Of the 281 identified breasts reconstructed with Ab-FF, operating microscopes were sterilely covered with microscope drapes (n = 215) or handle covers (n = 66) composed of polyethylene-based plastic. Overall, postoperative infections occurred in 9.3% of cases (n = 26) in either the recipient breast (n = 11, 3.9%) or abdominal donor site (n = 15, 5.3%), primarily due to S. aureus and Streptococcus species. The handle (n = 6, 9.1%) and drape (n = 20, 9.3%) cohorts had similar infection rates with no sequelae of operative complications. In multivariate analysis, radiation was the only independent predictor of postoperative infection, while bilateral reconstructions were independently protective. Replacing a microscope drape with a handle reduces carbon emissions by 1276 grams of CO2 and direct costs by $7.84 per item.

Conclusions

The principles of “Lean and Green” surgery prioritize reducing operating room generated waste to achieve financial and environmental sustainability. This cohort study of 281 breast free flaps demonstrates that switching from whole microscope draping to handle wrapping was not associated with an increased rate or odds of infection. Adopting a microscope handle wrapping protocol decreased the carbon footprint and operative costs. The results of this study offer evidence to support adoption and further exploration of pragmatic, cost-effective, and sustainable approaches to microsurgical breast reconstruction.
Employer-Sponsored Medicare Advantage Plans and the 2018 Therapy Cap Repeal
Authors: Fahmy Joseph N. , Kong Lingxuan , Wang Lu , Chung Kevin C.
Published: August 2024

Background

Policy impacting traditional Medicare beneficiaries may have unintended effects for privately insured patients. After the repeal of a longstanding $1500 outpatient therapy cap in 2018, we aimed to evaluate if this policy change was associated with differences in use of cost of postoperative therapy after common hand surgeries, including carpal tunnel release, trigger finger release, ganglion cyst excision, De Quervain tenosynovitis release, carpometacarpal arthroplasty, and distal radius fracture open reduction/internal fixation or percutaneous pinning.

Methods

The Medicare Supplement and Coordination of Benefits files from Marketscan were used. Frequency of therapy appointments, overall costs, and out-of-pocket costs were obtained. A segmented interrupted time series with Poisson and log-transformed linear regression was performed.

Results

No significant monthly change in odds of therapy use was found in the postpolicy period for patients who underwent trigger finger release, carpal tunnel release, Ganglion cyst excision, De Quervain tenosynovitis release, carpometacarpal arthroplasty, or distal radius fracture, pinning, or open reduction/internal fixation. Overall cost decreased in the postpolicy period by 2% for comprehensive plans (95% confidence interval [CI]: −0.03 to −0.01, P < 0.001), by 7% for those with exclusive provider organizations (95% CI: −0.10 to −0.04, P < 0.001), by 1% for HMOs (95% CI: −0.01 to 0.002, P = 0.01), and by 3% for preferred provider organizations (95% CI: −0.03 to −0.02, P < 0.001). In the postpolicy period, no monthly change in out-of-pocket cost was observed for patients with comprehensive, exclusive provider organization, health maintenance organization, preferred provider organization, or point of service with capitation insurance plans.

Conclusions

Patients with employer-sponsored Medicare Advantage plans experienced increased out-of-pocket costs for therapy despite lower net costs. These data highlight an urgent need for policy ensuring that patients benefit when overall costs of care decrease.
Course Review
Authors: Gundle Leo
Published: August 2024

Microsurgery is a unique and specific surgical skill, known to have a steep learning curve. Surgical trainees may wish to undertake a microsurgical skills course to learn the rudiments of microsurgery and to direct future practice and skill acquisition. The National Microsurgery Course in Newcastle, United Kingdom, aims to equip early-year surgical trainees with basic microsurgical skills including tissue handling, vessel anastomosis, and nerve coaptation. The course in 2024 gave delegates an excellent opportunity to learn and practice these skills in a well-resourced environment with a high delegate-to-faculty ratio. Overall, the course was an extremely high-quality educational experience with most of the course time allocated to practicing surgical skills. This course is recommended to surgical trainees wishing to learn the basics of microsurgery.
Open-source 3D printed manifolds for exposure studies using human airway epithelial cells
Authors: Singer Ryan , Ball Elizabeth , Milad Nadia , Nguyen Jenny P. , Cao Quynh , Selvaganapathy Ravi , Zhang Boyang , Dabaghi Mohammadhossein , Satia Imran , Hirota Jeremy A.
Published: August 2024

Rationale

Inhalation of airborne stimuli can damage the airway epithelium, increasing the risk of developing respiratory or systemic diseases.In vitrostudies using air-liquid interface cell cultures enable controlled investigation of cellular responses to relevant exposures. Commercialin vitroexposure systems provide precise and reproducible dosage but require significant capital investment and are not amenable to customization. Research groups interested in respiratory exposure science may benefit from a more accessible alternative open-source exposure system. We present 3D printed manifolds for applying a range of airborne exposures uniformly across standard, commercially available 6- and 24-well plates with air-liquid interface culture inserts.

Methods

A simple chamber-style exposure system and the manifolds were evaluated for exposure uniformity via computational fluid dynamics simulations and deposition of nebulized FITC-labelled dextran. The chamber and manifolds were manufactured using a stereolithography 3D printer. Cannabis concentrate vapor was generated from 3 different vaporizers and applied to well plates using the manifold system. Calu-3 cells were cultured on Transwell™ inserts and exposed to whole tobacco smoke or room air.

Results

The manifolds produced less variation in simulated air velocities and physical deposition of FITC-dextran aerosol deposition across well plates compared to those of the chamber-style exposure system. Distinct doses of cannabis concentrate vapour were delivered to well plates with low variation among wells. Whole tobacco smoke exposure using the manifold system induced functional changes in Calu-3 airway epithelial cell barrier function, cytokine production (IL-6 and IL-8), and cell membrane potential.

Conclusions

Collectively, our data demonstrate the feasibility and the validity of our open-source 3D printed manifolds for use in studying various respiratory exposures and position our designs as more accessible options in parallel with commercially available systems.

All article content is licensed under a Creative Commons Attribution (CC BY-NC 4.0) license (https://creativecommons.org/licenses/by-nc/4.0/).
Tailoring hydrophobicity and strength in spider silk-inspired coatings via thermal treatments
Authors: Seisto Anni , Borisova Anna S. , Pylkkänen Robert , Mohammadi Pezhman
Published: August 2024

The advent of advanced coatings has transformed material functionalities, extending their roles from basic coverage and visual appeal to include unique properties such as self-healing, superior hydrophobicity, and antimicrobial action. However, the traditional dependency on petrochemical-derived materials for these coatings raises environmental concerns. This study proposes the use of renewable and alternative materials for coating development. We present the use of bioengineered spider silk-inspired protein (SSIP), produced through recombinant technology, as a viable, eco-friendly alternative due to their ease of processing under ambient pressure and the utilization of water as a solvent, alongside their exceptional physicochemical properties. Our research investigates the effects of different thermal treatments and protein concentrations on the mechanical strength and surface water repellency of coatings on silica bases. Our findings reveal a direct correlation between the temperature of heat treatment and the enhancements in surface hydrophobicity and mechanical strength, where elevated temperatures facilitate increased resistance to water and improved mechanical integrity. Consequently, we advocate SSIPs present a promising, sustainable choice for advanced coatings, providing a pathway to fine-tune coating recipes for better mechanical and hydrophobic properties with a reduced ecological footprint, finding potential uses in various fields such as electronics.
Elexacaftor/Tezacaftor/Ivacaftor (Trikafta®) does not affect the Growth ofAspergillus fumigatus in vitro
Authors: Biquand Elise , Khau Sandra , Fouquenet Delphine , Costes Floriane , Chesnay Adélaïde , Desoubeaux Guillaume , Briard Benoit
Published: August 2024

Fungal infection, especially allergic bronchopulmonary aspergillosis, is a leading cause of infection-associated morbidity and death in patients with cystic fibrosis. We have previously discovered that the new leading therapeutic treatment in cystic fibrosis, CFTR modulators Elexakaftor/Tezacaftor/Ivacaftor (ETI, Trikafta®), drastically reduces the colonization and infection byAspergillus fumigatus. However, the reasons for this decrease in patients are not known so far. In this study we have shown, usingA. fumigatusreference strains and strains isolated from patients with cystic fibrosis, that CFTR modulators have no discernable impact on fungal growthin vitro. These results are consistent regardless of drugs concentration, demonstrating that treatment does not exert a direct antimicrobial or stimulatory effectin vitroonA. fumigatusconidia growth, when exposed to actualin vivoCFTR modulators concentration.
Explicitly Nonlinear Connectivity-Matrix Independent Component Analysis in Resting fMRI Data
Authors: Motlaghian S. M. , Baker B. , Ford J. M. , Iraji A. , Miller R. , Preda A. , Van Erp T.G. , Calhoun V. D.
Published: August 2024

Independent component analysis (ICA) is a widely used data-driven technique for investigating brain structure and function to extract intrinsic networks. However, the ability of ICA, a linear mixing model, to capture nonlinear relationships is inherently limited. While nonlinear ICA can be used to estimate nonlinear+ linear mixtures, it can be useful to study the degree to which there is nonlinearity above and beyond the widely studied linear resting networks. Here, we propose a way to divide the data into sources exhibiting linear-only or explicitly nonlinear dependencies in resting functional magnetic resonance imaging (fMRI) data. Such an approach can be very informative as it allows us to evaluate the degree to which a given network might be linear, nonlinear, or both linear and nonlinear. Here, we present an enhanced connectivity-domain ICA approach, connectivity-matrix ICA, incorporating normalized mutual information (NMI) after canceling the linear effects to measure explicitly nonlinear (EN) relationships within voxel connectivity. This integration enables the identification of brain spatial maps that exhibit pronounced explicitly nonlinear dependencies while excluding linear relationships. By eliminating linear dependencies and utilizing NMI, we discover highly structured resting networks that conventional functional connectivity methods would typically overlook. The results indicate that several maps show only linear or EN relationships, and the rest of the components display both linear and nonlinear patterns. We categorized these maps as linear-only, EN-only, and linear-EN maps. We also evaluate differences in the identified networks in a schizophrenia dataset. A significant global difference has been discovered between schizophrenia and controls in some linear-EN maps, such as the frontal lobe. Moreover, the temporal lobe and thalamus display linear group differences, while the visual and motor cortex display global differences in nonlinear relationships as their primary driver of these disparities. In sum, our findings emphasize the significance of accounting for explicitly nonlinear dependencies in functional connectivity analysis and demonstrate the effectiveness of the extended cmICA approach in revealing previously unrecognized brain dynamics.
Fibroblastic FLT3L supports lymph node dendritic cells in the interfollicular niche
Authors: Lane Ryan S. , Wu Sunny Z. , Davidson Christopher , Byrne Ashley , Kayser Brandon D. , Huang Hejin , Williams Katherine , Fernandez Matthew , Jiang Jian , Zhang Juan , Asuncion Raymond , Decalf Jérémie , Roose-Girma Merone , Lee Wyne P. , McGinnis Lisa , Warming Soren , Stephenson William , Rost Sandra , Moussion Christine , Biancalani Tommaso , Müller Sören , Turley Shannon J.
Published: August 2024

Dendritic cell (DC) homeostasis is maintained in secondary lymphoid organs (SLOs) by Fms-like tyrosine kinase 3 ligand (FLT3L). The specific niche providing this DC growth factor within human and mouse SLOs is unclear. Here, we show that Gremlin1 (Grem1)-expressing lymph node fibroblastic reticular cells (FRCs) support DC homeostasis via provision of FLT3L. Grem1 FRCs co-localize with DCs and express FLT3L in human and mouse lymph nodes. Using a new genetic model, we provide evidence that FLT3L produced by GREM1 FRCs maintains lymph node preDCs, cDCs, and plasmacytoid DCs (pDCs). Spatial transcriptomics and cytofluorometry reveal that Grem1 FRC-derived FLT3L supports not only proliferation, but also survival of lymph node cDCs within the interfollicular zone (IFZ). Functionally, loss of Grem1 FRC-derived FLT3L impairs cDC priming of antigen-specific T cell responses. These findings provide key mechanistic insights underlying stromal cell support of DC homeostasis and function.
The symbiosis of healthcare professionals and patients: understanding the dynamics of long-term care relationships between healthcare professionals and patients in oncology
Authors: Chung Liam Il-Young , Ahadi Awranoos , Lee Grace , Jung Chan Mi , Chae Lena , Hong Ilene , Kang Grace , Jang Jessica , Park Brandon , Chae Young Kwang
Published: August 2024

Background

Chronic diseases are a significant source of physical, emotional, mental, and social distress to patients, caregivers, and healthcare professionals (HCPs). In particular, cancer patients face immense challenges as they navigate their uncertain futures. These difficulties necessitate a collaborative environment where patients, caregivers, and HCPs support each other to improve everyone’s quality of life. This study aims to investigate factors that influence a healthy long-term care relationship between patients and HCPs.

Methods

This qualitative study analyzes the experiences of the HCPs with patients and their caregivers at a large metropolitan academic medical center. Twenty-two de-identified reflective essays written by HCPs as part of the Pacemakers initiative at the medical center, which seeks to empower HCPs, patients, and caregivers in creative ways along the management journey were analyzed. The essays describe meaningful experiences, such as patient/caregiver award ceremonies celebrating resilience and hope. Essays (N= 22) were thematically analyzed by two independent coders to identify key codes and themes (italicized).

Results

The presence ofsupport networks(n= 10) was crucial for patients and caregivers.Conveying solidarity(n= 21) helped patients experience companionship with their medical team, family, and friends.Small acts of kindness(n= 10) led to meaningful interactions that encouraged patients.Compassion(n= 19) andpatient-centeredness(n= 17) fostered a receptive environment where patients and caregivers felt heard. Celebrating and honoring theresilience(n= 10) of the patients made them feel recognized, and this process of celebration was also found to bolster arenewed sense of purpose for the HCPs(n= 11).

Conclusion

The results highlight the importance of holistic support for patients and their caregivers. Creative encouragement empowers both patients and HCPs, building trust and strengthening the pursuit of their health. This mutual care fosters an environment conducive to healing and recovery. This study offers insights into effectively supporting patients and HCPs in long-term care relationships.
Novel non-invasive physical photobiomodulation can treat congenital colour vision deficiency and enhance color vision recognition ability: a randomized, single blind, controlled clinical trial
Authors: Bao Nandi , Jia Liang
Published: August 2024

Background

Color vision deficiency (CVD) is a common congenital ophthalmic disease, and there are no effective therapeutic measures currently available for this patient population. This study aimed to explore the efficacy of photobiomodulation (PBM) in CVD patients.

Methods

A randomized controlled trial design was applied in this study, whereby 80 patients with red-green CVD were randomly divided into PBM treatment and control groups. Color vision was assessed after 1, 2 and 4 weeks of treatment. Statistical analysis of treatment was carried out using the Kruskal-Wallis test with Dunn’s test for multiple comparisons using SPSS and R software.

Findings

Compared to the control group, the color vision of CVD patients exhibited a significant improvement in the PBM treatment group for different parameters (Ps□0.05).

Interpretation

PBM therapy could significantly improve color vision in patients with congenital CVD, especially in patients with green CVD.
The new role of carbonic anhydrases and bicarbonate in acclimatization and hypoxia stress responses inArabidopsis thaliana
Authors: Białas Alex , Dąbrowska-Bronk Joanna , Gawroński Piotr , Karpiński Stanisław
Published: August 2024

Plant growth and stress responses largely depend on the chloroplast retrograde signaling. Stoichiometry of carbon dioxide assimilation and transpiration, efficiency of photosynthesis, and absorbed energy fate in photosystems between photochemistry, fluorescence and heat channels impact on the chloroplast retrograde signaling. Recent studies revealed that 22 kDa photosystem II protein (PsbS) and plant β carbonic anhydrases (βCAs), except their obvious functions, are also involved in regulation of plant stress responses. Obtained results suggest that simultaneous overexpression ofβCA1and/orβCA2withPsbSgenes leads to improved photoprotection, acclimation to variable light conditions, and water use efficiency. However, this was achieved on the costs of lower biomass gain in double and triple (oePsbSoeβCA1 and oePsbSoeβCA1βCA2, respectively) transgenic lines in comparison to Col-0, andnpq4-1mutant. After bicarbonate fertilization we observed significant increase in biomass production in triple transgenic lines compared to oePsbS andnpq4-1plants, but not to Col-0. Transcriptomic analysis revealed that bicarbonate treatment of double and triple transgenic lines specifically induced expression of genes and transcription factors related to hypoxia, freezing, drought, high light, and pathogen attack stress responses, contrary to other genotypes. Interestingly, expression of two of these transcription factors, DREB - CBF2 subfamily (A-1 of ERF/AP2), and BT2 were reduced in oePsbStransgenic line. Our results suggest a novel regulatory role of βCAs and bicarbonate in the regulation of stress responses and plant productivity.
Persistent obesity since childhood or adolescence accelerates biological aging in young adults from Chile’s oldest birth cohort
Authors: Correa mP , Burrows R , Albala C , Sepúlveda C , Salech F , Troncoso R , Gonzalez-Billault C
Published: August 2024

Aging and obesity are primary risk factors for chronic conditions such as hypertension and diabetes. However, a mechanistic correlation between these risk factors has not been fully established. Using a historical birth cohort from Chile, we delve into the relationship between obesity and accelerated aging, spanning cellular to systemic levels. The cohort, comprising men and women in their late 20s, had their BMI recorded since birth, with 57% having obesity since childhood or adolescence. Our aim was to investigate if persistent obesity since childhood or adolescence leads to the display of molecular aging features in young adulthood. We also sought to determine whether cardiometabolic health issues accompanied this early aging phenotype. We used inferential statistics and data mining for analysis. Results show that persistent obesity since childhood or adolescence leads to epigenetic changes, telomere shortening, chronic inflammation, impaired nutrient sensing, mitochondrial stress, and diminished intercellular communication, resembling a compound network of interactions. This obesity-induced accelerated aging phenotype coincided with persistent decline of the cardiometabolic profile. Implications of our findings are significant and suggest that integrating molecular markers with clinical and epidemiological data could be valuable in identifying individuals at increased disease risk due to accelerated aging.
Plasma Short-Chain Fatty Acids and Hypertensive Disorders of Pregnancy: Results from a Nested Case-Control Study and Two-sample Mendelian Randomization Analysis
Authors: Wang Dandan , Wu Lei , Feng Pei , Sun Yexiu , Wu Di , Xu He , Peng Hao , Li Hongmei
Published: August 2024

Background

The temporal relationship between Short-chain fatty acids (SCFAs) and hypertensive disorders of pregnancy (HDP) is unclear. This study aimed to examine the temporal and probable causal relationship between them.

Methods

A nested case-control study including 387 pairs of cases with HDP and healthy controls was conducted. Seven SCFAs levels in plasma samples drawn at 16-20 gestational weeks before HDP were assayed by GC/MS. The individual and joint associations of SCFAs with HDP were examined by logistic regression and weighted quantile sum (WQS) regression, respectively, followed by two-sample bidirectional Mendelian randomization (MR) analysis to test the underlying causality.

Results

The univariate model found each interquartile increase in plasma valerate was associated with a 32.1% (OR=0.679, 95%CI=0.546-0.844) reduction in the risk of HDP, a 29.4%(OR=0.706, 95%CI=0.548-0.910) reduction in the risk of gestational hypertension (GH) and a 39.1% (OR=0.609, 95%CI=0.397-0.935) reduction in the risk of preeclampsia/chronic hypertension with superimposed preeclampsia (PE/CH-PE). However, after adjustment for covariates, valerate was only associated with the risk of HDP (OR=0.699, 95% CI=0.516-0.946). In addition, plasma isobutyrate and hexanoate were associated with lower risks of HDP and PE/CH-PE. Furthermore, SCFAs co-exposure could reduce the risks of HDP and GH. MR showed that plasma acetate (OR=0.784, 95%CI=0.64-0.962), valerate (OR=0.575, 95%CI=0.363-0.909) and isovalerate (OR=0.642, 95%CI=0.428-0.963) had protective causal effects on GH. Meanwhile, plasma acetate had protective causal effects on PE (OR=0.746, 95%CI=0.6-0.927).

Conclusions

The study suggested it is necessary to appropriately increase SCFAs levels during pregnancy to reduce the risk of HDP.
Placodiscus bijugus(Sapindaceae) a new species of Endangered lowland evergreen forest tree from the western foothills of Mt Cameroon and from Korup National Park, Cameroon
Authors: Gosline George , Ndam Nouhou , Cable Stuart , Cheek Martin
Published: August 2024

A new range-restricted species ofPlacodiscusRadlk. is described, mapped and illustrated.Placodiscus bijugusis a cauliflorous tree (4 –)5 – 10 m tall, characterised by having two pairs of leaflets, 1(– 2)-flowered cymules with minute bracts, a glabrous disk, pedicels 3 – 3.2 mm long and large (3 – 4 cm diam.), shortly stipitate, retuse fruits, orbicular in outline. It is similar toP. caudatusPierre ex Pellegr. which has been reported from surveys in Cameroon. We discuss the typification and range of the latter species which in fact appears to be absent from Cameroon.

Placodiscus bijugusis provisionally assessed as Endangered (EN B1ab(iii)+2ab(iii)) using the IUCN standard, since only three locations, with threats are reported. The species has a small, slightly range, disjunct between Mt Cameroon and Korup National Park in coastal SW region Cameroon. We review other species with this disjunct range.
Modelling medulloblastoma pathogenesis and treatment in human cerebellar organoids
Authors: Willott Thomas , Nicholson James G , Xiao Yunchen , Ogunbiyi Olumide , Mistry Talisa , Zabet Nicolae Radu , Merve Ashirwad , Badodi Sara , Marino Silvia
Published: August 2024

Faithful genetically engineeredin vivomodels of medulloblastoma (MB) are currently available only for some molecular subgroups, in keeping with recent studies showing the unique role of human-specific progenitors in the development of G3 and G4 MB subgroups. We generated human cerebellar organoids (CbO) from expanded potential stem cells (EPSC) and characterised in depth their epigenetic and transcriptomic profile. We show the presence of sub compartment-specific cerebellar lineages linked to MB formation, including populations expressing signature genes of G3 and G4 MB cells-of-origin in a 1 month-old CbO. Moreover, we demonstrate that CbO sustains MB cells proliferation and invasion in a 3D co-culture model (CbO-MB) while preserving their molecular identity, and that treatment of CbO-MB with anti-tumour compounds recapitulate the efficacy ofin vivodrug testing in PDX models.

Graphical Abstract
Evolutionary Measures Show that Recurrence of DCIS is Distinct from Progression to Breast Cancer
Authors: Fortunato Angelo , Mallo Diego , Cisneros Luis , King Lorraine M. , Khan Aziz , Curtis Christina , Ryser Marc D. , Lo Joseph Y. , Hall Allison , Marks Jeffrey R. , Hwang E. Shelley , Maley Carlo C.
Published: August 2024

Progression from pre-cancers like ductal carcinomain situ(DCIS) to invasive disease (cancer) is driven by somatic evolution and is altered by clinical interventions. We hypothesized that genetic and/or phenotypic intra-tumor heterogeneity would predict clinical outcomes for DCIS since it serves as the substrate for natural selection among cells. We profiled two samples from two geographically distinct foci from each DCIS in both cross-sectional (N = 119) and longitudinal cohorts (N = 224), with whole exome sequencing, low-pass whole genome sequencing, and a panel of immunohistochemical markers. In the longitudinal cohorts, the only statistically significant predictors of time to non-invasive DCIS recurrence were the combination of treatment (lumpectomy only vs mastectomy or lumpectomy with radiation, HR = 12.13,p= 0.003, Wald test with FDR correction), ER status (HR = 0.16 for ER+ compared to ER-,p= 0.0045), and divergence in SNVs between the two samples (HR = 1.33 per 10% divergence,p= 0.018). SNV divergence also distinguished between pure DCIS and DCIS synchronous with invasive disease in the cross-sectional cohort. In contrast, the only statistically significant predictors of time to progression to invasive disease were the combination of the width of the surgical margin (HR = 0.67 per mm,p= 0.043) and the number of mutations that were detectable at high allele frequencies (HR = 1.30 per 10 SNVs,p= 0.02). These results imply that recurrence with DCIS is a clinical and biological process different from invasive progression.

Significance

Evolutionary measures of breast pre-cancers associate with local recurrence after surgery, as well as progression to cancer. Recurrence and progression are different biological processes impacted differently by clinical interventions.
Acceptance of an Mpox Vaccine in the Democratic Republic of the Congo
Authors: Petrichko Skylar , Kindrachuk Jason , Nkamba Dalau , Halbrook Megan , Merritt Sydney , Kalengi Handdy , Kamba Leonard , Beya Michael , Hoff Nicole A. , Luhata Christophe , Kaba Didine K. , Rimoin Anne W.
Published: August 2024

We report general acceptance of an mpox vaccine (61.0%) in the Democratic Republic of the Congo (n = 5226) with higher acceptance among healthcare workers and respondents in historic mpox-endemic regions. These data highlight the need for increased community engagement and sensitization before widespread deployment of mpox vaccines.
Peer Education Intervention Reduced Sexually Transmitted Infections Among Male Tajik Labor Migrants Who Inject Drugs: Results of a Cluster-randomized Controlled Trial
Authors: Mackesy-Amiti Mary Ellen , Levy Judith A. , Luc Casey M. , Jonbekov Jonbek
Published: August 2024

Background

In a cluster-randomized controlled trial, the “Migrants’ Approached Self-Learning Intervention in HIV/AIDS for Tajiks” (MASLIHAT) reduced intervention participants’ sexual risk behaviour including any condomless sex, condomless sex with female sex workers, and multiple sexual partners. This analysis investigates if observed changes in sexual risk behaviors translated into fewer reported STIs among participants over 12-month follow-up.

Methods

The MASLIHAT intervention was tested in a cluster-randomized controlled trial with sites assigned to either the MASLIHAT intervention or comparison health education training (TANSIHAT). Participants and network members (n=420) were interviewed at baseline and 3-month intervals for one year to assess HIV/STI sex and drug risk behaviour. We conducted mixed effects robust Poisson regression analyses to test for differences between conditions in self-reported STIs during 12 months of follow-up, and to test the contribution of sexual risk behaviours to STI acquisition. We then tested the mediating effects of sexual behaviours during the first six months following the intervention on STIs reported at the 9 and 12-month follow-up interviews.

Results

Participants in the MASLIHAT condition were significantly less likely to report an STI during follow-up (IRR=0.27, 95% CI 0.13-0.58). Condomless sex with a non-main (casual or commercial) partner was significantly associated with STI acquisition (IRR=2.30, 95% CI 1.26-4.21). Adjusting for condomless sex with a non-main partner, the effect of MASLIHAT intervention participation was reduced (IRR=0.36, 95% CI 0.16-0.80), signalling possible mediation. Causal mediation analysis indicated that the intervention’s effect on reported STI was partially mediated by reductions among MASLIHAT participants in condomless sex with a non-main partner.

Conclusions

The MASLIHAT peer-education intervention reduced reported STIs among Tajik labour migrants partly through reduced condomless sex with casual and commercial partners.

Clinical trial registration

ClinicalTrials.gov, 2021-04-16,NCT04853394.
Implementation and adaptation of WASH FIT in healthcare facilities: A systematic scoping review
Authors: Kpodzro Sena , Cronk Ryan , Lineberger Hannah , Lansing Lauren , Anderson Darcy M.
Published: August 2024

Environmental health services (e.g., water, sanitation, hygiene, energy) are important for patient safety and strong health systems, yet services in many low- and middle-income countries are poor. To address this, the World Health Organization (WHO) and the United Nations Children’s Fund (UNICEF) developed the Water and Sanitation for Health Facility Improvement Tool (WASH FIT) to drive improvements. While widely used, there is currently no systematic documentation of how WASH FIT has been adapted in different contexts and the implications of these adaptations. We conducted a systematic scoping review to assess WASH FIT adaptation and implementation, specifically evaluating context and implementing stakeholders, the WASH FIT process and adaptation, and good practices for implementation. Our search yielded 20 studies. Implementation was typically government-led or had a high level of government engagement. Few details on healthcare facility contexts were reported. Adaptation was widespread, with nearly all studies deviating from the five-step WASH FIT cycle as designed in the WHO/UNICEF manual. Notably, many studies conducted only one facility assessment and one or no rounds of improvement. However, reporting quality across studies was poor, and some steps may have been conducted but not reported. Despite substantial deviations, WASH FIT was favorably described by all studies. Good practices for implementation included adequate resourcing, government leadership, and providing WASH FIT teams with sufficient training and autonomy to implement improvements. Low-quality reporting and a high degree of adaptation make it challenging to determine how and why WASH FIT achieves change. We hypothesize that healthcare-facility level action by WASH FIT teams to assess conditions and implement improvements has some effect. However, advocacy that uses WASH FIT indicators to highlight deficiencies and promotion of WASH FIT by WHO and UNICEF to pressure governments to act may be equally or more powerful drivers of change. More rigorous evidence to understand how and why WASH FIT works is essential to improve its performance and inform scale-up.

Highlights

Adaptation in WASH FIT programs is common but not always evidence-based

Some programs initiate WASH FIT assessments but never implement improvements

Some programs complete one round of improvements but never iterate the WASH FIT cycle

Low-quality evidence impedes research to identify WASH FIT’s theory of change

WASH FIT may drive change through national advocacy and peer pressure to unlock funding
Quantifying the intangible: Evidence from Nigeria on the impact of supervision, autonomy, and management practices on PHC performance in the context of Direct Facility Financing
Authors: Hagedorn Brittany , Loevinsohn Benjamin , Odutolu Oluwole
Published: August 2024

Previous studies have shown that facility autonomy, especially control over budget allocation, can have a modest positive effect on performance, but the findings depend on the context. Similarly, management practices are often cited as important contributors to facility performance, but the evidence is limited and usually qualitative. Data from the large-scale randomized evaluation of the Nigeria States Health Investment Project (NSHIP) offers an opportunity to quantitatively examine these relationships in the context of a lower middle-income country. We utilize non-parametric statistics to test for difference in means and apply regression analysis to test the hypothesis that autonomy and management affected facility performance. Our results show that facilities with greater autonomy, more budget control, and better management practices generally outperform their peers on a range of facility readiness and service delivery measures. For example, regression results found that facilities with high autonomy held on average 2.1 more outreach sessions per month than those without, and facilities with an annual business plan offered 1.8 additional outreach services. Supervision practices, such as more frequent visits and use of a quantitative checklist, are associated with 26% higher productivity and up to a 28.6% increase in equipment availability (percentage points), respectively. We conduct sensitivity analyses on our variable selection and use a random forest approach to validate that results are robust to changes in the model structure. We conclude that facility-level autonomy and especially budget control can improve primary healthcare facility readiness and service availability, even in resource-constrained contexts, Further, this can be achieved through good management practices that are reinforced through supportive supervision and routine performance monitoring to maximize the gains that result from incremental financing. This shows that these policies and practices can be critical contributors to efficiently achieving the goals of universal healthcare policies in the context of limited resources.
Chemotherapy causes a reversible decrease inVMP1/MIR21DNA methylation in granulocytes from breast cancer survivors
Authors: Abrahamsen Marie-Louise , Jachowicz Zuzanna , Buch-Larsen Kristian , Marina Djordje , Andersson Michael , Schwarz Peter , Dela Flemming , Gillberg Linn
Published: August 2024

Background

DNA methylation alterations within theVMP1/MIR21gene region, a potential epigenetic biomarker of systemic inflammation, have been demonstrated in mononuclear blood cells from early breast cancer (BC) patients after chemotherapy. Whether these changes are present in granulocytes, persist in the years after treatment, and affectVMP1orMIR21gene expression, remains unknown.

Aim

We aimed to investigate whether adjuvant chemotherapy alters the DNA methylation and gene expression ofVMP1/MIR21in granulocytes from postmenopausal BC patients and, if so, whether these treatment-induced changes are reversible in the first two years after completed chemotherapy.

Methods

Whole blood samples were obtained from 30 postmenopausal BC patients before chemotherapy and every six months for two years, and from 10 healthy age- and BMI-matched controls. DNA and RNA was extracted from isolated granulocytes, and DNA methylation of four CpG sites located in the gene body ofVMP1, which is situated in the promoter region ofMIR21, was assessed through bisulfite pyrosequencing. qPCR was used for assessment ofVMP1andMIR21expression.

Results

VMP1/MIR21was significantly demethylated in granulocytes from BC patients shortly after completed chemotherapy compared to before (10 percentage points decrease,p<0.0001). Six months thereafter, DNA methylation values were significantly increased (6 percentage points, p = 0.002), and they were further increased to pre-chemotherapy levels 12, 18 and 24 months post chemotherapy. Chemotherapy did not cause significant changes in the expression ofVMP1orMIR21.

Conclusion

The unique follow-up samples in this study demonstrated that chemotherapy induced a transient reduction in DNA methylation of theVMP1/MIR21region in granulocytes from postmenopausal BC patients. Although transient, chemotherapy-induced epigenetic changes in blood cells may contribute to the increased risk of inflammatory-related comorbidities in BC survivors.
Cappable-Seq reveals the transcriptional landscape of stress responses in the bacterial endosymbiontWolbachia
Authors: Suliman Youseuf , Li Zhiru , Sinha Amit , Dyer Philip D. , Hartley Catherine S. , Darby Alistair C. , Carlow Clotilde K. , Makepeace Benjamin L.
Published: August 2024

Bacterial endosymbionts are highly prevalent among invertebrate animals, in which they can confer fitness benefits such as pathogen defence and/or act as reproductive manipulators, inducing phenotypes including cytoplasmic incompatibility (CI). For the alpha-proteobacteriumWolbachia, its wide distribution among macroparasites and disease-transmitting arthropods coupled with mutualistic roles, reduction of vector competence, and CI have found recent applications in the control of several vector-borne tropical diseases. However, in common with other bacterial endosymbionts, which often lose regulatory elements during genomic erosion, the degree to whichWolbachiacan respond to environmental or pharmacological stressors is poorly understood. Here, we apply Cappable-Seq methodology to achieve unprecedented depth and resolution of transcriptional start sites (TSS) in twoWolbachiastrains (wMelPop-CLA andwAlbB) that have been used to transinfect mosquitoes for arbovirus control. We exposedWolbachiain mosquito cell lines to temperature stress (both strains) or antibiotics (wAlbB only) and observed that all classes of TSS (including antisense) exhibited differential regulation, some of which were associated with mobile elements and may control ncRNA expression. Cappable-Seq also resolved the organisation of the bicistroniccifA/cifBoperon that is responsible for inducing CI inWolbachiahosts and shows great promise for revealing regulation of symbiont functions in whole invertebrates.
HSP90 interacts with VP37 to facilitate the cell-to-cell movement of broad bean wilt virus 2
Authors: Kim Myung-Hwi , Jang Seok-Yeong , Choi Ji-Soo , Kim Sora , Lee Yubin , Park Suejin , Kwon Sun-Jung , Seo Jang-Kyun
Published: August 2024

The systemic spread of viruses in plants requires successful viral cell-to-cell movement through plasmodesmata (PD). Viral movement proteins (MPs) interact with cellular proteins to modify and utilize host transport routes. Broad bean wilt virus 2 (BBWV2), a widespread plant RNA virus, moves from cell to cell as a virion through the PD gated by VP37, the MP of BBWV2. However, the host proteins that function in the cell-to-cell movement of BBWV2 remain unclear. In this study, we identified cellular heat shock protein 90 (HSP90) as an interacting partner of VP37. The interaction between HSP90 and VP37 was assessed using the yeast two-hybrid assay, co-immunoprecipitation, and bimolecular fluorescence complementation. Tobacco rattle virus-based virus-induced gene silencing analysis revealed thatHSP90silencing significantly inhibited the systemic spread of BBWV2 inN. benthamianaplants. Furthermore,in plantatreatment with geldanamycin (GDA), an inhibitor of the chaperone function of HSP90, demonstrated the necessity of HSP90 in successful cell-to-cell movement and systemic infection of BBWV2. Interestingly, GDA treatment inhibited the HSP90-VP37 interaction at the PD, resulting in the inhibition of VP37-derived tubule formation through the PD. Our results suggest that the HSP90-VP37 interaction regulates VP37-derived tubule formation through the PD, thereby facilitating the cell-to-cell movement of BBWV2.

IMPORTANCE

This study highlights the regulatory role of heat shock protein 90 (HSP90) in facilitating the cell-to-cell movement of broad bean wilt virus 2 (BBWV2). HSP90 interacted with VP37, the movement protein of BBWV2, specifically at plasmodesmata (PD). This study demonstrated that the HSP90-VP37 interaction is crucial for viral cell-to-cell movement and the formation of VP37-derived tubules, which are essential structures for virus transport through the PD. The ATP-dependent chaperone activity of HSP90 is integral to this interaction, as demonstrated by the inhibition of virus movement upon treatment with geldanamycin (GDA), which disrupts the function of HSP90. These findings elucidate the molecular mechanisms underlying the cell-to-cell movement of plant viruses, and highlight the role of HSP90 in viral infection. This study suggests that the chaperone activity of HSP90 may function in changing the conformational structure of VP37, thereby facilitating the assembly and function of virus-induced structures required for viral cell-to-cell movement.
Serum Amyloid P Secreted by Bone Marrow Adipocytes Drives Skeletal Amyloidosis
Authors: Kumar Surendra , Song Kangping , Wang Jiekang , Baghel Meghraj Singh , Wong Philip , Cao Xu , Wan Mei
Published: August 2024

The accumulation of amyloid fibrils has been identified in tissues outside the brain, yet little is understood about the formation of extracerebral amyloidosis and its impact on the aging process of these organs. Here, we demonstrate that both transgenic mice modeling Alzheimer’s disease (AD) and naturally aging mice exhibit accumulated senescent bone marrow adipocytes (BMAds), accompanied by amyloid deposits surrounding the BMAds. Senescent BMAds acquire a secretory phenotype, resulting in a marked increase in the secretion of serum amyloid P component (SAP), also known as pentraxin 2 (PTX2). SAP/PTX2 colocalizes with amyloid deposits around senescent BMAdsin vivoand is sufficient to promote the formation of insoluble amyloid deposits from soluble Aβ peptides inin vitroandex vivo3D BMAd-based culture experiments. Additionally, Combined treatment with SAP/PTX2 and Aβ peptides promotes osteoclastogenesis but inhibits osteoblastogenesis of the precursor cells. Transplantation of senescent BMAds into the bone marrow cavity of healthy young mice is sufficient to induce bone loss. Finally, pharmacological depletion of SAP/PTX2 from aged mice abolishes bone marrow amyloid deposition and effectively rescues the low bone mass phenotype. Thus, senescent BMAds, through the secretion of SAP/PTX2, contribute to the age-associated development of skeletal amyloidosis and resultant bone deficits.
Membrane tension regulation is required for wound repair
Authors: Raj Nikita , Weiss Martin , Vos Bart E. , Weischer Sarah , Brinkmann Frauke , Betz Timo , Trappmann Britta , Gerke Volker
Published: August 2024

Disruptions of the eukaryotic plasma membrane due to chemical and mechanical challenges are frequent and detrimental, and thus need to be repaired to maintain proper cell function and avoid cell death. However, the cellular mechanisms involved in wound resealing and restoration of homeostasis are diverse and contended. Here, we show that clathrin-mediated endocytosis is induced at later stages of plasma membrane wound repair following the actual resealing of the wound. This compensatory endocytosis occurs near the wound, predominantly at sites of previous early endosome exocytosis which is required in the initial stage of membrane resealing, suggesting a spatio-temporal co-ordination of exo- and endocytosis during wound repair. Using cytoskeletal alterations and modulation of membrane tension and membrane area, we identify membrane tension as a major regulator of the wounding-associated exo- and endocytic events that mediate efficient wound repair. Thus, membrane tension changes are a universal trigger for plasma membrane wound repair modulating the exocytosis of early endosomes required for resealing and subsequent clathrin-mediated endocytosis acting at later stages to restore cell homeostasis and function.