bluuebunny/crossref_metadata_2025 huggingface dataset:
Tip orientation under real-time point-of-care neck ultrasonic monitoring is advantageous in peripherally inserted central catheter procedures: a retrospective cohort study
Authors: Liu Shuiqing , Jiang Shaowei , Ma Jing , Qian Feng , Gao Chengjin
Published: May 2023

Background

We analyzed the success and catheter tip malposition rates of peripherally inserted central catheter (PICC) placement using ultrasonic monitoring.

Methods

A total of 564 patients were recruited and assigned to either the intervention or control group. In the intervention group, 282 patients underwent ultrasound-guided PICC insertion, which helped to identify the position and depth of the catheter tip. From a total of 9000 patients, 282 were selectively chosen to receive the traditional method using body surface measurements (control group). The primary endpoint was the success rate; the secondary endpoint was the catheter tip malposition rate as detected by postprocedure chest radiography.

Results

In the intervention group, a total of 94 catheters were in a suboptimal position; 26 were too deep, 68 were too shallow, and 1 was inserted into the subclavian vein, with success and malposition rates of 66.3% and 0.4%, respectively. In the control group, 139 catheters were in a suboptimal position; 88 were too deep, 51 were too shallow, 9 were inserted into the jugular vein, and 2 were inserted into the subclavian vein, with success and malposition rates of 46.8% (P < 0.001) and 3.9% (P = 0.004), respectively. Significant differences were observed in success and malposition rates between the 2 groups.

Conclusion

Ultrasound-guided PICC procedures achieved higher success rates and lower malposition rates.
Cardiopulmonary haemodynamic effects and gas exchange during apnoeic oxygenation with high-flow and low-flow nasal oxygen
Authors: Forsberg Ida-Maria , Al-Saadi Jonathan , Sjöblom Albin , Grape Lisa , Petersson Johan , Lundberg Johan , Lodenius Ase , Eriksson Lars I. , Fagerlund Malin Jonsson
Published: May 2023

BACKGROUND

Apnoeic oxygenation with high-flow nasal oxygen prolongs the safe apnoeic period during induction of general anaesthesia. However, central haemodynamic effects and the characteristics of central gaseous exchange remain unexplored.

OBJECTIVE

To describe mean pulmonary arterial pressure along with arterial and mixed venous blood gases and central haemodynamic parameters during apnoeic oxygenation with low-flow and high-flow nasal oxygen in pigs.

DESIGN

Experimental crossover study.

SETTING

Animal study of 10 healthy Swedish landrace pigs at Karolinska Institutet, Sweden, April–May 2021.

INTERVENTION

The pigs were anaesthetised, their tracheas intubated and their pulmonary arteries catheterised. The animals were preoxygenated and paralysed before apnoea. Apnoeic periods between 45 and 60 min were implemented with either 70 or 10 l min−1 100% O2 delivered via nasal catheters. In addition, seven animals underwent an apnoea without fresh gas flow. Cardiopulmonary parameters and blood gases were measured repeatedly.

MAIN OUTCOME MEASURES

Mean pulmonary arterial pressure during apnoeic oxygenation with high-flow and low-flow oxygen.

RESULTS

Nine pigs completed two apnoeic periods of at least 45 min with a P
aO2 not lower than 13 kPa. The mean pulmonary arterial pressure increased during 45 min of apnoea, from 18 ± 1 to 33 ± 2 mmHg and 18 ± 1 to 35 ± 2 mmHg, at 70 and 10 l min−1 O2, respectively (P < 0.001); there was no difference between the groups (P = 0.87). The P
aCO2 increased by 0.48 ± 0.07 and 0.52 ± 0.04 kPa min−1, at 70 and 10 l min−1 O2, respectively; there was no difference between the groups (P = 0.22). During apnoea without fresh gas flow, the SpO2 declined to less than 85% after 155 ± 11 s.

CONCLUSION

During apnoeic oxygenation in pigs, the mean pulmonary arterial pressure increased two-fold and P
aCO2 five-fold after 45 min, while the arterial oxygen levels were maintained over 13 kPa, irrespective of high-flow or low-flow oxygen.
Overexpression of microRNA-93-5p and microRNA-374a-5p Suppresses the Osteogenic Differentiation and Mineralization of Human Aortic Valvular Interstitial Cells Through the BMP2/Smad1/5/RUNX2 Signaling Pathway
Authors: Liu Cuiying , Zhang Yajie , Guo Jing , Sun Wei , Ji Yue , Wang Yaqing , Liu Jing , Kong Xiangqing
Published: May 2023

Aortic valve calcification commonly occurs in patients with chronic kidney disease (CKD). However, the regulatory functions of microRNAs (miRNAs/miRs) in the osteogenic differentiation of human aortic valvular interstitial cells (hAVICs) in patients with CKD remain largely unknown. This study aimed to explore the functional role and underlying mechanisms of miR-93-5p and miR-374a-5p in the osteogenic differentiation of hAVICs. For this purpose, hAVICs calcification was induced with high-calcium/high-phosphate medium and the expression levels of miR-93-5p and miR-374a-5p were determined using bioinformatics assay. Alizarin red staining, intracellular calcium content, and alkaline phosphatase activity were used to evaluate calcification. The expression levels of bone morphogenetic protein-2 (BMP2), runt-related transcription factor 2 (Runx2), and phosphorylated (p)-Smad1/5 were detected by luciferase reporter assay, reverse transcription-quantitative polymerase chain reaction (RT-qPCR), and western blot analysis. The results revealed that the expression levels of miR-93-5p and miR-374a-5p were significantly decreased in hAVICs in response to high-calcium/high-phosphate medium. The overexpression of miR-93-5p and miR-374a-5p effectively suppressed the high-calcium/high-phosphate–induced calcification and osteogenic differentiation makers. Mechanistically, the overexpression of miR-93-5p and miR-374a-5p inhibits osteogenic differentiation by regulating the BMP2/Smad1/5/Runx2 signaling pathway. Taken together, this study indicates that miR-93-5p and miR-374a-5p suppress the osteogenic differentiation of hAVICs associated with calcium–phosphate metabolic dyshomeostasis through the inhibition of the BMP2/Smad1/5/Runx2 signaling pathway.
Closed Incision Negative Pressure Therapy in Oncoplastic Surgery Prevents Delays to Adjuvant Therapy
Authors: Ockerman Kyle M. , Bryan Jaimie , Wiesemann Gayle , Neal Dan , Marji Fady P. , Heath Frederik , Kanchwala Suhail , Oladeru Oluwadamilola , Spiguel Lisa , Sorice-Virk Sarah
Published: May 2023

Background:

Breast reductions, including oncoplastic breast surgery (OBS), have high postoperative wound healing complication (WHC) rates, ranging from 17% to 63%, thus posing a potential delay in the onset of adjuvant therapy. Incision management with closed incision negative pressure therapy (ciNPT) effectively reduces postoperative complications in other indications. This retrospective analysis compares postoperative outcomes and delays in adjuvant therapy in patients who received ciNPT on the cancer breast versus standard of care (SOC) after oncoplastic breast reduction and mastopexy post lumpectomy.

Methods:

Patient demographics, ciNPT use, postoperative complication rates, and time to adjuvant therapy were analyzed from the records of 150 patients (ciNPT = 29, SOC = 121). Propensity score matching was used to match patients based on age, body mass index, diabetes, tobacco use, and prior breast surgery.

Results:

In the matched cohort, the overall complication rate of ciNPT-treated cancerous breasts was 10.3% (3/29) compared with 31% (9/29) in SOC-treated cancerous breasts (P = 0.096). Compared with the SOC-treated cancerous breasts, the ciNPT breasts had lower skin necrosis rates [1/29 (3.4%) versus 6/29 (20.7%); P = 0.091] and dehiscence rates [0/29 (0%) versus 8/29 (27.6%); P = 0.004]. In the unmatched cohort, the total number of ciNPT patients who had a delay in adjuvant therapy was lower compared to the SOC group (0% versus 22.5%, respectively; P = 0.007).

Conclusion:

Use of ciNPT following oncoplastic breast reduction effectively lowered postoperative wound healing complication rates and, most importantly, decreased delays to adjuvant therapy.
Treatment Protocol on Using Microfocused Ultrasound with Visualization for Skin Quality Improvement: The Korean Experience
Authors: Park Je-Young , Youn Seongjae , Hong Wonkyu , Lee Kyou Chae , Kim Inyong
Published: May 2023

Facial skin quality profoundly influences an individual’s perceived appearance and is an important aspect of facial rejuvenation. Facial pore enlargement is one of the most common concerns among Asian individuals that adversely impacts perceived skin surface evenness and affects overall skin quality. One of the major causes of enlarged pores is facial skin laxity. Microfocused ultrasound with visualization (MFU-V; Ultherapy; Merz North America, Inc., Raleigh, N.C.) is indicated for lifting and tightening of the face and neck, and improving the appearance of wrinkles on the décolletage. In addition, it is useful for addressing several aspects of facial rejuvenation, including facial pores, skin laxity, skin unevenness, etc., but there is limited literature on these applications. Thus, we present our proposed MFU-V treatment protocol for achieving a harmonious outcome for attractive skin, along with practical strategies for its application, illustrated in patients presenting with enlarged pores as their main concern. Drawing on our collective experience in using MFU-V for facial rejuvenation and the recently published skin quality framework that advocates addressing interrelated attributes of skin quality for optimal outcomes, we developed a treatment protocol for improving skin quality using MFU-V. This MFU-V treatment protocol reliably improves overall skin quality in patients presenting with enlarged pores, through MFU-V’s effects on skin lifting and tightening, and consequent improvement in facial pores and skin texture. This treatment protocol can be readily used as part of a multimodal layering approach to yield successful outcomes in patients with various facial skin concerns.
Ptotic versus Nonptotic Breasts in Nipple-sparing Mastectomy and Immediate Prepectoral Breast Reconstruction
Authors: Ostapenko Edvin , Nixdorf Larissa , Devyatko Yelena , Exner Ruth , Math Pia , Wimmer Kerstin , Haeusler Theresa , Fitzal Florian
Published: May 2023

Background:

In recent years, nipple-sparing mastectomy followed by implant-based breast reconstruction has gained popularity due to improved cosmetic and psychological benefits. However, patients with ptotic breasts remain the main challenge for surgeons, owing to the potential risk of postoperative complications.

Methods:

A retrospective chart review was performed for patients who underwent nipple-sparing mastectomy and prepectoral implant-based breast reconstruction between March 2017 and November 2021. Patient demographics, incidence of complications, and quality of life assessed using the BREAST-Q questionnaire were compared between the two different incisions [inverted-T for ptotic versus inframammary fold (IMF) for nonptotic breasts].

Results:

A total of 98 patients were examined: 62 in the IMF cohort and 36 in the inverted-T cohort. The results demonstrated equivalence in the safety metrics between the two groups, including hematoma (p=0.367), seroma (p=0.552), infection (P = 1.00), skin necrosis (P = 1.00), local recurrence (P = 1.00), implant loss (P = 0.139), capsular contracture (P = 1.00), and nipple-areolar complex necrosis (P = 0.139). The BREAST-Q scores were equally high in both groups.

Conclusion:

Our results suggest that inverted-T incision for ptotic breasts is a safe modality with similar complication rates and high aesthetic results compared with IMF incision for nonptotic breasts. A higher rate of nipple-areolar complex necrosis in the inverted-T group, although not significant, should be considered during careful preoperative planning and patient selection.
Telemonitoring Wound Recovery with Smartphone: An Italian Experience during Pandemic Period
Authors: Gesuete Francesco Paolo , Molle Marcello , Gubitosi Adelmo , Izzo Sara , Todde Salvatore , Nicoletti Giovanni Francesco , Ferraro Giuseppe Andrea
Published: May 2023

An important problem of plastic surgeons is monitoring wound healing, loss of substance, and postsurgical scar in different pathologies of the skin. Face to face monitoring is expensive and cannot be performed in periods of social crisis such as the recent COVID-19 pandemic. The use of telemedicine techniques is rising in this field of healthcare, promising the same results as the standard follow-up with more flexibility and savings. The purpose of this case study was to evaluate the effectiveness of remote monitoring and treatment through remote follow-up using digital applications. We followed up 25 patients with postoperative or diabetic ulcers for a period of 6 months (ranging from 2 to 6 months). We have performed clinical assessments using the Scar Cosmesis Assessment and Rating scale, and we have measured patient satisfaction using questionnaires. We chose to use the application for smartphone, describing the types of ulcers, number and average consultations, and the type of recovery, whether partial or complete. Monitoring wound recovery was very easy, and the patients found the experience very satisfactory. The total number of consultations was 255 with a significant reduction in outpatient visits during the pandemic period. Telemedicine is a useful tool in wound management and can be used to provide an optimal health care service with no inferior results to standard care.
Meningococcal Purpura Fulminans After Rectal Sexual Intercourse in Men Having Sex With Men
Authors: Bush Larry M. , Patel Janak B. , Byrd Lauren , Wilson Danielle D.
Published: May 2023

Over the past few decades, the incidence of meningococcal disease in the United States has been steadily declining and has reached historic lows. Much of this decrease in numbers of cases is attributed to the effectiveness and acceptance of immunization with conjugate meningococcal vaccines. Although the Advisory Committee on Immunization Practices has expanded its recommendation for vaccination to include all persons older than 2 years with HIV infection, uninfected men who have sex with men (MSM) without other underling conditions have never been singled out for vaccination. However, outbreaks of invasive meningococcal infection in MSM have been reported in recent years, including the largest and most recent one in Florida. The increased rate of urogenital and anorectal colonization with Neisseria meningitidis in MSM and risk of sexual transmission suggests that MSM, regardless of HIV status, should also be vaccinated against meningococcal disease.
Exploring Parents' Perceptions of an Early Intervention for Toddlers With Autism
Authors: Amsbary Jessica , Able Harriet
Published: May 2023

Early intervention (EI) services are intended to be delivered in a family-centered manner. Thus, it is important to obtain family perspectives as they relate to implementation experiences in EI. Using an implementation science framework to guide the questioning. Twelve interviews were conducted with parents who participated in 1 EI program to explore their perceptions of challenges and successes around the intervention practice components, parent coaching processes, and contextual factors in which the intervention was delivered. Parents perceived many of the aspects of the intervention such as specific strategies, strong relationships with their interventionists, and intervention delivery in home and clinic settings as useful and beneficial. They reported challenges related to embedding the intervention into daily activities, feelings of discomfort when practicing intervention strategies, and struggles with scheduling sessions. Implications for research and practice are discussed.
Level of Overestimation Among Dutch Recreational Skiers: Unskilled Tourists in the Mountains
Authors: Luppino Floriana , van Diepen Merel , den Hollander-Gijsman Margien , Bartlema Kornelis , Dekker Friedo
Published: May 2023

Objective:

To examine the level of overestimation (LO), associated factors, and identify the group of severe overestimators, among recreational skiers.

Design:

Cross-sectional observational study.

Setting:

An intermediate difficulty slope in an artificial snow indoor ski hall, and one in the mountains (Flachau, Austria).

Participants:

Dutch recreational skiers.

Independent Variables:

Participants were asked to rate themselves (SRSS, self-reported skill score). While skiing downhill they were objectively evaluated by 2 expert assessors (OSS, observed skill score). Potential associated factors and predictors for severe overestimation were assessed by a questionnaire.

Main outcome measures:

The LO, calculated by subtracting the OSS from the SRSS, was categorized into “no,” “mild,” and “severe.” Potential differences between these groups were analyzed, and regression analyses were performed to identify the factors associated with severe overestimation. To construct a profile of severe overestimators, the dataset was stratified based on 3 variables.

Results:

Overestimation was largely present (79.8%), and was severe in 32%. The LO decreased toward the more skilled skiers. Severe overestimators were mainly male, skied the least hours per day, were more avoidant, and showed the highest proportions of beginners and slightly advanced skiers. The profile of “severe overestimator” is characterized by physically unprepared males, avoidant for certain weather circumstances.

Conclusions:

Overestimation among recreational Dutch skiers is largely present, particularly among physically unprepared males, avoidant of certain snow and weather conditions. These features may function as a proxy to identify “severe overestimators” in comparable populations. Preventive strategies should focus to increase awareness particularly among these subjects.
MHC Class I Masking to Prevent AMR in a Porcine Kidney Transplantation Model in Alloimmunized Recipients
Authors: Kervella Delphine , Branchereau Julien , Prudhomme Thomas , Nerrière-Daguin Véronique , Renaudin Karine , Minault David , Hervouet Jérémy , Martinet Bernard , Bruneau Sarah , Le Bas-Bernardet Stéphanie , Blancho Gilles
Published: May 2023

Background:

Presensitized patients awaiting a kidney transplant have a lower graft survival and a longer waiting time because of the limited number of potential donors and the higher risk of antibody-mediated rejection (AMR), particularly in the early posttransplant period, because of preformed donor-specific antibodies binding major histocompatibility complex (MHC) molecules expressed by the graft endothelium followed by the activation of the complement. Advances in kidney preservation techniques allow the development of ex vivo treatment of transplants. We hypothesized that masking MHC ex vivo before transplantation could help to prevent early AMR in presensitized recipients. We evaluated a strategy of MHC I masking by an antibody during ex vivo organ perfusion in a porcine model of kidney transplantation in alloimmunized recipients.

Methods:

Through the in vitro calcein-release assay and flow cytometry, we evaluated the protective effect of a monoclonal anti–swine leukocyte antigen class I antibody (clone JM1E3) against alloreactive IgG complement-dependent cytotoxicity toward donor endothelial cells. Kidneys perfused ex vivo with JM1E3 during hypothermic machine perfusion were transplanted to alloimmunized recipients.

Results:

In vitro incubation of endothelial cells with JM1E3 decreased alloreactive IgG cytotoxicity (mean complement-dependent cytotoxicity index [% of control condition] with 1 µg/mL 74.13% ± 35.26 [calcein assay] and 66.88% ± 33.46 [cytometry]), with high interindividual variability. After transplantation, acute AMR occurred in all recipients on day 1, with signs of complement activation (C5b-9 staining) as soon as 1 h after transplantation, despite effective JM1E3 binding on graft endothelium.

Conclusions:

Despite a partial protective effect of swine leukocyte antigen I masking with JM1E3 in vitro, ex vivo perfusion of the kidney with JM1E3 before transplantation was not sufficient alone at preventing or delaying AMR in highly sensitized recipients.
Identification of Nocardioides marmotae sp. nov. and Nocardioides faecalis sp. nov., two new members of the genus Nocardioides
Authors: Zhang Gui , Liu Yue , Cheng Yanpeng , Yang Jing , Jin Dong , Lu Shan , Pu Ji , Li Weiguang , Ge Yajun , Ma Caiyun , Luo Wenbo , Xu Jianguo
Published: May 2023

A polyphasic taxonomic characterization of two novel strain pairs (designated zg-579T/zg-578 and zg-536T/zg-ZUI104) isolated from the faeces of Marmota himalayana was conducted based on phylogenetic analysis of the nearly full-length 16S rRNA gene and genome, digital DNA–DNA hybridization, ortho-average nucleotide identity (Ortho-ANI), and phenotypic and chemotaxonomic traits. Comparative analysis of the nearly full-length 16S rRNA gene sequences showed that strain zg-579T was most closely related to

Nocardioides dokdonensis

FR1436T (97.57 %) and

Nocardioides deserti

SC8A-24T (97.36 %), whereas strain zg-536T had the highest similarity to

Nocardioides caeni

MN8T (98.33 %),

Nocardioides convexus

W2-2-3T (98.26 %) and

Nocardioides daeguensis

2C1-5T (98.19 %). Low levels of DNA–DNA relatedness and Ortho-ANI values (19.8–31.0 %/78.6–88.2 %, zg-579T; 19.9–31.3 %/78.8–86.2 %, zg-536T) between the two new type strains and previously known species within the genus

Nocardioides

support the hypothesis that the four newly characterized strains could be considered to represent two novel species within this genus. The dominant cellular fatty acids found in strain pair zg-536T/zg-ZUI104 were iso-C16 : 0 and C18 : 1
 ω9c, whereas C17 : 1
 ω8c was major component in zg-579T/zg-578. Galactose and ribose were the main cell-wall sugars in these two new strain pairs. Diphosphatidylglycerol (DPG), phosphatidylcholine, phosphatidylglycerol (PG) and phosphatidylinositol (PI) were the major polar lipids in zg-579T, whereas DPG, PG and PI predominated in zg-536T. Both strain pairs had MK8(H4) as the major respiratory quinone and ll-diaminopimelic acid as the major cell-wall peptidoglycan. The optimal growth conditions for the two novel strain pairs were 30 °C, pH 7.0 and 0.5 % NaCl (w/v). Based on these polyphasic characterizations, two novel species within the genus

Nocardioides

are proposed, i.e. Nocardioides marmotae sp. nov. and Nocardioides faecalis sp. nov., with zg-579T (=CGMCC 4.7663T=JCM 33892T) and zg-536T (=CGMCC 4.7662T=JCM 33891T) as the type strains.
Clustering by Multiple Long-Term Conditions and Social Care Needs: A cohort study amongst 10,025 older adults in England
Authors: Khan Nusrat , Chalitsios Christos V. , Nartey Yvonne , Simpson Glenn , Zaccardi Francesco , Santer Miriam , Roderick Paul , Stuart Beth , Farmer Andrew , Dambha-Miller Hajira
Published: May 2023

Background

People with Multiple Long-Term Conditions (MLTC) face health and social care challenges. This study aimed to classify people by MLTC and social care need (SCN) into distinct clusters and quantify the association between derived clusters and care outcomes.

Methods

A cohort study was conducted using the English Longitudinal Study of Ageing (ELSA), including people with up to ten MLTC. Self-reported SCN was assessed through 13 measures of difficulty with activities of daily living, ten measures of mobility difficulties, and whether health status was limiting earning capability. Latent class analysis was performed to identify clusters. Multivariable logistic regression quantified associations between derived SCN/MLTC clusters, all-cause mortality, and nursing home admission.

Results

The cohort included 9171 people at baseline with a mean age of 66·3 years; 44·5% were males. Nearly 70·8% had two or more MLTC, the most frequent being hypertension, arthritis, and cardiovascular disease. We identified five distinct clusters classified as high SCN/MLTC through to low SCN/MLTC clusters. The high SCN/MLTC included mainly women aged 70 to 79 years who were white and educated to the upper secondary level. This cluster was significantly associated with higher nursing home admission (OR = 8·97; 95% CI: 4·36 to 18·45). We found no association between clusters and all-cause mortality.

Conclusions

This results in five clusters with distinct characteristics that permit the identification of high-risk groups who are more likely to have worse care outcomes, including nursing home admission. This can inform targeted preventive action to where it is most needed amongst those with MLTC.

What is already known on this topic

While it is established that multiple long-term conditions are linked to an increased risk of hospitalisation, nursing home admission and mortality, no previous research has examined this risk in relation to clusters of MLTC and social care needs in England.

What this study adds

Using latent class analysis, this study identified five clusters by multiple long-term conditions and social care needs with distinct characteristics and quantified their relationship with nursing home admission and mortality.

How this study might affect research, practice or policy

The findings permit the identification of high-risk groups who are more likely to have worse care outcomes, including nursing home admission in the future. This can inform targeted preventive action to where it is most needed amongst those with MLTC. Recognition of MLTC and SCN clusters may also aid clinicians in moving away from a single disease management approach in older adults.
Somatic structural variation signatures in pediatric brain tumors
Authors: Yang Yang , Yang Lixing
Published: May 2023

Brain cancer is the leading cause of cancer-related death in children. Somatic structural variations (SVs), large scale alterations in DNA, remain poorly understood in pediatric brain tumors. Here, we detect a total of 13,199 high confidence somatic SVs in 744 whole-genome-sequenced pediatric brain tumors from Pediatric Brain Tumor Atlas. The somatic SV occurrences have tremendous diversity among the cohort and across different tumor types. We decompose mutational signatures of clustered complex SVs, non-clustered complex SVs, and simple SVs separately to infer the mutational mechanisms of SV formation. Our finding of many tumor types carrying unique sets of SV signatures suggests that distinct molecular mechanisms are active in different tumor types to shape genome instability. The patterns of somatic SV signatures in pediatric brain tumors are substantially different from those in adult cancers. The convergence of multiple signatures to alter several major cancer driver genes suggesting the functional importance of somatic SVs in disease progression.
Accounting for intensity variation in image analysis of large-scale multiplexed clinical trial datasets
Authors: Frei Anja L , McGuigan Anthony , Sinha Ritik RAK , Glaire Mark A , Jabbar Faiz , Gneo Luciana , Tomasevic Tijana , Harkin Andrea , Iveson Tim J , Saunders Mark , Oein Karin , Maka Noori , Pezella Francesco , Campo Leticia , Hay Jennifer , Edwards Joanne , Sansom Owen , Kelly Caroline , Tomlinson Ian , Kildal Wanja , Kerr Rachel S , Kerr David J , Danielsen Håvard E , Domingo Enric ,   TransSCOT consortium, Church David N , Koelzer Viktor H
Published: May 2023

Multiplex immunofluorescence (mIF) imaging can provide comprehensive quantitative and spatial information for multiple immune markers for tumour immunoprofiling. However, application at scale to clinical trial samples sourced from multiple institutions is challenging due to pre-analytical heterogeneity. This study reports an analytical approach to the largest multiparameter immunoprofiling study of clinical trial samples to date. We analysed 12,592 tissue microarray (TMA) spots from 3,545 colorectal cancers (CRC) sourced from more than 240 institutions in two clinical trials (QUASAR 2 and SCOT) stained for CD4, CD8, CD20, CD68, FoxP3, pan-cytokeratin and DAPI by mIF. TMA slides were multi-spectrally imaged and analysed by cell-based and pixel-based marker analysis. We developed an adaptive thresholding method to account for inter- and intra-slide intensity variation in TMA analysis. Applying this method effectively ameliorated inter- and intra-slide intensity variation improving the image analysis results compared to methods using a single global threshold. Correlation of CD8 data derived by our mIF analysis approach with single-plex chromogenic immunohistochemistry (IHC) CD8 data derived from subsequent sections indicates the validity of our method (Spearman’s rank correlation coefficients ρ between 0.63 and 0.66, p-value ≪ 0.01) as compared to current gold standard analysis approach. Evaluation of correlation between cell-based and pixel-based analysis results confirms equivalency (ρ > 0.8, p ≪ 0.01, except for CD20 in epithelium region) of both analytical approaches. These data suggests that our adaptive thresholding approach can enable analysis of mIF-stained clinical trial TMA datasets by digital pathology at scale for precision immunoprofiling.
Statin Use And The Risk Of Venous Thromboembolism In Women Taking Hormone Therapy
Authors: Davis John W. , Weller Susan C. , Porterfield Laura , Chen Lu , Wilkinson Gregg
Published: May 2023

Importance

While hormone therapy (HT) in perimenopausal women can increase risk for venous thromboembolism (VTE), it is unclear to what extent statins may reduce HT-related risk.

Objective

To estimate VTE risk in 50–64-year-old women taking HT with or without statins and by statin intensity.

Design

A nested case-control study.

Setting

A US, commercially insured claims database.

Participants

Women aged 50-64 with at least one year of continuous membership between 2008-2019.

Exposure

Filled prescriptions for estrogens, progestogens, and statins were recorded in 12 months prior to index. Recent HT was defined as any estrogen or progestogen exposure within 60 days before the index date. Current statin exposure was defined as 90 or more days of continuous exposure prior to and including the index date. Statin intensity was defined by the statin exposure 30 days prior to index.

Main Outcomes and Measures

Cases were identified with VTE diagnoses (ICD codes) preceded by at least 12 months without VTE and followed within 30 days by anticoagulation, an inferior vena cava filter placement, or death. Controls were matched to cases (10:1) on date and age. Conditional logistic regression models estimated risk for HT and statin exposures with odds ratios (OR), adjusted for comorbidities.

Results

The total sample (mean age 57.5) included 20,359 cases and 203,590 matched controls; 9% had recent HT exposure and 16% had current statin exposure. In adjusted models, the OR for any recent HT exposure was 1.51 (95%CI:1.43-1.60) compared to no recent HT exposure. The OR for current statin therapy was 0.88 (95%CI:0.84-0.93) compared to no current statin exposure. The OR was 1.53 (95%CI:1.44-1.63) for those with HT without statins, 1.25 (95%CI:1.10-1.43) with HT with statins, and 0.89 (95%CI:0.85-0.94) with statins without HT compared to no recent HT and no current statins. HT with statin therapy had a 18% significantly lower OR than HT without statins (OR=0.82,95%CI:0.71-0.94) and greater risk reduction with higher intensity statins.

Conclusions and Relevance

In this case-control study, statin therapy was associated with reduced risk of VTE in women taking HT with greater risk reduction with high-intensity statins.

Key Points

Question

What is the impact of statin therapy in perimenopausal women exposed to hormone therapy?

Findings

In this case-control study of approximately 225,000 women aged 50-64, the VTE odds ratio was 53% higher in women recently exposed to HT without current statin therapy and 25% higher with recent HT exposure and current statin therapy compared to women without recent HT and current statin exposures,

Meaning

These findings suggest statins may reduce risk of VTE in women exposed to HT and further, HT may not be contraindicated in women taking statins.
Tumor microenvironment exploration and therapeutic target identification in bladder cancer based on Cuproptosis signature and chemotherapy-resistant model: results from bioinformatics and experimental validation
Authors: Gu Jun , Shi Zhen-duo , Pang Kun , Hao Lin , Wang Wei , Han Cong-hui
Published: May 2023

Background

The discovery of cuproptosis provides a new way to make full use of the pathophysiological effects of copper for anticancer therapy and could help identify a therapeutic target in bladder cancer.

Methods

In this study, 411 BLCA tumor samples from the Cancer Genome Atlas (TCGA) cohort were obtained. Differentially expressed genes (DEGs) between chemotherapy-sensitive and chemotherapy-resistant mouse bladder cancers were also obtained. Sixteen genes were defined as cuproptosis-related genes (CRGs), and the cutoff score was calculated based on LASSO Cox regression. CCK-8 and Transwell assays were used to detect the migration and proliferation of 5637 and T24 cells, respectively. Liarozole dihydrochloride (L-D), a mild P450, inhibits the expression of CYP26B1. Multiple immunohistochemistry analyses were used to explore the association between the immune microenvironment and CRGs.

Results

A higher Cuproptosis score was significantly associated with worse overall survival in BLCA (p<0.0001, HR=2.32). Single-cell transcriptional data were used to assess the function ofCYP26B1andCYP26B1may be negatively associated with DNA damage and repair. In vitro experiments indicated that overexpression of CYP26B1 enhanced the migration and proliferation of BLCA cells, while L-D inhibited the migration and proliferation of BLCA cells. A higher expression level of Dihydrolipoamide S-Succinyltransferase (DLST) serves could as a risk factor in patients treated with atezolizumab and higher expression ofDLSTsuggest an immunosuppressive microenvironment.

Conclusions

CYP26B1may be a therapeutic target for bladder cancer, and the higher expression of DLST may suggest an immunosuppressive microenvironment in BLCA.

Key Messages

Cuproptosis may be associated with the chemotherapy-resistance of bladder cancer and our findings may provide new ideas for the treatment of bladder cancer.
Dichotomy of neutralizing antibody, B cell and T cell responses to SARS-CoV-2 vaccination and protection in healthy adults
Authors: Carr Edward J , Townsley Hermaleigh , Wu Mary Y , Wilkinson Katalin A , Hobson Philip S , Levi Dina , Namjou Sina , Mears Harriet V , Hobbs Agnieszka , Ragno Martina , Herman Lou S , Harvey Ruth , Bailey Chris , Fowler Ashley S , Hatipoglu Emine , Ngai Yenting , Clayton Bobbi , Miah Murad , Bawumia Philip , Miranda Mauro , Smith Callie , Sawyer Chelsea , Kelly Gavin , Mahalingasivam Viyaasan , Zheng Bang , Evans Stephen JW , Libri Vincenzo , Riddell Andrew , Nicod Jerome , O’Reilly Nicola , Howell Michael , Williams Bryan , Wilkinson Robert J , Kassiotis George , Swanton Charles , Gandhi Sonia , Beale Rupert CL , Bauer David LV , Wall Emma C
Published: May 2023

Heterogeneity in SARS-CoV-2 vaccine responses is not understood. Here, we identify four patterns of live-virus neutralizing antibody responses: individuals with hybrid immunity (with confirmed prior infection); rare individuals with low responses (paucity of S1-binding antibodies); and surprisingly, two further groups with distinct serological repertoires. One group – broad responders – neutralize a range of SARS-CoV-2 variants, whereas the other – narrow responders – neutralize fewer, less divergent variants. This heterogeneity does not correlate with Ancestral S1-binding antibody, rather the quality of the serological response. Furthermore, IgDlowCD27-CD137+B cells and CCR6+CD4+T cells are enriched in broad responders before dose 3. Notably, broad responders have significantly longer infection-free time after their third dose. Understanding the control and persistence of these serological profiles could allow personalized approaches to enhance serological breadth after vaccination.
Inherited CDA-I disease: anemia-associated mutations disrupt CDIN1-Codanin1 complex
Authors: Stojaspal Martin , Brom Tomáš , Nečasová Ivona , Janovič Tomáš , Veverka Pavel , Uhrík Lukáš , Hernychova Lenka , Hofr Ctirad
Published: May 2023

Congenital dyserythropoietic anemia type I (CDA-I) is a rare hereditary disease characterized by ineffective erythropoiesis, spongy heterochromatin of erythroblasts, and associated mutations in two proteins – Codanin1 and CDIN1. Codanin1 regulates nucleosome assembly through histone chaperone ASF1. The function of recently discovered CDIN1 remains unknown, but CDIN1 has been known to interact directly with the C-terminus of Codanin1. Despite the critical role of identified mutations in Codanin1 and CDIN1, the effects of CDA-I-related mutations at the molecular level have not been elucidated. Here, we determine how low-resolution structural data align with predicted models of CDIN1, Codanin1 C-terminus, and their complex. We define that CDIN1 and Codanin1 assemble with 1:1 stoichiometry and bind with low nanomolar binding affinity. We identify essential interacting regions of CDIN1 and Codanin1. We found that CDA-I-associated mutations disrupt CDIN1-Codanin1 binding, suggesting a potential molecular mechanism underlying the CDA-I disease.

Highlights

CDA-I-associated proteins CDIN1 and Codanin1Cterm bind in equimolar ratio with nanomolar affinity.

Full-length CDIN1 preferentially forms dimers, Codanin1Cterm monomers.

Identified interacting regions of CDIN1 and Codanin1Cterm contain mutations associated with CDA-I disease.

CDA-I-related mutations impair binding of CDIN1 and Codanin1Cterm suggesting a potential molecular mechanism underlying the disease.

Graphical Abstract
Internal Ribosome Entry Sites act as Effector Domain in linear and circular antisense long non-coding SINEUP RNAs
Authors: D’Agostino Sabrina , Tettey-Matey Abraham , Volpe Massimiliano , Pierattini Bianca , Ansaloni Federico , Lau Pierre , Bon Carlotta , Peruzzo Omar , Braccia Clarissa , Armirotti Andrea , Scarpato Margherita , Damiani Devid , Carlo Valerio Di , Broglia Laura , Bechara Elias , Tartaglia Gian Gaetano , Carninci Piero , Santoro Claudio , Persichetti Francesca , Pandolfini Luca , Espinoza Stefano , Zucchelli Silvia , Sanges Remo , Gustincich Stefano
Published: May 2023

SINEUPs are antisense long non-coding RNAs that enhance translation of overlapping sense mRNAs through the activity of two domains: aSINEB2 sequenceUP-regulating translation (Effector Domain, ED) and an antisense region providing target specificity (Binding Domain, BD). In this study, we demonstrate that the invSINEB2 sequence from the natural SINEUPAS Uchl1RNA is an Internal Ribosomal Entry Site (IRES) when acting incisand that known viral and cellular IRES sequences can act as Effector Domain in synthetic SINEUPs.

To identify natural IRES-containing, non-coding RNAs with SINEUP-like activity, we focused on circular RNAs showing that the non-codingcirc5533, transcribed from thec-myc locus, enhances endogenous protein expression of its targetPX Domain Containing Serine/Threonine Kinase Like(Pxk)by increasing mRNA association to polysomes.

In summary, this study shows that natural and synthetic SINEUPs include linear and circular transcripts with an embedded IRES sequence as ED.
Arrive and wait: inactive bacterial taxa contribute to perceived soil microbiome resilience after a multidecadal press disturbance
Authors: Barnett Samuel E. , Shade Ashley
Published: May 2023

Long-term (press) disturbances like the climate crisis and other anthropogenic pressures are fundamentally altering ecosystems and their functions. Many critical ecosystem functions, such as biogeochemical cycling, are facilitated by microbial communities. Understanding the functional consequences of microbiome responses to press disturbances requires ongoing observations of the active populations that contribute functions. This study leverages a 7-year time series of a 60-year-old coal seam fire (Centralia, Pennsylvania, USA) to examine the resilience of soil bacterial microbiomes to a press disturbance. Using 16S rRNA and 16S rRNA gene amplicon sequencing, we assessed the interannual dynamics of the active subset and the “whole” bacterial community. Contrary to our hypothesis, the whole communities demonstrated greater resilience than active subsets, suggesting that inactive members contributed to overall resilience. Thus, in addition to selection mechanisms of active populations, perceived microbiome resilience is also supported by mechanisms of dispersal, persistence, and revival from the local dormant pool.
Characterization ofB646L(p72) gene and the resistance pattern of African swine fever Virus tolerant to indigenous Doom Pig breeds of India
Authors: Das Pranab Jyoti , Sonowal Joyshikh , Sengar Gyanendra Singh , Pegu Seema Rani , Deb Rajib , Kumar Satish , Banik Santanu , Rajkhowa Swaraj , Gupta Vivek Kumar
Published: May 2023

African Swine Fever (ASF) has affected all pig breeds in North-East India since 2020, except Doom pigs, a unique indigenous breed from Assam and the closest progenitor to Indian wild pigs, resulting in significant economic losses for pig farmers in the region. Based on the complete sequences of theB646L(p72) gene, it has been determined that the virus responsible for the outbreak is ASFV genotype II. The further characterization of three complete sequences of theB646L(p72) gene established 100% identical with other existing sequences of different parts of the world as well as confirmed that there is no co-circulation of different genotypes of ASFV in India except genotype II. Present studies also corroborate thatMYD88, LDHBandIFIT1were important genes of the immune system involved in the pathogenesis of ASFV. The differential expression patterns of these genes in ASFV-infected survived, and healthy Doom breed pigs, compared to healthy control pigs, were studied to distinguish the expression pattern at different stages. The hardiness and ability of the Doom pig to withstand common pig diseases, along with its genetic resemblance to wild pigs, make it an ideal candidate for studying tolerance to ASFV infection. So, the present study investigates the natural resistance to ASF in Doom pigs from an endemic area in North-East India to support the proposition that Doom pigs can co-exist with virulent ASFVs recently break in North-East India. The results of this study also provide important molecular insights into the regulation of the ASFV-tolerant gene.

Importance

Studying the natural resistance to African Swine Fever (ASF) in Doom pigs from North-East India holds crucial importance. ASF has inflicted significant economic losses on pig farmers in the region, necessitating the identification and comprehension of factors contributing to resistance and tolerance in specific pig breeds such as Doom pigs. Understanding the molecular mechanisms and genetic factors associated with ASFV tolerance could help in breeding programs and the selection of resilient pig breeds, ultimately aiding in disease control efforts.
Type-2 diabetes alters hippocampal neural oscillations and disrupts synchrony between hippocampus and cortex
Authors: Rabiller Gratianne , Ip Zachary , Zarrabian Shahram , Zhang Hongxia , Sato Yoshimichi , Yazdan-Shahmorad Azadeh , Liu Jialing
Published: May 2023

Type 2 diabetes mellitus (T2DM) increases the risk of neurological diseases, yet how brain oscillations change as age and T2DM interact is not well characterized. To delineate the age and diabetic effect on neurophysiology, we recorded local field potentials with multichannel electrodes spanning the somatosensory cortex and hippocampus (HPC) under urethane anesthesia in diabetic and normoglycemic control mice, at 200 and 400 days of age. We analyzed the signal power of brain oscillations, brain state, sharp wave associate ripples (SPW-Rs), and functional connectivity between the cortex and HPC. We found that while both age and T2DM were correlated with a breakdown in long-range functional connectivity and reduced neurogenesis in the dentate gyrus and subventricular zone, T2DM further slowed brain oscillations and reduced theta-gamma coupling. Age and T2DM also prolonged the duration of SPW-Rs and increased gamma power during SPW-R phase. Our results have identified potential electrophysiological substrates of hippocampal changes associated with T2DM and age. The perturbed brain oscillation features and diminished neurogenesis may underlie T2DM-accelerated cognitive impairment.
HTLV-1 reverse transcriptase homology model provides structural basis for sensitivity to existing nucleoside/nucleotide reverse transcriptase inhibitors
Authors: Tardiota Nicolas , Jaberolansar Noushin , Lackenby Julia A. , Chappell Keith J. , O’Donnell Jake S.
Published: May 2023

The human T-lymphotropic virus type 1 (HTLV-1) infects millions of people globally and is endemic to various resource-limited regions. Infections persist for life and are associated with increased susceptibility to opportunistic infections and severe diseases including adult T cell leukemia/lymphoma (ATLL) and HTLV-1-associated myelopathy-tropical spastic paraparesis (HAM-TSP). No HTLV-1-specific anti-retrovirals have been developed and it is unclear whether existing anti-retrovirals developed for treatment of human immunodeficiency virus (HIV) have efficacy against HTLV-1. To understand the structural basis for therapeutic binding, homology modelling and machine learning were used to develop a structural model of the HTLV-1 reverse transcriptase. With this, molecular docking experiments using a panel of FDA-approved inhibitors of viral reverse transcriptases to assess their capacity for binding, and in turn, inhibition. Importantly, nucleoside/nucleotide reverse transcriptase inhibitor (NRTI) but not non-nucleoside reverse transcriptase inhibitors (NNRTIs) were capable of binding the HTLV-1 reverse transcriptase, with similar affinity to HIV-1 reverse transcriptase. By strengthening the rationale for clinical testing of therapies such as tenofovir alafenamide, zidovudine, lamivudine, and azvudine for treatment of HTLV-1, this study has demonstrated the power ofin silicostructural biology approaches in drug design and therapeutic testing.
ARID1A governs the silencing of sex-linked transcription during male meiosis in the mouse
Authors: Menon Debashish U. , Chakraborty Prabuddha , Murcia Noel , Magnuson Terry
Published: May 2023

We present evidence implicating the BAF (BRG1/BRM Associated Factor) chromatin remodeler in meiotic sex chromosome inactivation (MSCI). By immunofluorescence (IF), the putative BAF DNA binding subunit, ARID1A (AT-rich Interaction Domain 1a), appeared enriched on the male sex chromosomes during diplonema of meiosis I. Those germ cells showing a Cre-induced loss of ARID1A were arrested in pachynema and failed to repress sex-linked genes, indicating a defective MSCI. Consistent with this defect, mutant sex chromosomes displayed an abnormal presence of elongating RNA polymerase II coupled with an overall increase in chromatin accessibility detectable by ATAC-seq. By investigating potential mechanisms underlying these anomalies, we identified a role for ARID1A in promoting the preferential enrichment of the histone variant, H3.3, on the sex chromosomes, a known hallmark of MSCI. Without ARID1A, the sex chromosomes appeared depleted of H3.3 at levels resembling autosomes. Higher resolution analyses by CUT&RUN revealed shifts in sex-linked H3.3 associations from discrete intergenic sites and broader gene-body domains to promoters in response to the loss of ARID1A. Several sex-linked sites displayed ectopic H3.3 occupancy that did not co-localize with DMC1 (DNA Meiotic Recombinase 1). This observation suggests a requirement for ARID1A in DMC1 localization to the asynapsed sex chromatids. We conclude that ARID1A-directed H3.3 localization influences meiotic sex chromosome gene regulation and DNA repair.