bluuebunny/crossref_metadata_2025 huggingface dataset:
Postoperative Increase in Intraocular Pressure After Penetrating Keratoplasty and Descemet Stripping Automated Endothelial Keratoplasty in Asian Patients
Authors: Kurita Junki , Hayashi Takahiko , Shimizu Toshiki , Sunouchi Chihiro , Hara Yusuke , Kobayashi Akira , Yamagami Satoru
Published: July 2023

Purpose:

We compared factors that contribute to postoperative intraocular pressure (IOP) elevation after penetrating or Descemet stripping automated endothelial keratoplasty in Asian patients.

Methods:

Consecutive patients who underwent corneal transplantation by penetrating or Descemet stripping automated endothelial keratoplasty were included. IOP was recorded preoperatively and at every postoperative visit for 2 years. Demographic factors and preoperative and maximum postoperative IOP were statistically compared between the groups. IOP elevation risk factors were identified using the log-rank test and multivariate Cox proportional hazards regression analysis with time-dependent covariates.

Results:

Twenty-two patients with penetrating keratoplasty (13 men, 9 women; aged 55.0 ± 21.6 years) and 46 patients with Descemet stripping automated endothelial keratoplasty (20 men, 26 women; aged 76.7 ± 10.7 years) were included. Preoperative IOP was lower in eyes treated with penetrating keratoplasty (10.5 ± 3.6 mm Hg, measurements of 2 cases were not recorded) than in eyes treated with Descemet stripping automated endothelial keratoplasty (14.0 ± 3.4 mm Hg, P < 0.001). Postoperative maximum IOP was higher in penetrating keratoplasty (21.1 ± 6.2 mm Hg) than in Descemet stripping automated endothelial keratoplasty (15.8 ± 5.3, P < 0.001). Intraocular pressure was elevated in 11 (50%) and 9 (19.6%) eyes treated with penetrating and Descemet stripping automated endothelial keratoplasty, respectively. Penetrating keratoplasty was identified as a risk factor for IOP elevation.

Conclusions:

Postoperative IOP elevation was more likely to occur after penetrating keratoplasty than after Descemet stripping automated endothelial keratoplasty. Postoperative IOP should be carefully monitored and managed in patients after corneal transplantation.
Defining the Value of Breast Reconstruction Surgeons: Quantifying Clinical Encounter and Operative Volume at an Academic Center
Authors: Sergesketter Amanda R. , Mundy Lily R. , Langdell Hannah C. , Shammas Ronnie L. , Geng Yisong , Rezak Kristen , Sisk Geoffroy C. , Phillips Brett T. , Hollenbeck Scott T.
Published: July 2023

Background:

Despite growing rates of postmastectomy breast reconstruction, the time contribution of breast reconstruction surgeons in comprehensive breast cancer care is often poorly accounted for by hospital and healthcare systems. This study models encounter volume and operative time utilization of breast reconstruction surgeons among patients undergoing postmastectomy breast reconstruction.

Methods:

All clinical encounters and operative time from a consecutive sample of breast cancer patients undergoing mastectomy and reconstruction were analyzed. Encounter volume and operative time utilization less than or equal to 4 years after diagnosis were modeled over time.

Results:

A total of 5057 breast cancer encounters were analyzed. Mean (SD) clinical encounter volume was 45.9 (28.5) encounters per patient, with encounter volume varying by specialty [plastic surgery: 16.5; medical oncology: 15.9; breast surgery: 7.2; radiation oncology: 6.3 mean encounters]. Receipt of adjuvant radiation, neoadjuvant chemotherapy, and major complications during reconstruction predicted higher encounter volume. Mean (SD) operative time utilization was 702 (317) minutes per patient [plastic surgery: 547 (305); breast surgery: 155 (71) minutes]. While both encounter volume and operative time for radiation oncologists and breast surgeons, respectively, were concentrated in the first year after diagnosis, medical oncologists and plastic surgeons sustained high clinical and operative time utilization 3 years after breast cancer diagnosis.

Conclusions:

Encounter volume and operative time utilization with breast reconstruction surgeons persist 3 years after a breast cancer diagnosis and are tied to treatment characteristics and incidence of reconstruction complications. Institutional- and system-level resource allocation must account for the complex and lengthy duration of care inherent to breast reconstruction care.
Sensate Reverse Medial Plantar Flap for Reliable Forefoot Reconstruction with Flow-through Anterolateral Thigh Flap
Authors: Murakami Masami , Hori Keijiro , Niimi Yosuke , Nagashima Yoji , Sakurai Hiroyuki
Published: July 2023

A reverse medial plantar flap is a major option for reconstructing the plantar forefoot. However, reconstruction of the distal forefoot stretches the vessels, causing tightness, and the skin graft to the donor site adds pressure to the vessel, precipitating venous congestion. We used a reverse medial plantar flap to reconstruct the lateral distal forefoot with a flow-through of the anterolateral thigh (ALT) flap for donor site coverage to maintain physiological and stable blood flow. A 74-year-old woman presented to our hospital with a 20-year history of left forefoot skin tumor. The tumor was resected, and histological examination revealed porocarcinoma in the cystic poroid hidradenoma. Additional excision was performed, and the defect area was covered with a biodegradable artificial dermis. The skin defect of the lateral distal plantar area was reconstructed with a reverse medial plantar flap with a reverse flow Y-V pedicle extension method, and the donor site was reconstructed with an ALT flap interposing the lateral circumflex femoral artery with the transected posterior tibial artery. The flap was completely engrafted without any complications, including arterial ischemia or venous congestion, during or after surgery. A distally based reverse medial plantar flap with a reverse flow Y-V pedicle extension method and flow-through of the ALT flap should be considered for the reconstruction of the lateral distal forefoot with a large defect. This method can maximize flap extension and maintain stable arterial inflow and venous drainage without the major complications of venous congestion.
A Modified Type III Keystone Flap for Digital Mucous Cyst of the Eponychium
Authors: Chen Ching-En , Wang Tien-Hsiang
Published: July 2023

Digital mucous cysts (DMCs), also known as myxoid cysts, periungual ganglion cysts, and myxomatous cutaneous cysts, commonly occurr at the distal interphalangeal joint (DIPJ) of the fingers and toes. Due to the dense and inflexible skin at the dorsal fingertip, wound dehiscence and necrosis may sometimes be caused by tension sutures. The keystone flap (KF), designed as a curvilinear-shaped trapezoidal keystone with two V-Y advancements at the exterior peripheral corners, has been gaining popularity as a local flap that can close defects with a lower tension. In the reported case, while facing the DMC at the eponychial fold, we applied a modified type III KF with minimal elevation of the eponychium and internal rotation of the opposite flaps to cover the triangular defect. Postoperative outcomes showed that the flap was viable with sufficient perfusion and no wound dehiscence or infection. During follow-up, the grooving deformity of the nail was corrected, and no tumor recurrence was noted. Moreover, there were no restrictive scars or limited range of motion on the DIPJ.
Minimally Invasive Mandibular Microsurgery: A Systematic Review and Meta-analysis
Authors: Godbe Kerilyn N. , O’Connor Michaela K. , Sinik Lauren M. , Vance Dylan T. , Nazir Niaman , Garg Ravi K.
Published: July 2023

Background:

Microsurgical advances have led to minimally invasive approaches for mandibular reconstruction. Currently, no resource compares all minimally invasive microvascular mandibular reconstruction (MIMMR) treatment options.

Methods:

All known cases of MIMMR were identified following the Preferred Reporting Items for Systematic Reviews, Meta-Analyses guidelines, and our own surgical experience. Patient demographics, MIMMR type [submandibular (SM), modified facelift/retroauricular (MFL/RA), or intraoral (IO)], methodology, and clinical outcomes were analyzed with the Fisher exact and Kruskal-Wallis tests.

Results:

Forty-seven patients underwent MIMMR. Ameloblastoma was the most common pathology treated using all approaches, and MFL/RA was the only approach used to treat squamous cell carcinoma (P = 0.0103). Reconstruction was reported for large, bilateral defects only via the SM or IO approach (P = 0.0216). The iliac crest or fibula was used as a donor site. The facial artery was the most common recipient vessel using the IO and SM approaches, whereas the superior thyroid and external carotid vessels were the most common in the MFL/RA approach (P < 0.0001). Virtual planning was used in all cases performed via an IO approach, 80.0% of cases using an SM approach, and no MFL/RA cases (P < 0.0001). Good aesthetic and functional outcomes were reported for every patient, and there was no difference in complication rates (P = 0.2880).

Conclusions:

Minimally invasive approaches are safe and effective treatment options for patients requiring mandibular microsurgery, usually in the setting of benign pathology. The IO and SM approaches usually rely on the facial vessels, whereas the MFL/RA approach permits access to the superior thyroid and external carotid vessels and cervical lymphadenectomy.
The rapid activation of cPKCβII by progesterone results in the negative regulation of Ca2+ influx in human resting T cells
Authors: Lin Veronica Hui-Chen , Chien Angela , Chien Eileen Jea
Published: July 2023

Background:

Progesterone-stimulated rapid suppression of phytohemagglutinin (PHA)-activated sustained membrane Ca2+ influx is revealed by Mn2+ quenching fura-2 fluorescence. Ca2+ influx suppression results in immunosuppression of T-cell proliferation. Downregulation of protein kinase C (PKC) activity by phorbol 12-myristate 13-acetate (PMA) enhances the PHA-activated increase in sustained intracellular Ca2+ concentration ([Ca2+]i) via Ca2+ influx in T cells. Conventional PKC (cPKC) inhibitors also enhance the [Ca2+]i increase in resting T cells caused by progesterone. This study explores whether cPKC activation by progesterone results in suppression of Ca2+ influx in resting T cells.

Methods:

Progesterone, its analogs (R5020/Org OD 02-0), and plasma membrane-impermeable progesterone-bovine serum albumin conjugate were used to stimulate human resting T cells. Inhibitors and PKC downregulation by PMA were used to investigate whether cPKC affects Ca2+ influx.

Results:

Progesterone and analogs dose-dependently suppressed Ca2+ influx in T cells. One cPKC inhibitor, Ro318220, attenuated Ca2+ influx suppression, and enhanced the increase in [Ca2+]i caused by progesterone and analogs. U73122 did not affect Ca2+ influx suppression but did decrease the [Ca2+]i increase. Ca2+ influx suppression was not attenuated by the cPKCα/βI isoform-selective inhibitor, Go6976, nevertheless, a cPKCβI/βII isoform-selective inhibitor, LY333531 did. Ca2+ influx suppression was attenuated by the cPKCβII-specific inhibitor CGP53353. After PKC downregulated by PMA, Ca2+ influx suppression by progesterone and analogs was almost abolished in parallel with a massive reduction in cPKCβII expression. This suggests cPKCβII activation by progesterone and analogs mediate Ca2+ influx suppression in resting T cells.

Conclusion:

Nongenomic membrane activation of cPKCβII by progesterone causes immunosuppression via negative regulation of Ca2+ influx into human resting T cells. This prevents resting T-cell activation and proliferation, which protects the fetus from maternal immune attack while decreasing maternal autoimmune disease flare-ups during pregnancy. Thus, cPKCβII modulators might provide a new therapeutic approach to balancing T-cell tolerance and immunity.
Dynamic evaluation based on acute-on-chronic liver failure predicts survival of patients after liver transplantation: a cohort study
Authors: Zhang Wei , Jin Pingbo , Liu Junfang , Wu Yue , Wang Rongrong , Zhang Yuntao , Shen Yan , Zhang Min , Bai Xueli , Fung John , Liang Tingbo
Published: July 2023

Background & Aims:

Dynamic evaluation of critically ill patients is the key to predicting their outcomes. Most scores based on Model for End-stage Liver Disease (MELD) and acute-on-chronic liver failure (ACLF) utilize point-in-time assessment. This study mainly aimed to investigate the impact of dynamic clinical course change on post-liver transplantation survival.

Methods

This study included 637 adults (overall cohort) with benign end-stage liver diseases. We compared the MELD scores and our ACLF-based dynamic evaluation scores. Patients enrolled or transplanted with ACLF3 were defined as ACLF-3 cohort (n = 158). The primary outcome was 1-year mortality. ΔMELD and ΔCLIF-OF represented the respective dynamic changes in liver transplant function. Discrimination was assessed using the area under the curve (AUC). Cox regression analysis identified independent risk factors for specific organ failure and 1-year mortality.

Results:

Patients were grouped as deterioration group, stable group, and improvement group. The deterioration group (ΔCLIF-OF ≥ 2) was more likely to receive national liver allocation (P=0.012) but experienced longer cold ischemia time (P=0.006) than other groups. The AUCs for ΔCLIF-OF were 0.752 for the entire cohort and 0.767 for ACLF-3 cohorts, both superior to ΔMELD (P<0.001 for both). Compared to the improvement group, the 1-year mortality hazard ratios (HR) of deterioration group were 12.57 (6.72–23.48) for overall cohort and 7.00 (3.73–13.09) for ACLF-3 cohort. Extrahepatic organs subscore change (HR=1.783 (1.266-2.512) for neurologic; 1.653 (1.205-2.269) for circulation; 1.906 (1.324-2.743) for respiration; 1.473 (1.097-1.976) for renal) were key to transplantation outcomes in the ACLF-3 cohort. CLIF-OF at LT (HR=1.193), ΔCLIF-OF (HR=1.354), and cold ischemia time (HR=1.077) were independent risk factors of mortality for the overall cohort, while ΔCLIF-OF (HR=1.384) was the only independent risk factor for the ACLF-3 cohort. Non-ACLF3 patients showed a higher survival rate than patients with ACLF-3 in all groups (P=0.002 for I, P=0.005 for S and P=0.001 for D).

Conclusion:

This was the first ACLF-based dynamic evaluation study. ΔCLIF-OF was a more powerful predictor of post-LT mortality than ΔMELD. Extrahepatic organ failures were core risk factors for ACLF-3 patients. CLIF-OF at LT, ΔCLIF-OF, and cold ischemia time were independent risk factors for post-LT mortality. Patients with a worse baseline condition and deteriorating clinical course had the worst prognosis. Dynamic evaluation was important in risk stratification and recipient selection.
Bicuspid aortic valve and its ascending aortopathy
Authors: Dunne Emma C. , Lacro Ronald V. , Flyer Jonathan N.
Published: July 2023

Purpose of review

To synthesize and critically assess recent clinical and research advancements in pediatric bicuspid aortic valve (BAV) and its associated aortopathy.

Recent findings

In pediatric patients with BAV, progressive aortic dilation (i.e. bicuspid aortopathy) is commonly present and associated with increased risk for aortic aneurysm, dissection, and surgery in adulthood. Ongoing research explores the cause, incidence, and progression of bicuspid aortopathy to promote earlier diagnosis and improve preventive management. Recent findings include: high familial incidence and need for improved familial screening; safety of recreational physical activity in most affected children; potential for medical management to slow aortic growth; feasibility of pediatric registries to evaluate longitudinal outcomes; and potential genetic and hemodynamic biomarkers for disease risk stratification.

Pediatric bicuspid aortopathy is an important area for investigation and preventive management to improve long-term cardiovascular outcomes. Recent literature promotes familial screening, recreational exercise, medical prophylaxis, registry-based longitudinal evaluation, and continued scientific inquiry.
Population-Level Disparities in Exposure to COVID-19 Mitigation Policies, April 2020-April 2021
Authors: Douglas Megan D. , Li Chaohua , Josiah Willock Robina , Baltrus Peter , Caplan Lee , Immergluck Lilly , McKinney Tonyka , Hopkins Jammie , Mack Dominic , Gaglioti Anne H.
Published: July 2023

Context:

Studies have found that COVID-19 stay-at-home orders (SHOs) and face mask policies (FMPs) were associated with reduced COVID-19 transmission and deaths. But it is unknown whether exposure to these policies varied by sociodemographic characteristics across the US population.

Objective:

The goal of this study was to quantify and characterize the sociodemographic characteristics and geographic distribution of populations exposed to evidence-based COVID-19 mitigation policies.

Design:

We obtained statewide SHOs and FMPs for all US counties from April 10, 2020, to April 10, 2021, calculated median policy lengths, and categorized counties into 4 groups based on length of policy exposure: low SHO-low FMP, high SHO-low FMP, low SHO-high FMP, and high SHO-high FMP. We described exposure groups by COVID-19 cumulative case/death and vaccination rates and county sociodemographic characteristics.

Setting:

In total, 3142 counties from all 50 states and Washington, District of Columbia, were included in the analysis.

Main Outcome Measures:

County-level sociodemographic factors and county cumulative rates for COVID-19 cases, deaths, and vaccinations.

Results:

The largest percentage of the US population lived in counties with high exposure to SHOs and FMPs. However, populations living in high SHO-high FMP counties had the lowest percent non-Hispanic Black (NHB) and highest percent non-Hispanic White (NHW) populations. Populations living in high SHO-low FMP counties had the highest percent NHB and Hispanic populations and the lowest percent NHW population.

Conclusion:

This study identified county-level racial, ethnic, and sociodemographic disparities in exposure to evidence-based statewide COVID-19 mitigation policies.

Policy Implications:

Exposure to evidence-based policies is an important consideration for studies evaluating the root causes of health inequities.
Community-Dwelling Adults' Perceived Versus Actual Risk of Cardiovascular Disease, Body Mass Index, and Physical Activity Levels and Related Factors
Authors: Gözüm Sebahat , Dağıstan Akgöz Ayşe
Published: July 2023

Context:

The difference between actual and perceived risk levels shows distorted risk perception. Unrealistic perceptions of cardiovascular disease (CVD) risks and insufficient knowledge about CVD risk factors can not only hinder the adoption of a positive lifestyle change but also obstruct preventive efforts.

Objective:

The aim of this study was to evaluate the concordance between perceived and actual risks, body mass index (BMI), and physical activity levels.

Design:

This descriptive study included 522 community-dwelling adults in 2 different regions of Antalya/Turkey. The actual CVD risk level of the participants was determined using the “HeartScore program,” actual body weight was determined according to BMI, and actual activity levels were found using the “International Physical Activity Questionnaire Short Form (IPAQ-SF).” The perceived risks were measured with the CVD Risk and Risk Factors Perception Determination Questionnaire. CVD Risk Factors Knowledge Level (CARRF-KL) Scale was used to calculate the participants' level of knowledge about the risk factors.

Results:

There was no concordance between the participants' actual and perceived CVD risks. A below-average agreement was found between the participants' actual and perceived BMI levels. In terms of actual measurements, it was seen that slightly obese individuals have a realistic perception. There was a weak agreement between the actual and perceived physical activity levels of the adults. Knowledge about the CVD risk factors of adults does not affect the perception of CVD risk and BMI and physical activity.

Conclusions:

Adults have an optimistic risk perception regarding CVD risk, BMI, and physical activity levels. It may be beneficial to periodically assess actual risks to change skewed perceptions of CVD and risk factors. These findings will inform the development of tailored intervention strategies and policies for these adults.
A Strategy for Strengthening: Implementation of the Capabilities Opportunities Assessment Tool for the Public Health Workforce
Authors: Hughes Monica J. , Kuehnert Paul , Swider Susan M.
Published: July 2023

Context:

Strengthening the national public health infrastructure is crucial to ensure provision of necessary public health services in all jurisdictions. Public health agencies and their governing bodies need an evidence-based understanding of workforces' capabilities to operationalize this effort.

Program:

The Capabilities Opportunities Assessment Tool for the Public Health Workforce (COAT-PH) is an assessment of workforce foundational capabilities (FCs), based on the Foundational Public Health Services (FPHS) framework. The COAT-PH provides data on employees' capabilities to health departments to help them improve and operationalize the FPHS.

Implementation:

This article describes the development and pilot testing of the COAT-PH in a convenience sample of 8 health departments in Texas of various sizes and accreditation statuses. Participating leadership teams were provided easily interpretable reports to deliver clear evidence of division and organization-level workforce capability gaps and strengths. Follow-up semistructured interviews were conducted with leaders to capture insights into the tool and the usefulness of the findings.

Evaluation:

Eighty-eight percent of pilot health departments reported successfully appraising employee capability deficits, and 83% of small and medium health departments successfully assessed division or organizational FC strengths and gaps. All participating departments identified ways they could use their findings in future improvement efforts. Instrument psychometrics included the Cronbach α of internal reliability using a small test-retest sample (n = 6) of 0.956. Item test-retest reliability using Cohen's κ revealed 89% of items demonstrated at least slight reliability and 43% demonstrated moderate to substantial reliability. Content validity was established through review by 15 subject matter experts in the field of public health.

Discussion:

To provide the FPHS, health department leadership teams need a strong, prepared workforce and an effective method to demonstrate employee capabilities and provide evidence of health department workforce strengths and gaps to their governing bodies in the form of data that are clear and easy to understand. Early results demonstrated the usefulness of the COAT-PH in this effort.
The Juvenile Spondyloarthritis Disease Activity Index Is a Useful Tool in Enthesitis-Related Arthritis
Authors: Polat Merve Cansu , Ekici Tekin Zahide , Çelikel Elif , Güngörer Vildan , Kurt Tuba , Kaplan Melike Mehveş , Tekgöz Nilüfer , Sezer Müge , Karagöl Cüneyt , Coşkun Serkan , Öner Nimet , Sezer Serdar , Çelikel Acar Banu
Published: July 2023

Objective

To compare enthesitis-related arthritis (ERA) patients with active and inactive disease at 6 months and define baseline predictors for disease inactivity. In addition, to evaluate the demographic, clinical, and laboratory characteristics of ERA patients and to identify the real-life impact of the Juvenile Spondyloarthritis Disease Activity Index (JSpADA) in predicting active disease in ERA.

Methods

This medical record review study was conducted with 56 patients who were diagnosed with ERA at our clinic between June 2009 and June 2022. Demographic and clinical characteristics, laboratory parameters, treatment, and JSpADA were recorded.

Results

The patients were divided into 2 groups as active (n = 34) and inactive (n = 22) according to their disease activity at month six. Sex, age at diagnosis, number and type of affected joints, and presence of sacroiliitis were similar in both groups. There was no difference in baseline erythrocyte sedimentation rate, but there was a significant difference in erythrocyte sedimentation rate at the third month (p = 0.52 and p = 0.018, respectively). The median JSpADA values at disease onset were 3.5 (interquartile range [IQR], 3.0–4.5) and 3.3 (IQR, 2.5–4.0) in the active and inactive groups, respectively (p = 0.27). At the third month, the median JSpADA values were 1.5 (IQR, 0.5–2.1) in the active group and 0.5 (IQR, 0.5–1.5) in the inactive group (p = 0.037). The cutoff value for JSpADA at the third month for active disease persisting at the month six was determined as 1 point (area under the curve, 0.662 ± 0.06; p = 0.042; 95% confidence interval, 0.51–0.80) by receiver operating characteristic curve analysis.

Conclusion

In ERA patients, a persistently high JSpADA value at follow-up is a predictive factor for active disease at the sixth month.
Congenital Midline Cervical Cleft and Thyroglossal Duct Fibrous Cord-Like, is There a Mixed Presentation?
Authors: Kruschewsky Leonardo de Souza , Matos Leandro Luongo de , Alonso Nivaldo , Seidler Cariline da Silva , Lisboa Sonyara Rauedys Oliveira , Silva Roberto Cintra Lomanto Santos , Goldenberg Dov Charles , Silva Tatiana Valeria Novais
Published: July 2023

Introduction:

Congenital midline cervical cleft is a rare condition and is frequently misdiagnosed as thyroglossal duct cyst. Otherwise, the combination of congenital midline cervical cleft and thyroglossal duct fibrosis in the same patient is as rare as important to be registered with the intention to inform and offer specific managements details for the literature.

Case Presentation:

Eight-year-old boy with simultaneous congenital midline cervical cleft and a thyroglossal duct fibrosis. The anatomic, clinical, radiologic, and pathologic characteristics of the congenital midline cervical cleft are described as well as surgical technique for removal and repair with Z-plasty.

Conclusion:

Congenital midline cervical cleft is a rare condition and when diagnosed must be surgically treated as early as possible. Its differential diagnosis is a clinical challenge.
A Transcriptomic Approach to Understand Patient Susceptibility to Pneumonia After Abdominal Surgery
Authors: Torrance Hew D , Zhang Ping , Longbottom E Rebecca , Mi Yuxin , Whalley Justin P , Allcock Alice , Kwok Andrew J , Cano-Gamez Eddie , Geoghegan Cyndi G , Burnham Katie L , Antcliffe David B , Davenport Emma E , Pearse Rupert M , O’Dwyer Michael J , Hinds Charles J , Knight Julian C , Gordon Anthony C
Published: July 2023

Objective:

To describe immune-pathways and gene-networks altered following major-abdominal surgery and identify transcriptomic patterns associated with postoperative pneumonia.

Summary Background Data:

Nosocomial infections are a major healthcare challenge, developing in over 20% of patients aged 45 or over undergoing major-abdominal surgery, with postoperative pneumonia associated with an almost five-fold increase in 30-day mortality.

Methods:

From a prospective consecutive cohort (n=150) undergoing major-abdominal surgery whole-blood RNA was collected preoperatively and at three time-points postoperatively (2-6, 24 and 48hrs). Twelve patients diagnosed with postoperative pneumonia and 27 matched patients remaining infection-free were identified for analysis with RNA-sequencing.

Results:

Compared to preoperative sampling, 3,639 genes were upregulated and 5,043 downregulated at 2-6hrs. Pathway-analysis demonstrated innate-immune activation with neutrophil-degranulation and Toll-like-receptor signalling upregulation alongside adaptive-immune suppression. Cell-type deconvolution of preoperative RNA-sequencing revealed elevated S100A8/9-high neutrophils alongside reduced naïve CD4 T-cells in those later developing pneumonia. Preoperatively, a gene-signature characteristic of neutrophil-degranulation was associated with postoperative pneumonia acquisition (P=0.00092). A previously reported Sepsis Response Signature (SRSq) score, reflecting neutrophil-dysfunction and a more dysregulated host response, at 48hrs postoperatively, differed between patients subsequently developing pneumonia and those remaining infection-free (P=0.045). Analysis of the novel neutrophil gene-signature and SRSq scores in independent major-abdominal surgery and polytrauma cohorts indicated good predictive performance in identifying patients suffering later infection.

Conclusions:

Major-abdominal surgery acutely upregulates innate-immune pathways while simultaneously suppressing adaptive-immune pathways. This is more prominent in patients developing postoperative pneumonia. Preoperative transcriptomic signatures characteristic of neutrophil-degranulation and postoperative SRSq scores may be useful predictors of subsequent pneumonia risk.
Brief PROMIS Assessment Screens for Frailty and Predicts Hospitalizations in Liver Transplant Candidates
Authors: Thuluvath Avesh J. , Duarte-Rojo Andres , Lai Jennifer C. , Peipert John , Dietch Zachary C. , Siddiqui Osama , Morrissey Sheila , Belfanti Kimberly , Zhao Lihui , Guo Kexin , Nizamuddin Mohammad , Polineni Praneet , Levitsky Josh , Flores Ann-Marie , Ladner Daniela P.
Published: July 2023

Background.

Frailty is prevalent in patients with end-stage liver disease and predicts waitlist mortality, posttransplant mortality, and frequency of hospitalizations. The Liver Frailty Index (LFI) is a validated measure of frailty in liver transplant (LT) candidates but requires an in-person assessment.

Methods.

We studied the association between patient-reported physical function and LFI in a single-center prospective study of adult patients with cirrhosis undergoing LT evaluation from October 2020 to December 2021. Frailty was assessed with the LFI and 4-m gait speed. Patient-reported physical function was evaluated using a brief Patient-Reported Outcomes Measurement Information System (PROMIS) survey.

Results.

Eighty-one LT candidates were enrolled, with a mean model of end-stage liver disease–sodium of 17.6 (±6.3). The mean LFI was 3.7 (±0.77; 15% frail and 59% prefrail) and the mean PROMIS Physical Function score was 45 (±8.6). PROMIS Physical Function correlated with LFI (r = –0.54, P < 0.001) and 4-m gait speed (r = 0.48, P < 0.001). The mean hospitalization rate was 1.1 d admitted per month. After adjusting for age, sex, and model of end-stage liver disease–sodium, patient-reported physical function–predicted hospitalization rate (P = 0.001).

Conclusions.

This study suggests that a brief patient-reported outcome measure can be used to screen for frailty and predict hospitalizations in patients with cirrhosis.
Hyperexcitability and translational phenotypes in a preclinical model ofSYNGAP1mutations
Authors: Fenton Timothy A , Haouchine Olivia Y , Hallam Elizabeth L , Smith Emily M , Jackson Kiya C. , Rahbarian Darlene , Canales Cesar , Adhikari Anna , Nord Alexander S. , Ben-Shalom Roy , Silverman Jill L
Published: July 2023

SYNGAP1is a critical gene for neuronal development, synaptic structure, and function. Although rare, the disruption ofSYNGAP1directly causes a genetically identifiable neurodevelopmental disorder (NDD) called SYNGAP1-related intellectual disability. Without functional SynGAP1 protein, patients present with intellectual disability, motor impairments, and epilepsy. Previous work using mouse models with a variety of germline and conditional mutations has helped delineate SynGAP1’s critical roles in neuronal structure and function, as well as key biochemical signaling pathways essential to synapse integrity.

Homozygous loss ofSYNGAP1is embryonically lethal. Heterozygous mutations ofSynGAP1result in a broad range of phenotypes including increased locomotor activity, impaired working spatial memory, impaired cued fear memory, and increased stereotypic behavior. Ourin vivofunctional data, using the original germline mutation mouse line from the Huganir laboratory, corroborated robust hyperactivity and learning and memory deficits. Here, we describe impairments in the translational biomarker domain of sleep, characterized using neurophysiological data collected with wireless telemetric electroencephalography (EEG). We discoveredSyngap1+/-mice exhibited elevated spike trains in both number and duration, in addition to elevated power, most notably in the delta power band. Primary neurons fromSyngap1+/-mice displayed increased network firing activity, greater spikes per burst, and shorter inter-burst intervals between peaks using high density micro-electrode arrays (HD-MEA). This work is translational, innovative, and highly significant as it outlines functional impairments inSyngap1mutant mice. Simultaneously, the work utilized untethered, wireless neurophysiology that can discover potential biomarkers of Syngap1R-ID, for clinical trials, as it has done with other NDDs. Our work is substantial forward progress toward translational work for SynGAP1R-ID as it bridgesin-vitroelectrophysiological neuronal activity and function within vivoneurophysiological brain activity and function. These data elucidate multiple quantitative, translational biomarkersin vivoandin vitrofor the development of treatments for SYNGAP1-related intellectual disability.
Individual patterns of functional connectivity in neonates as revealed by surface-based Bayesian modeling
Authors: Derman Diego , Pham Damon D. , Mejia Amanda F. , Ferradal Silvina L.
Published: July 2023

Resting-state functional connectivity is a widely used approach to study the functional brain network organization during early brain development. However, the estimation of functional connectivity networks in individual infants has been rather elusive due to the unique challenges involved with functional magnetic resonance imaging (fMRI) data from young populations. Here, we use fMRI data from the developing Human Connectome Project (dHCP) database to characterize individual variability in a large cohort of term-born infants (N = 289) using a novel data-driven Bayesian framework. To enhance alignment across individuals, the analysis was conducted exclusively on the cortical surface, employing surface-based registration guided by age-matched neonatal atlases. Using 10 minutes of resting-state fMRI data, we successfully estimated subject-level maps for fourteen brain networks/subnetworks along with individual functional parcellation maps that revealed differences between subjects. We also found a significant relationship between age and mean connectivity strength in all brain regions, including previously unreported findings in higher-order networks. These results illustrate the advantages of surface-based methods and Bayesian statistical approaches in uncovering individual variability within very young populations.
SparrKULee: A Speech-evoked Auditory Response Repository of the KU Leuven, containing EEG of 85 participants
Authors: Accou Bernd , Bollens Lies , Gillis Marlies , Verheijen Wendy , Van hamme Hugo , Francart Tom
Published: July 2023

Researchers investigating the neural mechanisms underlying speech perception often employ electroencephalography (EEG) to record brain activity while participants listen to spoken language. The high temporal resolution of EEG enables the study of neural responses to fast and dynamic speech signals. Previous studies have successfully extracted speech characteristics from EEG data and, conversely, predicted EEG activity from speech features.

Machine learning techniques are generally employed to construct encoding and decoding models, which necessitate a substantial amount of data. We present SparrKULee: A Speech-evoked Auditory Repository of EEG, measured at KU Leuven, comprising 64-channel EEG recordings from 85 young individuals with normal hearing, each of whom listened to 90-150 minutes of natural speech. This dataset is more extensive than any currently available dataset in terms of both the number of participants and the amount of data per participant. It is suitable for training larger machine learning models. We evaluate the dataset using linear and state-of-the-art non-linear models in a speech encoding/decoding and match/mismatch paradigm, providing benchmark scores for future research.
Multiple clines within an ecotype of the yellow monkeyflower, Mimulus guttatus
Authors: Zambiasi Thomas , Lowry David Bryant
Published: July 2023

Premise: A key goal of evolutionary biologists is to understand how and why genetic variation is partitioned within species. In the yellow monkeyflower, Mimulus guttatus (syn. Erythranthe guttata), coastal perennial populations collectively constitute a single genetically and morphologically differentiated ecotype compared to inland populations of M. guttatus. While the distinctiveness of the coastal ecotype has now been well documented, there is also variation in environmental factors across the range of the coastal ecotype that could drive differentiation among its component populations in a more continuous way. Methods: Based on previous observations of a potential cline within this ecotype, we quantified plant height across coastal perennial accessions from 74 total populations in a greenhouse common garden experiment. To evaluate possible environmental factors driving the relationship between trait variation and latitude, we regressed height against multiple climatic factors, including temperature, precipitation, and coastal wind speeds. Results: Multiple traits were correlated with latitude of origin, but none more than plant height. Plant height was negatively correlated with latitude and plants directly exposed to the open ocean were shorter than those that were more protected from onshore coastal winds. Further analyses revealed that height was correlated with climatic factors (precipitation, temperature, and windspeeds) that were autocorrelated with latitude. We hypothesize that one or more of these climatic factors drove the evolution of latitudinal clinal variation within the coastal ecotype. Conclusion: Overall, our study illustrates the complexity of how the distribution of environmental variation can simultaneously drive the evolution of distinct ecotypes as well as continuous clines within those ecotypes.
A Novel Milli-fluidic Liver Tissue Chip with Continuous Recirculation for Predictive Pharmacokinetics Applications
Authors: Priya Rajan Shiny Amala , Sherfey Jason , Ohri Shivam , Nichols Lauren , Smith J. Tyler , Parekh Paarth , Kadar Eugene P. , Clark Frances , George Billy T. , Gregory Lauren , Tess David , Gosset James R. , Liras Jennifer , Geishecker Emily , Obach R. Scott , Cirit Murat
Published: July 2023

A crucial step in lead selection during drug development is accurate estimation and optimization of hepatic clearance usingin vitromethods. However, current methods are limited by factors such as lack of physiological relevance, short culture/incubation times that are not consistent with drug exposure patterns in patients, use of drug absorbing materials, and evaporation during long-term incubation. To address these technological needs, we developed a novel milli-fluidic human liver tissue chip (LTC) that was designed with continuous media recirculation and optimized for hepatic cultures using human primary hepatocytes. Here, we characterized the LTC using a series of physiologically relevant metrics and test compounds to demonstrate that we could accurately predict the PK of both low and high clearance compounds. The non-biological characterization indicated that the cyclic olefin copolymer (COC)-based LTC exhibited negligible evaporation and minimal non-specific binding of drugs of varying ionic states and lipophilicity. Biologically, the LTC exhibited functional and polarized hepatic culture with sustained metabolic CYP activity for at least 15 days. This long-term culture was then used for drug clearance studies for low and high-clearance compounds for at least 12 days and clearance was estimated for a range of compounds with high in vitro in vivo correlation (IVIVC). We also demonstrated that LTC can be induced by rifampicin, and the culture age had insignificant effect on depletion kinetic and predicted clearance value. Thus, we used advances in bioengineering to develop a novel purpose-built platform with high reproducibility and minimal variability to address unmet needs for PK applications.
Physical Chemistry of Drug Permeation through the Cell Membrane with Atomistic Detail
Authors: Paulikat Mirko , Piccini GiovanniMaria , Ippoliti Emiliano , Rossetti Giulia , Arnesano Fabio , Carloni Paolo
Published: July 2023

We provide a molecular-level description of the thermodynamics and mechanistic aspects of drug permeation through the cell membrane. As a case study, we considered the anti-malaria, FDA approved drug chloroquine. Molecular dynamics simulations of the molecule (in its neutral and protonated form) were performed in the presence of different lipid bilayers, with the aim of uncovering key aspects of the permeation process, a fundamental step for drug’s action. Free energy values obtained by well-tempered metadynamics simulations suggest that the neutral form is the only permeating protomer, consistent with experimental data. H-bond interactions of the drug with water molecules and membrane headgroups play a crucial role for permeation. The presence of the transmembrane potential, investigated here for the first time in a drug permeation study, does not qualitatively affect these conclusions.

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Learning high-dimensional reaction coordinates of fast-folding proteins using State Predictive information bottleneck and Bias Exchange Metadynamics
Authors: Pomarici Nancy D. , Mehdi Shams , Quoika Patrick K. , Lee Suemin , Loeffler Johannes R. , Liedl Klaus R. , Tiwary Pratyush , Fernández-Quintero Monica L.
Published: July 2023

Biological events occurring on long timescales, such as protein folding, remain hard to capture with conventional molecular dynamics (MD) simulation. To overcome these limitations, enhanced sampling techniques can be used to sample regions of the free energy landscape separated by high energy barriers, thereby allowing to observe these rare events. However, many of these techniques require a priori knowledge of the appropriate reaction coordinates (RCs) that describe the process of interest. In recent years, Artificial Intelligence (AI) models have emerged as promising approaches to accelerate rare event sampling. However, integration of these AI methods with MD for automated learning of improved RCs is not trivial, particularly when working with undersampled trajectories and highly complex systems. In this study, we employed the State Predictive Information Bottleneck (SPIB) neural network, coupled with bias exchange metadynamics simulations (BE-metaD), to investigate the unfolding process of two proteins, chignolin and villin. By utilizing the high-dimensional RCs learned from SPIB even with poor training data, BE-metaD simulations dramatically accelerate the sampling of the unfolding process for both proteins. In addition, we compare different RCs and find that the careful selection of RCs is crucial to substantially speed up the sampling of rare events. Thus, this approach, leveraging the power of AI and enhanced sampling techniques, holds great promise for advancing our understanding of complex biological processes occurring on long timescales.

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Development of a hepatic cryoinjury model to study liver regeneration
Authors: Sande-Melon Marcos , Bergemann David , Fernandez-Lajarin Miriam , Gonzalez-Rosa Juan Manuel , Cox Andrew Graham
Published: July 2023

The liver is a remarkable organ that can regenerate in response to injury. Depending on the extent of injury, the liver can undergo compensatory hyperplasia or fibrosis. Despite decades of research, the molecular mechanisms underlying these processes are poorly understood. Here, we developed a new model to study liver regeneration based on cryoinjury. To visualise liver regeneration at cellular resolution, we adapted the CUBIC tissue-clearing approach. Hepatic cryoinjury induced a localised necrotic and apoptotic lesion characterised by inflammation and infiltration of innate immune cells. Following this initial phase, we observed fibrosis, which resolved as regeneration re-established homeostasis in 30 days. Importantly, this approach enables the comparison of healthy and injured parenchyma with an individual animal, providing unique advantages to previous models. In summary, the hepatic cryoinjury model provides a fast and reproducible method for studying the cellular and molecular pathways underpinning fibrosis and liver regeneration.
Enhancer plasticity in endometrial tumorigenesis demarcates non-coding somatic mutations and 3D-genome alterations boosting the oncogenic driver ESR1
Authors: Gregoricchio Sebastian , Kojic Aleksandar , Hoogstraat Marlous , Schuurman Karianne , Stelloo Suzan , Severson Tesa M. , O’Mara Tracy A. , Droog Marjolein , Singh Abhishek A. , Glubb Dylan M. , Wessels Lodewyk F.A. , Vermeulen Michiel , van Leeuwen Flora E. , Zwart Wilbert
Published: July 2023

The incidence and mortality of Endometrial Cancer (EC) is on the rise. 85% of ECs depend on Estrogen Receptor alpha (ERα) for proliferation, but little is known about its transcriptional regulation in these tumors.

We generated epigenomics, transcriptomics and Hi-C datastreams in healthy and tumor endometrial tissues, identifying robust ERα reprogramming and profound alterations in 3D genome organization that lead to a gain of tumor-specific enhancer activity during EC development. Integration with endometrial cancer risk single-nucleotide polymorphisms, as well as WGS data from primary tumors and metastatic samples revealed a striking enrichment of risk variants and non-coding somatic mutations at tumor-enriched ERα sites. Through machine learning-based predictions and interaction proteomics analyses, we identified an enhancer mutation which alters 3D genome conformation, impairing recruitment of the transcriptional repressor EHMT2/G9a/KMT1C, thereby alleviating transcriptional repression ofESR1in EC.

In summary, we identified a complex genomic-epigenomic interplay in EC development and progression, altering 3D genome organization to enhance expression of the critical driver ERα.