bluuebunny/crossref_metadata_2025 huggingface dataset:
Eye Drop Adherence With an Eye Drop Bottle Cap Monitor
Authors: Kinast Robert M. , Sanchez Facundo G. , Rees Jack P. , Yeh Kaileen , Gardiner Stuart K. , Dawes Jacob , Johnston Matthew L. , Porter J. David , Klei Viridian , Mansberger Steven L.
Published: April 2023

Précis:

An eye drop bottle cap monitor with audio and visual alarms measured eye drop adherence in 50 subjects with glaucoma. Baseline adherence rates were too high to test if the alarms could improve adherence.

Purpose:

To determine if an eye drop bottle cap monitor can measure and improve adherence.

Materials and Methods:

The Devers Drop Device (D3, Universal Adherence LLC) was designed to measure eye drop adherence by detecting bottle cap removal and replacement, and it can provide text, visual and audio alerts when a medication is due. In Stage 1, we determined baseline adherence for 50 subjects using a nightly eye drop over a 25-day period. Subjects with less than 90% baseline adherence were eligible for Stage 2. In Stage 2, we randomized subjects to receive either no reminder or automated D3 alerts for their nightly eye drop over a subsequent 25-day period. We defined adherence as the proportion of drops administered within 3 hours of the subjects’ scheduled dosing time. Subjects completed 3 questions regarding satisfaction with the device and willingness to pay.

Results:

The D3 monitor remained attached to the eye drop bottle cap for the duration of the study and collected adherence data in all 50 patients. In Stage 1, the mean adherence rate was 90 ± 18% (range 32–100%). Forty (80%) subjects had an adherence rate greater than 90%. Adherence rates were too high in Stage 1 to adequately test the effects of reminders in Stage 2. Ninety-eight percent (49/50) and 96% (48/50) of subjects agreed “the device always stayed attached to the bottle cap” and “I was able to use the device to take the drops”, respectively. Patients would pay $61±83 (range $0-400) for a similar device to improve adherence.

Conclusions:

The D3 can measure eye drop adherence. Research subjects reported high satisfaction and willingness to pay for an eye drop bottle cap monitor. Glaucoma patients have high adherence when they are being monitored, and future studies with research subjects screened for poor adherence may further determine the benefit of electronic monitoring of adherence with and without electronic reminders.
Acute Necrotizing Retinopathy After Xen Gel Stent Implantation
Authors: Lo Wen-Jung , Kuang Tung-Mei , Chen Shih-Jen , Hwang De-Kuang
Published: April 2023

Précis:

We report a case of a 45-year-old woman who developed serous retinal detachment, hypotony, and retinal necrosis after Xen gel stent implantation.

A 45-year-old woman developed sudden blurring of vision 4 days after Xen gel stent replacement surgery. Persistent hypotony, uveitis, and serious retinal detachment rapidly progressed despite medical and surgical treatments. Retinal necrosis, optic atrophy, and total blindness developed within 2 months. Although infectious and autoimmune-related uveitis were ruled out through negative culture and blood test results, acute postoperative infectious endophthalmitis could not be completely excluded in this case. However, toxic retinopathy related to mitomycin-C was suspected eventually.
The Effect of Blue-Light Filtering Intraocular Lenses on the Development and Progression of Glaucoma
Authors: Hecht Idan , Kanclerz Piotr , Achiron Asaf , Elbaz Uri , Tuuminen Raimo
Published: April 2023

Précis:

Among patients who underwent uneventful cataract surgery, an advantage was seen to blue-light filtering (BLF) intraocular lenses (IOLs) in terms of glaucoma-free survival and glaucoma procedure-free survival. Among patients with preexisting glaucoma, no advantage was seen.

Purpose:

To assess the effect of BLF IOLs on the development and progression of glaucoma after cataract surgery.

Patients and Methods:

A retrospective cohort study of patients who underwent uneventful cataract surgery between 2007 and 2018 at Kymenlaakso Central Hospital, Finland. Survival analyses for the overall risk of developing glaucoma or undergoing glaucoma procedures were assessed between patients who received a BLF IOL (SN60WF) and a non-BLF IOL (ZA9003 and ZCB00). A separate analysis was performed on patients with preexisting glaucoma.

Results:

Included 11,028 eyes of 11,028 patients with a mean age of 75 ± 9 years (62% females). The BLF IOL was used in 5188 eyes (47%) and the non-BLF IOL in 5840 eyes (53%). During the follow-up (mean: 55 ± 34 mo), 316 cases of glaucoma were diagnosed. Glaucoma-free survival rates showed an advantage to the BLF IOL (P = 0.036). In a Cox regression analysis controlling for age and sex the use of a BLF IOL was again associated with a lower ratio of glaucoma development (hazard ratio:0.778; 95% CI: 0.621–0.975). Furthermore, glaucoma procedure-free survival analysis revealed an advantage to the BLF IOL (hazard ratio:0.616; 95% CI: 0.406–0.935). Among 662 cases, which already had glaucoma at the time of surgery, no significant differences were seen in any outcome.

Conclusions:

Among a large cohort of patients who underwent cataract surgery, the use of BLF IOLs was associated with favorable glaucoma outcomes compared with the use of non-BLF IOLs. Among patients with preexisting glaucoma, no significant advantage was seen.
Progressive Macular Vessel Density Loss Observed on Optical Coherence Tomography Angiography in Glaucoma Patients With Single-Hemifield Visual Field Defects
Authors: Lin Sigeng , Zhang Shaodan , Shang Xiao , Gu Juan , Ye Cong , Wang Xiaoyan , Zhou Kun , Kong Yu Xiang George , Liang Yuanbo
Published: April 2023

Précis:

Faster hemispheric mVD loss was found in the affected hemifield of POAG patients without significant changes in hemispheric thickness. The progression of mVD loss was associated with the severity of VF damage.

Purpose:

To evaluate the changes in macular vessel density (mVD) loss in primary open angle glaucoma (POAG) patients with visual field (VF) defects confined to 1 hemifield.

Materials and Methods:

This longitudinal cohort study used linear mixed models to evaluate the changes in the hemispheric mean total deviation (mTD), mVD, macular ganglion cell complex, macular ganglion cell-inner plexiform layer, and retinal nerve fiber layer between affected hemifields, unaffected hemifields, and healthy controls.

Results:

Twenty-nine POAG eyes and 25 healthy eyes were followed for an average of 29 months. In POAG eyes, the rates of decline in hemispheric mTD and hemispheric mVD in the affected hemifields were significantly faster than those in the unaffected hemifields (−0.42±1.24 vs. 0.02±0.69 dB/year, P=0.018 and −2.16±1.01 vs. −1.77±0.90% / year, P=0.031, respectively). There were no differences in the rate of hemispheric thickness change between the 2 hemifields. The rate of hemispheric mVD decline in both hemifields of POAG eyes was significantly faster than that of the healthy controls (All P<0.05). An association between the reduced mTD of the VF and the rate of hemispheric mVD loss in the affected hemifield was observed (r=0.484, P=0.008). Faster rates of mVD loss (β=−1.72±0.80, P =0.050) were significantly related to reduced hemispheric mTD in the multivariate analysis.

Conclusions:

Faster hemispheric mVD loss was found in the affected hemifield of POAG patients without significant changes in hemispheric thickness. The progression of mVD loss was associated with the severity of VF damage.
Research on Early Identification Model of Intravenous Immunoglobulin Resistant Kawasaki Disease Based on Gradient Boosting Decision Tree
Authors: Yang Yinan , Yang Chao , Wang Lixia , Cao Shuting , Li Xiaomin , Bai Yana , Hu Xiaobin
Published: April 2023

Background:

To construct a predictive model for intravenous immunoglobulin (IVIG) resistant Kawasaki disease (KD) based on the gradient boosting decision tree (GBDT), so as to early identify children with IVIG resistance and actively take additional treatment to prevent adverse events.

Methods:

The case data of KD children hospitalized in the Pediatric Department of Lanzhou University Second Hospital from October 2015 to July 2020 were collected. All KD patients were divided into IVIG responsive group and IVIG resistant group. GBDT was used to explore the influencing factors of IVIG-resistant KD and to construct a prediction model. Then compared with previous models, the optimal model was selected.

Results:

In the process of GBDT model construction, 80% of the data were used as the test set, and 20% of the data were used as the validation set. Among them, the verification set was used to adjust the hyperparameters in GDBT learning. The model performed best with a hyperparameter tree depth of 5. The area under the curve of the GBDT model constructed based on the best parameters was 0.87 (95% CI: 0.85–0.90), the sensitivity was 72.62%, the specificity was 89.04%, and the accuracy was 61.65%. The contribution degree of each feature value to the model was total bilirubin, albumin, C-reactive protein, fever time, and Na in order.

Conclusion:

The GBDT model is more suitable for the prediction of IVIG-resistant KD in this study area.
Neurologic Complications of Rotavirus Infections in Children
Authors: Slotboom David E. F. , Peeters Daphne , Groeneweg Stefan , van Rijn-Klink Anneloes , Jacobs Elke , Schoenaker Michiel H. D. , van Veen Mirjam
Published: April 2023

Background:

Rotavirus is the leading cause of complicated gastroenteritis in children younger than 5 years in countries where rotavirus vaccination is not implemented as a routine vaccination. Besides the intestinal symptoms that are associated with ordinary gastroenteritis, rotavirus can cause neurological complications. The aim of this study is to describe the clinical characteristics of complicated rotavirus infections.

Methods:

From January 1, 2016 to January 31, 2022, all children (below the age of 18 years) with a positive rotavirus test in feces that were either hospitalized or presented at the outpatient clinic or emergency department of a large pediatric hospital in the Netherlands were included. Rotavirus was only tested in case of a severe or abnormal disease course. We described the clinical characteristics and outcomes with a particular focus on neurological manifestations.

Results:

In total, 59 patients with rotavirus were included of whom 50 (84.7%) were hospitalized and 18 (30.5%) needed intravenous rehydration. Ten patients (16.9%) had neurologic complications, of whom 6 patients (60.0%) presented encephalopathy. Two patients (20.0%) with neurological symptoms showed abnormalities on diagnostic imaging.

Conclusions:

Rotavirus can cause gastroenteritis with severe, but apparently self-limiting, neurological manifestations. Considering rotavirus in pediatric patients with neurological symptoms such as encephalopathy and encephalitis is therefore important. Early detection of rotavirus infection may predict a favorable course of the disease and may thereby prevent unnecessary treatment and should be further investigated.
Volume outcome relationship in postesophagectomy leak: a systematic review and meta-analysis
Authors: Rahouma Mohamed , Baudo Massimo , Mynard Nathan , Kamel Mohamed , Khan Faiza M. , Shmushkevich Shon , Mehta Kritika , Hosny Mohamed , Dabsha Anas , Khairallah Sherif , Demetres Michelle , Saad Reda , Mohamed Abdelrahaman , Port Jeffrey L. , Altorki Nasser K. , Gaudino Mario
Published: April 2023

Background:

Anastomotic leak after esophagectomy carries important short- and long-term sequelae. The authors conducted a systematic review and meta-analysis to determine its association with surgical volume.

Materials and methods:

A systematic literature review was performed to identify all studies reporting on anastomotic leak after esophagectomy. Studies with less than 100 cases were excluded. The primary outcome was postesophagectomy anastomotic leak, while secondary outcomes were operative mortality overall and after anastomotic leak. Pooled event rates (PER) were calculated, and the association with annual esophagectomy volume by center was investigated.

Results:

Of the 3932 retrieved articles, 472 were included (n=177 566 patients). The PER of anastomotic leak was 8.91% [95% CI=8.32; 9.53%]. The PER of early mortality overall and after an anastomotic leak was 2.49% [95% CI=2.27; 2.74] and 11.39% [95% CI=9.66; 13.39], respectively. Centers with less than 37 annual esophagectomies had a higher leak rate compared to those with greater than or equal to 37 annual esophagectomies (9.58% vs. 8.34%; P=0.040). On meta-regression, surgical volume was inversely associated with the PER of esophageal leak and of early mortality.

Conclusions:

The frequency of anastomotic leaks after esophagectomy, perioperative, and leak associated mortality are inversely associated with esophagectomy volume.
Proactive Glucose Screening Tool Effective for Time-sensitive Identification of Hyperglycemia in Childhood Cancer Patients
Authors: Hill Rachel , Hamby Tyler , Levitt Mike , Siebert Garland , Diaz Maranda , Mohamed Ashraf
Published: April 2023

Approximately 4% to 35% of pediatric patients undergoing treatment for acute lymphoblastic leukemia (ALL) and lymphoblastic lymphoma (LLy) develop drug-induced hyperglycemia. Though hyperglycemia is associated with poor outcomes, no guidelines for identifying drug-induced hyperglycemia currently exist, and the time course for developing hyperglycemia remains relatively uncharacterized after induction therapy. The present study evaluated a hyperglycemia screening protocol that was implemented to identify hyperglycemia more promptly, examined predictors of hyperglycemia during ALL and LLy therapy, and described the timeline for developing hyperglycemia. A retrospective review of 154 patients diagnosed with ALL or LLy at Cook Children’s Medical Center between March 2018 and April 2022 was performed. Predictors of hyperglycemia were examined with Cox regression. The hyperglycemia screening protocol was ordered for 88 (57%) patients. Fifty-four (35%) patients developed hyperglycemia. In multivariate analyses, age 10 years or older (hazard ratio = 2.50, P = 0.007) and weight loss (vs gain) during induction (hazard ratio = 3.39, P < 0.05) were associated with hyperglycemia. The present study identified a population of patients at risk of developing hyperglycemia and identifies strategies for hyperglycemia screening. In addition, the present study showed that some patients developed hyperglycemia after induction therapy, which highlights the importance of continued blood glucose monitoring in at-risk patients. Implications and suggestions for further research are discussed.
Lateral Tarsal Strip versus Tensor Fascia Lata Sling for Paralytic Ectropion - Comparison and Long-Term Outcomes
Authors: Sanchez Cristina V. , Thachil Roshni , Mitchell Dalia N. , Reisch Joan S. , Rozen Shai M.
Published: April 2023

Background:

Paralytic ectropion increases risk for corneal injury in facial palsy patients. While a lateral tarsal strip (LTS) provides corneal coverage through supero-lateral lower eyelid pull, the unopposed lateral force may result in lateral displacement of the lower eyelid punctum and overall worsening asymmetry. A tensor fascia lata (TFL) lower eyelid sling may overcome some of these limitations. This study quantitatively compares scleral show, punctum deviation, lower marginal reflex distance (MRD), and peri-orbital symmetry between the two techniques.

Methods:

Retrospective review was performed on facial paralysis patients who underwent a LTS or TFL sling with no prior lower lid suspension procedures. Standardized pre- and post-operative images in primary gaze position were used to measure scleral show and lower punctum deviation using ImageJ, and lower MRD using Emotrics.

Results:

Of 449 facial paralysis patients, 79 met inclusion criteria. Fifty-seven underwent a LTS and twenty-two a TFL sling. Compared to pre-operatively, lower medial scleral show significantly improved with both LTS (10.9 mm2, p<0.01) and TFL (14.7 mm2, p<0.01). The LTS group showed significant worsening of horizontal and vertical lower punctum deviation when compared to the TFL group (both p<0.01). While the LTS group failed to achieve periorbital symmetry between the healthy and paralytic eye across all parameters measured post-operatively (p<0.01); the TFL group achieved symmetry in medial scleral show, lateral scleral show, and lower punctum deviation.

Conclusions:

In patients with paralytic ectropion, TFL sling provides similar outcomes to LTS with added advantages of symmetry without lateralization or caudalization the lower medial punctum.
Enhancing Philtrum Morphology Using Fat Grafting Combined with Percutaneous Rigottomy in Repaired Unilateral Cleft Lip: Three-Dimensional Morphometric- and Panel Assessment-Based Outcome Study
Authors: Denadai Rafael , Tangco Ivy , Valentine Maria , Wallace Christopher Glenn , Hsiao Yen-Chang , Huang Jung-Ju , Chang Frank Chun-Shin , Lo Lun-Jou , Chen Jyh-Ping , Chen Yu-Ray
Published: April 2023

Improving the philtrum morphology of patients with a secondary cleft lip deformity has been a challenge in cleft care. Combining fat grafting with percutaneous rigottomy has been advocated for treatment of volumetric deficiency associated with a scarred recipient site. This study assessed the outcome of synchronous fat grafting and rigottomy for improvement of cleft philtrum morphology. Consecutive young adult patients (n=13) with a repaired unilateral cleft lip who underwent fat grafting combined with rigottomy expansion technique for enhancement of philtrum morphology were included. Preoperative and postoperative three-dimensional facial models were used for 3D morphometric analyses including philtrum height, projection, and volume parameters. Lip scar was qualitatively judged by a panel composed by two blinded external plastic surgeons using a 10-point visual analogue scale. 3D morphometric analysis revealed a significant (all p<0.05) postoperative increase of the lip height-related measurements for cleft philtrum height, noncleft philtrum height, and central lip length parameters, with no difference (p>0.05) between cleft and noncleft sides. The postoperative 3D projection of the philtral ridges was significantly (p<0.001) larger in cleft (1.01±0.43 mm) than noncleft sides (0.51±0.42 mm). The average philtrum volume change was 1.01±0.68 cm3, with an average percentage fat graft retention of 43.36±11.35 percent. The panel assessment revealed significant (p<0.001) postoperative scar enhancement for qualitative rating scale, with mean preoperative and postoperative scores of 6.69±0.93 and 7.88±1.14, respectively. Synchronous fat grafting and rigottomy improved philtrum length, projection, and volume and lip scar in patients with repaired unilateral cleft lip.

CLINICAL QUESTION/LEVEL OF EVIDENCE:

Therapeutic, IV.
“Autologous Cranioplasty Using a Dental SafeScraper Device.”
Authors: Ng Jinggang J. , Blum Jessica D. , Cheung Liana , Cho Daniel Y. , Romeo Dominic J. , Kalmar Christopher L. , Villavisanis Dillan F. , Bartlett Scott P. , Taylor Jesse A. , Swanson Jordan W.
Published: April 2023

Conventional methods to reconstruct cortical bone defects introduced by pediatric cranial vault remodeling (CVR) procedures have shortcomings. Use of bone burr shavings as graft material leads to variable ossification and harvesting split-thickness cortical grafts is time-intensive and often not possible in thin infant calvaria. Since 2013, our team has used the Geistlich SafeScraper (Baden-Baden, Germany), originally developed as a dental instrument, to harvest cortical and cancellous bone grafts during CVR. We assessed the effectiveness of this technique by analyzing postoperative ossification using computed tomography (CT) scans among 52 patients, comparing cohorts treated with the SafeScraper versus those who received conventional methods of cranioplasty during fronto-orbital advancement (FOA). The SafeScraper cohort had a greater reduction in total surface area of all defects (-83.1 ± 14.9 versus -68.9 ± 29.8%, p = 0.034), demonstrating a greater and more consistent degree of cranial defect ossification compared to conventional methods of cranioplasty, suggesting potential adaptability of this tool. This is the first study that describes the technique and efficacy of the SafeScraper in reducing cranial defects in CVR.
A self-help virtual therapeutic experience intervention for overcoming psychological distress related to the COVID-19 pandemic: Results from the European multicentric COVID Feel Good trial
Authors: Riva Giuseppe , Di Lernia Daniele , Tuena Cosimo , Bernardelli Luca , Gutiérrez Maldonado Jose , Ferrer-Garcia Marta , Porras-Garcia Bruno , Meyer Marie , Shiban Youssef , Castelnuovo Gianluca , Pagnini Francesco , Pedroli Elisa , Sforza Francesca , Clementi Alex , Sansoni Maria , Wiederhold Brenda K. , Serino Silvia
Published: April 2023

Objective

The general objective of the current study was to investigate the efficacy of a novel self-help virtual therapeutic experience (specifically, the COVID Feel Good intervention) in lowering the psychological burden experienced during the COVID-19 lockdowns in four European countries.

Methods

We focused on participants recruited from June 2020 to May 2021 in the context of a European multicenter project including four university/academic sites. The total number of participants in the longitudinal studies was 107 (Study 1- N = 40; Study 2: N = 29; Study 3: N = 38). The randomized controlled trial (Study 4) included 31 participants in total, 16 in the intervention group and 15 in the control group. Primary outcome measures were depression, anxiety, stress symptoms, perceived stress level, and perceived hopelessness. The secondary outcome was experienced social connectedness.

Results

Using separate linear mixed-effect models, the most consistent result across countries was a reduction in perceived stress following the participation in the COVID Feel Good intervention. By pooling the results of the models using a random-effect meta-analysis, we found that after the COVID Feel Good intervention, participants reported a decrease in perceived general distress [mean standardized effect size for general distress in the treatment groups compared to the control conditions was -0.52 (p = 0.008, 95% CI: -0.89, -0.14)] and an increase in the perceived social connection [mean standardized effect size for social connection using COVID Feel Good compared to the control conditions was 0.50 (p = < 0.001, 95% CI: 0.25, 0.76)].

Conclusion

Findings of this study indicate that a virtual self-help intervention is effective in reducing psychological distress. These results contribute to the growing literature supporting the use of digital psychological therapies to relieve psychological distress among the general population during the COVID-19 pandemic.

Trial registration: ISRCTN63887521
Racial Differences in Mental Stress-Induced Transient Endothelial Dysfunction and Its Association with Cardiovascular Outcomes
Authors: Okoh Alexis K. , Young An , Garcia Mariana , Sullivan Samaah , Almuwaqqat Zakaria , Hu Yingtian , Liu Chang , Moazzami Kasra , Uphoff Irina , Lima Bruno B. , Ko Yi-An , Elon Lisa , Jajeh Nour , Rout Pratik , Gupta Shishir , Shah Amit J. , Bremner J. Douglas , Lewis Tene , Quyyumi Arshed , Vaccarino Viola
Published: April 2023

OBJECTIVES

To investigate differences in transient endothelial dysfunction (TED) with mental stress in Black and non-Black individuals with coronary heart disease (CHD), and their potential impact on cardiovascular outcomes.

METHODS

We examined 812 patients with stable CHD between June 2011 and March 2016 and followed through February 2020 at a University-affiliated hospital network. Flow mediated vasodilation (FMD) was assessed before and 30 minutes after mental stress. TED was defined as a lower post-stress FMD than pre-stress FMD. We compared pre-stress FMD, post-stress FMD, and TED between Black and non-Black participants. In both groups, we examined the association of TED with an adjudicated composite end point of cardiovascular death or nonfatal myocardial infarction (First and recurring events) after adjusting for demographic, clinical, and socioeconomic factors.

RESULTS

Pre-stress FMD was lower in Black than non-Black participants: 3.7 (2.8) vs. 4.9 (3.8), p < 0.001, and significantly declined with mental stress in both groups. TED occurred more often in Black (76%) than non-Black patients (67%); multivariable-adjusted odds ratio, 1.6, 95% CI, 1.5-1.7. Over a median (interquartile range) follow-up period of 75 (65-82) months, 142 (18%) patients experienced either cardiovascular death or nonfatal myocardial infarction. Black participants had a 41.9% higher risk of the study outcome than non-Black participants (95% CI, 1.01-1.95). TED with mental stress explained 69% of this excess risk.

CONCLUSIONS

Among CHD patients, Black individuals are more likely than non-Black individuals to develop endothelial dysfunction with mental stress, which in turn explains a substantial portion of their excess risk of adverse events.
Direct and Indirect Effects of Race and Socioeconomic Deprivation on Outcomes After Lower Extremity Bypass
Authors: Powell Chloé A. , Albright Jeremy , Culver Jacob , Osborne Nicholas H. , Corriere Matthew A. , Sukul Devraj , Gurm Hitinder , Henke Peter K.
Published: April 2023

Objective:

To evaluate the potential pathway, through which race and socioeconomic status, as measured by the social deprivation index (SDI), affect outcomes after lower extremity bypass chronic limb-threatening ischemia (CLTI), a marker for delayed presentation.

Background:

Racial and socioeconomic disparities persist in outcomes after lower extremity bypass; however, limited studies have evaluated the role of disease severity as a mediator to potentially explain these outcomes using clinical registry data.

Methods:

We captured patients who underwent lower extremity bypass using a statewide quality registry from 2015 to 2021. We used mediation analysis to assess the direct effects of race and high values of SDI (fifth quintile) on our outcome measures: 30-day major adverse cardiac event defined by new myocardial infarction, transient ischemic attack/stroke, or death, and 30-day and 1-year surgical site infection (SSI), amputation and bypass graft occlusion.

Results:

A total of 7077 patients underwent a lower extremity bypass procedure. Black patients had a higher prevalence of CLTI (80.63% vs 66.37%, P < 0.001). In mediation analysis, there were significant indirect effects where Black patients were more likely to present with CLTI, and thus had increased odds of 30-day amputation [odds ratio (OR): 1.11, 95% CI: 1.068–1.153], 1-year amputation (OR: 1.083, 95% CI: 1.045–1.123) and SSI (OR: 1.052, 95% CI: 1.016–1.089). There were significant indirect effects where patients in the fifth quintile for SDI were more likely to present with CLTI and thus had increased odds of 30-day amputation (OR: 1.065, 95% CI: 1.034–1.098) and SSI (OR: 1.026, 95% CI: 1.006–1.046), and 1-year amputation (OR: 1.068, 95% CI: 1.036–1.101) and SSI (OR: 1.026, 95% CI: 1.006–1.046).

Conclusions:

Black patients and socioeconomically disadvantaged patients tended to present with a more advanced disease, CLTI, which in mediation analysis was associated with increased odds of amputation and other complications after lower extremity bypass compared with White patients and those that were not socioeconomically disadvantaged.
The Goal of Intraoperative Blood Loss in Major Hepatobiliary Resection for Perihilar Cholangiocarcinoma
Authors: Kawakatsu Shoji , Mizuno Takashi , Yamaguchi Junpei , Watanabe Nobuyuki , Onoe Shunsuke , Sunagawa Masaki , Baba Taisuke , Igami Tsuyoshi , Yokoyama Yukihiro , Imaizumi Takahiro , Ebata Tomoki
Published: April 2023

Objective:

To determine the goal of intraoperative blood loss in hepatectomy for perihilar cholangiocarcinoma.

Background:

Although massive bleeding can negatively affect the postoperative course, the target value of intraoperative bleeding to reduce its adverse impact is unknown.

Methods:

Patients who underwent major hepatectomy for perihilar cholangiocarcinoma between 2010 and 2019 were included. Intraoperative blood loss was adjusted for body weight [adjusted blood loss (aBL)], and the overall postoperative complications were evaluated by the comprehensive complication index (CCI). The impact of aBL on CCI was assessed by the restricted cubic spline regression.

Results:

A total of 425 patients were included. The median aBL was 17.8 (interquartile range, 11.8–26.3) mL/kg, and the CCI was 40.6 (33.7–49.5). Sixty-three (14.8%) patients had an aBL<10 mL/kg, nearly half (45.4%) of the patients were in the range of 10 ≤aBL<20 mL/kg, and 37 (8.7%) patients had an aBL >40 mL/kg. The spline regression analysis showed a nonlinear incremental association between aBL and CCI; CCI remained flat with an aBL under 10 mL/kg; increased significantly with an aBL ranging from 10 to 20 mL/kg; grew gradually with an aBL over 20 mL/kg. These inflection points of ~10 and 20 mL/kg were almost consistent with the cutoff values identified by the recursive partitioning technique. After adjusting for other risk factors for the postoperative course, the spline regression identified a similar model.

Conclusions:

aBL had a nonlinear aggravating effect on CCI after hepatectomy for perihilar cholangiocarcinoma. The primary goal of aBL should be <10 mL/kg to minimize CCI.
Discordance Between Conventional and Detailed Lymph Node Analysis in Resected, Node-negative Pancreatic or Ampullary Adenocarcinomas and Association With Adverse Survival Outcomes
Authors: Elshami Mohamedraed , Ammoun Alwalid K. , Mneimneh Wadad S. , Stitzel Henry J. , Hue Jonathan J. , Wu Victoria S. , Kyasaram Ravi K. , Shanahan John , Musonza Tashinga , Ammori John B. , Hardacre Jeffrey M. , Winter Jordan M. , ElHag Mohamed , Ocuin Lee M.
Published: April 2023

Objective:

To assess the frequency of occult metastases (OM) in patients with resected pancreatic ductal adenocarcinoma (PDAC) or ampullary adenocarcinoma (AA) discovered on detailed pathologic examination on lymph nodes (LNs) previously considered negative by conventional analysis and to examine the association between OM and overall survival (OS).

Background:

Poor prognosis of patients with no pathologic evidence of LN metastases may be due to OM that is not detected on conventional LN analysis.

Methods:

Patients with LN-negative resected PDAC or AA (2010–2020) were identified from our institutional database. Original hematoxylin and eosin (H and E) slides were reanalyzed. In addition, selected LN were analyzed by H and E (3 sections/LN) and pan-cytokeratin (AE1-AE3/PCK26) immunohistochemistry.

Results:

A total of 598 LNs from 74 LN-negative patients were reexamined. Nineteen patients (25.7%) had OM; 9 (47.4%) were found with immunohistochemistry but not on H and E. The number of positive LNs ranged from 1 to 3. No clinicodemographic, pathologic, or treatment-related factors were associated with OM. On conventional LN analysis, 3/19 patients (15.8%) had stage IA, 9/34 (26.5%) had stage IB, and 7/19 (36.8%) had stage IIA. On detailed LN analysis, 11/19 patients (57.9%) were upstaged to IIB, whereas 8/19 (42.1%) had isolated tumor cells only (N0i+). OM was associated with shorter OS (median OS: 22.3 vs 50.5 months; hazard ratio=3.95, 95% CI: 1.58–9.86).

Conclusions:

There is a 26% discordance rate between conventional and detailed LN pathologic analysis in resected PDAC and AA. The presence of OM is associated with shorter OS.
Macroperiodic Oscillations: A Potential Novel Biomarker of Outcome in Neonatal Encephalopathy
Authors: Keene Jennifer C. , Loe Maren E. , Fulton Talie , Keene Maire , Mathur Amit , Morrissey Michael J. , Tomko Stuart R. , Vesoulis Zachary A. , Zempel John M. , Ching ShiNung , Guerriero Réjean M.
Published: April 2023

Purpose:

Neonatal encephalopathy (NE) is a common cause of neurodevelopmental morbidity. Tools to accurately predict outcomes after therapeutic hypothermia remain limited. We evaluated a novel EEG biomarker, macroperiodic oscillations (MOs), to predict neurodevelopmental outcomes.

Methods:

We conducted a secondary analysis of a randomized controlled trial of neonates with moderate-to-severe NE who underwent standardized clinical examination, magnetic resonance (MR) scoring, video EEG, and neurodevelopmental assessment with Bayley III evaluation at 18 to 24 months. A non-NE cohort of neonates was also assessed for the presence of MOs. The relationship between clinical examination, MR score, MOs, and neurodevelopmental assessment was analyzed.

Results:

The study included 37 neonates with 24 of whom survived and underwent neurodevelopmental assessment (70%). The strength of MOs correlated with severity of clinical encephalopathy. MO strength and spread significantly correlated with Bayley III cognitive percentile (P = 0.017 and 0.046). MO strength outperformed MR score in predicting a combined adverse outcome of death or disability (P = 0.019, sensitivity 100%, specificity 77% vs. P = 0.079, sensitivity 100%, specificity 59%).

Conclusions:

MOs are an EEG-derived, quantitative biomarker of neurodevelopmental outcome that outperformed a comprehensive validated MRI injury score and a detailed systematic discharge examination in this small cohort. Future work is needed to validate MOs in a larger cohort and elucidate the underlying pathophysiology of MOs.
Breast Cancer Recurrence by Subtype in a Diverse, Contemporary Cohort of Young Women
Authors: Vuong Brooke , Darbinian Jeanne , Savitz Alison , Odele Patience , Perry Lauren M. , Sandhu Lakhbir , Habel Laurel , Kuehner Gillian
Published: April 2023

Background:

Young breast cancer (YBC) patients are a unique subpopulation that are often underrepresented in randomized clinical trials. Furthermore, large national cancer databases lack detailed information on recurrence, a meaningful oncologic outcome for young patients.

Study Design:

Retrospective review of YBC patients (age ≤40) with Stage I-III breast cancer diagnosed from 2008 to 2018 was performed. Information on clinicopathologic characteristics, demographics, and outcomes were obtained from the electronic health record and chart review. Chi-square and Fisher exact tests were used for comparisons of categorical variables and parametric and nonparametric tests for continuous variables.

Results:

The cohort included 1,431 women with a median follow-up of 4.8 years (range: 0.3-12.9 years). The median age was 37 (IQR: 34-39). The study population included 598 (41.8%) White, 112 (7.8%) Black, 420 (29.4%) Asian/Pacific Islander, 281 (19.6%) Hispanic, and 20 (1.4%) “other” race/ethnicity patients. Tumor subtype was as follows: [1] Hormone Receptor (HR)+/HER2-, Grade (G) 1-2 =541 (37.8%); [2] HR+/HER2-, G3 =268 (18.7%); [3] HR+/HER2+ =262 (18.3%); [4] HR-/HER2+ =101 (7.1%); [5] HR-/HER2- =259 (18.1%). The majority (64.2%) presented with Stage II/III disease. There were 230 (16.1%) recurrences during follow-up; 74.8% were distant. Locoregional only recurrence was seen in 17/463 (3.7%) patients who underwent breast conservation versus 41/968 (4.2%) of patients undergoing mastectomy (p<0.001). Recurrence varied by tumor subtype: [1] HR+/HER2-, G1-2 (14.0%); [2] HR+/HER2-, G3 (20.9%); [3] HR+/HER2+ (11.1%); [4] HR-/HER2+ (22.8%); [5] HR-/HER2- (17.8%) (p=0.005).

Conclusion:

In this large, diverse YBC cohort, recurrences were most frequent among HR+/HER2-, G3 or HR-/HER2+ invasive tumors; most were distant. There were numerically similar locoregional-only recurrences after breast conservation versus mastectomy. Additional research is needed to identify predictors of recurrence.
Identification of a specific inflammatory protein biosignature in coronary and peripheral blood associated with increased risk of future cardiovascular events
Authors: Proudfoot Diane , Gigante Bruna , West Nick E.J. , Hoole Stephen P. , Strawbridge Rona J. , Tremoli Elena , Baldassarre Damiano , Williams Simon
Published: April 2023

Background and rationale

As an adjunct to coronary intervention, the Liquid Biopsy System (LBS, PlaqueTec, UK) enables accurate intracoronary blood sampling at discrete sites simultaneously. We investigated variation between local coronary and remote (peripheral) blood levels of a panel of atherosclerosis-associated proteins and examined how this might relate to cardiovascular risk assessment.

Methods and Results

In a previous proof-of-concept trial, coronary blood samples were collected using the LBS in 28 patients. For 12 of these patients, sampling was conducted across the uninstrumented lesion, prior to percutaneous coronary intervention (PCI). Peripheral blood samples were also collected, at baseline and after PCI. Protein levels in coronary and peripheral plasma samples were analysed by proximity extension assay (PEA, Olink).

Before PCI, in 10 out of 12 patients, coronary levels of hepatocyte growth factor (HGF), pappalysin-1 (PAPPA) and spondin-1 (SPON1) were elevated compared with peripheral levels, in some cases >10-fold. Following PCI, involving iatrogenic plaque rupture prior to stenting, peripheral levels of these proteins were elevated to a similar degree as coronary levels. In 2 patients, peripheral elevations of HGF, PAPPA and SPON1 (all >90thcentile) were observed at baseline, prior to PCI. The protein pattern that was identified, consisting of high levels of a combination of HGF, PAPPA and SPON1 was absent in healthy control peripheral blood, but when investigated in baseline peripheral blood samples from reference cardiovascular and COVID-19 patient cohorts, was associated with the occurrence of major adverse cardiovascular events (MACE) and mortality.

Conclusions

From investigation of coronary and peripheral blood samples, we identified a novel inflammatory protein signature, which when present in peripheral blood appears to portend worse outcomes. Measurement of these proteins could therefore aid identification of individuals at high risk of cardiovascular events or death.

Translational Perspective

Through sampling of local coronary blood, we discovered a novel protein biosignature consisting of a combination of elevated levels of HGF, PAPPA and SPON1. When this biosignature was assessed in peripheral samples from reference cardiovascular and COVID-19 cohorts, it associated with the occurrence of MACE and mortality. The biosignature protein levels correlated with markers of mast cell and neutrophil activity but not with CRP, possibly indicating a specific inflammatory status. Early detection of this protein signal has potential clinical utility to identify specific patients at increased risk of poor outcomes.

Graphical Abstract
Elevated blood pressure accelerates white matter brain aging among late middle-aged women: a Mendelian Randomization study in the UK Biobank
Authors: Feng Li , Ye Zhenyao , Mo Chen , Wang Jingtao , Liu Song , Gao Si , Ke Hongjie , Canida Travis A , Pan Yezhi , Hatch Kathryn S , Ma Yizhou , Chen Chixiang , Mitchell Braxton D. , Hong L.Elliot , Kochunov Peter , Chen Shuo , Ma Tianzhou
Published: April 2023

Background

Elevated blood pressure (BP) is a modifiable risk factor associated with cognitive impairment and cerebrovascular diseases. However, the causal effect of BP on white matter (WM) brain aging remains unclear.

Methods

In this study, we focused on N=219,968 non-pregnant, family-unrelated individuals of European ancestry who had genotype data and two non-null clinical BP measurements available (99,532 male and 120,436 female, mean age=56.55, including 16,901 participants with neuroimaging data available) collected from UK Biobank (UKB). We adopted a chronological age-adjusted brain age metric, Brain Age Gap (BAG), as the outcome variable to measure the brain aging status. As a first step, we established a machine learning model to compute BAG based on white matter microstructure integrity measured by fractional anisotropy (FA) derived from diffusion tensor imaging data in a training set of subjects without hypertension (N=7,728). We then performed a two-sample Mendelian Randomization (MR) analysis to estimate the causal effect of BP on WM BAG in the whole population and subgroups stratified by gender and age brackets using two non-overlapping data sets (N=20,3067 for the set with genotype and BP data but no FA data; and N=8,822 for the set with genotype, BP and FA data). The main MR method used was generalized inverse variance weighted (gen-IVW) with other MR methods also included as sensitivity analysis.

Results

The hypertension group is on average 0.3098 years (95%CI=0.1313,0.4884; p <0.0001) older in WM brain age than the non-hypertension group of the same chronological age. Females are on average 0.8143 years (95% CI=0.6797 to 0.949; p <0.0001) younger in WM brain age than males of the same chronological age. The MR analyses showed an overall significant positive causal effect of diastolic blood pressure (DBP) on WM BAG, where every 10 mm Hg increase in DBP can lead to 0.371 years increase in brain age (CI: 0.034-0.709, p=0.0311). The stratified analysis by age and gender group found such significant causal effect of DBP on BAG to be most prominent among female women aged 50-59 (0.686 years/10mm Hg, CI: 0.054-1.318, p=0.0335) and aged 60-69 (0.962 years/10mm Hg, CI: 0.209-1.714, p=0.0122).

Conclusion

Hypertension and genetic predisposition to higher BP can accelerate WM brain aging specifically targeting at late middle-aged women, providing insights on planning effective control of BP for women in this age group.
A high-throughput 3D kinetic killing assay
Authors: Zhao Renping , Yanamandra Archana K. , Qu Bin
Published: April 2023

In vivo, immune killer cells must infiltrate into tissues and search for their cognate target cells in 3D environments. To investigate the cytotoxic function of immune killer cells, there is currently a significant need for an in vitro kinetic assay that resembles 3D in vivo features. Our work presents a high-throughput kinetic killing assay in 3D that is a robust and powerful tool for evaluating the killing efficiency of immune killer cells, as well as the viability of tumor cells under in vivo-like conditions. This assay holds particular value for assessing primary human CTLs and NK cells and can also be applied to primary murine killer cells. By utilizing collagen concentrations to mimic healthy tissue, soft tumors, and stiff tumors, this assay enables the evaluation of cell function and behavior in physiologically and pathologically relevant scenarios, particularly in the context of solid tumors. Furthermore, this assay shows promise as a personalized strategy for selecting more effective drugs/treatments against tumors, using primary immune cells for individual patients to achieve improved clinical outcomes.
Genetic sex determination in three closely related hydrothermal vent gastropods, including one species with intersex individuals
Authors: Castel J , Pradillon F , Cueff V , Leger G , Daguin-Thiébaut C , Ruault S , Mary J , Hourdez S , Jollivet D , Broquet T
Published: April 2023

Molluscs have a wide variety of sexual systems and have undergone many transitions from separate sexes to hermaphroditism or vice versa, which is of interest for studying the evolution of sex determination and differentiation. Following the serendipitous observation that sex was the primary driver of genetic structure in the hydrothermal vent gastropodAlviniconcha boucheti, we investigated sexual systems and sex determination in this species and two others of the same genus. We combined genome-wide multi-locus genotypes obtained from RAD sequencing with anatomical observations of the gonads of the threeAlviniconchaspecies occurring in the southwest Pacific Ocean:A. boucheti(n=199),A. strummeri(n=41 ind.) andA. kojimai(n=246). In two of the species (A. bouchetiandA. strummeri), the sexes are separate and genetically determined by a male-heterogametic (XY) system. External observation of the gonads in the third species (A. kojimai) also suggested that the sexes were separate, but histological analyses revealed that 76% of the individuals classified as females from external observation of the gonads presented a mosaic of male and female reproductive tissue. Empirical analyses and simulations showed nonetheless that 14 RAD loci were sex-linked with an XY signature inA. kojimai(as compared with 64 inA. strummeriand 373 inA. boucheti). Comparison across species and mapping of RAD loci to a non-contiguous reference genome assembly of the related speciesA. marisindicashowed that all sex-linked loci identified inA. kojimaiare located on five scaffolds that also contain 15 and 67 sex-linked RAD loci in the other two species, respectively. These results suggest that all threeAlviniconchaspecies share the same XY sex determination system, but that the gonad of XXA. kojimaiindividuals are invaded by a variable proportion of male reproductive tissue. It remains to be seen whether the male tissue in these intersex individuals is functional or not. The identification of Y-specific RAD loci (found only inA. boucheti) and the phylogenetic analysis of three sex-linked loci shared by all species suggested that X-Y recombination has evolved differently within each species. This situation of three species showing variation in gonadal development around a probably common sex determination system provides new insights into the reproductive mode of poorly known deep-sea species and questions the evolution of gametogenetic polymorphism in these species.
Local heterogeneity analysis of crystallographic and cryo-EM maps using shell-approximation
Authors: Lunin Vladimir Y. , Lunina Natalia L. , Urzhumtsev Alexandre G.
Published: April 2023

In X-ray crystallography and cryo-EM, experimental maps can be heterogeneous, showing different regions of the structure with different level of details. In this work we interpret the heterogeneity in terms of two parameters, assigned individually for each atom, combining the conventional parameter of atomic displacement with the resolution of the atomic image in the map. We propose a local real-space procedure to estimate the values of these heterogeneity parameters, assuming that a fragment of the density map and preliminary values of atomic coordinates are given. The procedure is based on the representation of the atomic image in an analytical form, as a function of the inhomogeneity parameters and atomic coordinates. In this article, we report the results of the tests both with simulated maps and maps derived from experimental data. For simulated heterogeneous maps containing regions with different resolutions, the method determines the local map resolution near the atomic centers and the values of the atomic displacement parameter with reasonable accuracy. For experimental maps, obtained as a Fourier synthesis of a given global resolution, estimated values of the local resolution are close to the global one, and the values of the estimated displacement parameters are close to the respective values in the refined model. Shown examples of the application of the proposed method to the experimental crystallographic and cryo-EM maps can be seen as a practical proof of method.
Ion-mediated condensation controls the mechanics of mitotic chromosomes
Authors: Witt Hannes , Harju Janni , Chameau Emma M.J. , Bruinsma Charlotte M.A. , Clement Tinka V.M. , Nielsen Christian F. , Hickson Ian D. , Peterman Erwin J.G. , Broedersz Chase P. , Wuite Gijs J.L.
Published: April 2023

During mitosis in eukaryotic cells, mechanical forces generated by the mitotic spindle pull the sister chromatids into the nascent daughter cells. How do mitotic chromosomes achieve the necessary mechanical stiffness and stability to maintain their integrity under these forces? Here, we use optical tweezers to show that ions involved in physiological chromosome condensation are crucial for chromosomal stability, stiffness and viscous dissipation. We combine these experiments with high-salt histone-depletion and theory to show that chromosomal elasticity originates from the chromatin fiber behaving as a flexible polymer, whereas energy dissipation can be explained by interactions between chromatin loops. Taken together, we show how collective properties of mitotic chromosomes, a biomaterial of incredible complexity, emerge from molecular properties, and how they are controlled by the physico-chemical environment.