bluuebunny/crossref_metadata_2025 huggingface dataset:
The association of hysterectomy with or without ovarian conservation with subclinical atherosclerosis progression in healthy postmenopausal women
Authors: Chen Irene J. , Shoupe Donna , Karim Roksana , Stanczyk Frank Z. , Kono Naoko , Sriprasert Intira , Hodis Howard N. , Mack Wendy J.
Published: May 2023

Objective

While the deleterious associations of surgical menopause after bilateral oophorectomy with cardiovascular disease are documented, less is specifically known concerning subclinical atherosclerosis progression.

Methods

We used data from 590 healthy postmenopausal women randomized to hormone therapy or placebo in the Early versus Late Intervention Trial with Estradiol (ELITE), which was conducted from July 2005 to February 2013. Subclinical atherosclerosis progression was measured as annual rate of change in carotid artery intima-media thickness (CIMT) over a median 4.8 years. Mixed-effects linear models assessed the association of hysterectomy and bilateral oophorectomy compared with natural menopause with CIMT progression adjusted for age and treatment assignment. We also tested modifying associations by age at or years since oophorectomy or hysterectomy.

Results

Among 590 postmenopausal women, 79 (13.4%) underwent hysterectomy with bilateral oophorectomy and 35 (5.9%) underwent hysterectomy with ovarian conservation, a median of 14.3 years before trial randomization. Compared with natural menopause, women who underwent hysterectomy with and without bilateral oophorectomy had higher fasting plasma triglycerides while women who underwent bilateral oophorectomy had lower plasma testosterone. The CIMT progression rate in bilaterally oophorectomized women was 2.2 μm/y greater than natural menopause (P = 0.08); specifically, compared with natural menopause, the associations were significantly greater in postmenopausal women who were older than 50 years at the time of bilateral oophorectomy (P = 0.014) and in postmenopausal women who underwent bilateral oophorectomy more than 15 years before randomization (P = 0.015). Moreover, the CIMT progression rate in hysterectomized women with ovarian conservation was 4.6 μm/y greater than natural menopause (P = 0.015); in particular, compared with natural menopause, the association was significantly greater in postmenopausal women who underwent hysterectomy with ovarian conservation more than 15 years before randomization (P = 0.018).

Conclusions

Hysterectomy with bilateral oophorectomy and ovarian conservation were associated with greater subclinical atherosclerosis progression relative to natural menopause. The associations were stronger for later age and longer time since oophorectomy/hysterectomy. Further research should continue to examine long-term atherosclerosis outcomes related to oophorectomy/hysterectomy.
Rectus Muscle Plication in Mini-abdominoplasty with Umbilicus Preservation
Authors: El Israwi Daniel , Watfa William
Published: May 2023

Diastasis recti is a frequent problem that women, particularly, experience after pregnancy. It is an abdominal wall defect in which there is more than 2 cm separation between the abdominal rectus muscles. Aside from being repaired most commonly with a full abdominoplasty, in some cases, diastasis might present with minimal excessive adipocutaneous tissue, thus requiring a mini-abdominoplasty. Because umbilical transposition is not needed in that latter scenario, diastasis repair is only possible by ligating and cutting the existing umbilical stalk to be able to have a direct clear access to the supraumbilical linea alba. However, detaching the umbilical stalk will most certainly lead to the displacement of the umbilicus inferiorly. To overcome this problem, we performed a modified mini-abdominoplasty technique, which repairs the recti diastasis, keeps the umbilical stalk in place, and leaves behind a mini-abdominoplasty scar, thus providing a more cosmetically appealing result in addition to a radical solution to the defect. Moreover, this technique can be performed by any qualified plastic surgeon under basic operating settings.
Evaluation of contemporary methods to determine vascular impedance
Authors: Liulu Xingzhou , Hungerford Sara
Published: May 2023

The past decade has seen considerable growth in therapeutics and device technologies to treat patients with hypertension and other cardiovascular disease states. Uncoupling ventriculo-arterial interactions in these patients, however, is often complex and not adequately accounted for by arterial pressure or vascular resistance measurement alone. In reality, the global vascular load presented to the left ventricle (LV) includes both steady-state and pulsatile components. Whereas steady-state load is best represented by the vascular resistance, pulsatile load, which incorporates wave reflections and arterial stiffness, may oscillate during various phases of the cardiac cycle and is best determined by the vascular impedance (Z). In recent years, measurement of Z has become more readily accessible through an array of simultaneous applanation tonometry, echocardiography and cardiac magnetic resonance (CMR) techniques. In the following review, we evaluate existing and newer methods to assess Z so as to better understand the pulsatile characteristics of the human circulation in hypertension and other cardiovascular disease states.
Skin sympathetic nerve activity and nocturnal blood pressure nondipping in patients with postural orthostatic tachycardia syndrome
Authors: Liu Xiao , Rosenberg Carine , Reaso Jewel N. , Lee Andrew M. , Ricafrente Joselyn , Ebinger Joseph E. , Chen Lan S. , Li Xiaochun , Merz C. Noel Bairey , Rader Florian , Chen Peng-Sheng
Published: May 2023

Objective:

Postural orthostatic tachycardia syndrome (POTS) is associated with abnormal blood pressure (BP) regulation and increased prevalence of nocturnal nondipping. We hypothesized that nocturnal nondipping of BP is associated with elevated skin sympathetic nerve activity (SKNA) in POTS.

Method:

We used an ambulatory monitor to record SKNA and electrocardiogram from 79 participants with POTS (36 ± 11 years, 72 women), including 67 with simultaneous 24-h ambulatory BP monitoring.

Results:

Nocturnal nondipping of BP was present in 19 of 67 (28%) participants. The nondipping group had a higher average SKNA (aSKNA) from midnight of day 1 to 0100 h on day 2 than the dipping group (P = 0.016, P = 0.030, respectively). The differences (Δ) of aSKNA and mean BP between daytime and night-time were more significant in the dipping group compared with the nondipping group (ΔaSKNA 0.160 ± 0.103 vs. 0.095 ± 0.099 μV, P = 0.021, and Δmean BP 15.0 ± 5.2 vs. 4.9 ± 4.2 mmHg, P < 0.001, respectively). There were positive correlations between ΔaSKNA and standing norepinephrine (NE) (r = 0.421, P = 0.013) and the differences between standing and supine NE levels (r = 0.411, P = 0.016). There were 53 (79%) patients with SBP less than 90 mmHg and 61 patients (91%) with DBP less than 60 mmHg. These hypotensive episodes were associated with aSKNA of 0.936 ± 0.081 and 0.936 ± 0.080 μV, respectively, which were both significantly lower than the nonhypotensive aSKNA (1.034 ± 0.087 μV, P < 0.001 for both) in the same patient.

Conclusion:

POTS patients with nocturnal nondipping have elevated nocturnal sympathetic tone and blunted reduction of SKNA between day and night. Hypotensive episodes were associated with reduced aSKNA.
Pacemakers, Implantable Defibrillators and 5G Technology: What We Need to Know
Authors: Mattei Eugenio , Vivarelli Cecilia , Franci Daniele , Pavoncello Settimio , Aureli Tommaso , Calcagnini Giovanni , Censi Federica
Published: May 2023

Pacemakers (PM) and implantable cardioverter defibrillators (ICD) are active implantable medical devices (AIMD) needed in case of cardiac arrhythmias. Given their potentially life-sustaining nature, the interaction between any source of electromagnetic field and these AIMDs is an ongoing concern of patients, industry, and regulators. According to the current regulatory framework, the required immunity of PM and ICD provides a reasonable unperturbed behavior in the presence of cell phones and base stations that use pre-5G technologies. PM/ICD international standards do not consider some peculiar characteristics of 5G technology and some of the 5G technology frequency bands (those above 3 GHz), since these frequencies are considered not to add risks to the AIMD functioning. Here we analyze the theoretical issues about the interference between 5G technology and PM/ICD and propose an experimental approach to perform a measurement campaign.
Influence of Body Posture on Internal Organ Dosimetry: Radiocesium Exposure Modeling Using Novel Posture-dependent Mesh Computational Phantoms
Authors: Carter Lukas M. , Bellamy Michael B. , Choi Chansoo , Kim Chan Hyeong , Bolch Wesley E. , Jokisch Derek , Kesner Adam L.
Published: May 2023

Current practice in reference internal dosimetry assumes a fixed upright standing posture is maintained throughout the dose-integration period. Recently, the mesh-type ICRP adult reference computational phantoms were transformed into different body postures (e.g., sitting, squatting) for use in occupational dose reconstruction applications. Here, for the first time, we apply this phantom series to the study of organ dose estimates following radionuclide intake. We consider the specific cases of 137Cs and 134Cs ingestion (accidental/occupational intake) with attention to variability in absorbed dose as a function of posture. The ICRP Publication 137 systemic biokinetic model for soluble cesium ingestion was used to compute organ-level time-integrated activity coefficients for reference adults, over a 50-y dose-integration period, for 134Cs and 137Cs (and its radioactive progeny 137mBa). Mean posture time-allocations (h d−1 for standing, sitting, and lying) were taken from published survey data. In accord with modern dosimetry formalisms (e.g., MIRD, ICRP), a posture weighting factor was introduced that accounts for the fraction of time spent within each independent posture. Absorbed dose coefficients were computed using PHITS Monte Carlo simulations. ICRP 103 tissue weighting factors were applied along with the posture weighting factors to obtain committed effective dose per unit intake (Sv Bq−1). For 137Cs ingestion, most organ absorbed dose coefficients were negligibly to marginally higher (< ~3%) for sitting or crouched (lying fetal/semi-fetal) postures maintained over the dose commitment period, relative to the upright standing posture. The committed effective dose coefficients were 1.3 × 10−8 Sv Bq−1 137Cs for standing, sitting, or crouched postures; thus, the posture-weighted committed effective dose was not significantly different than the committed effective dose for a maintained upright standing posture. For 134Cs ingestion, most organ absorbed dose coefficients for the sitting and crouched postures were significantly larger than the standing posture, but the differences were still considered minor (< ~8% for most organs). The committed effective dose coefficients were 1.2 × 10−8 Sv Bq−1 134Cs for the standing posture and 1.3 × 10−8 Sv Bq−1 134Cs for the sitting or crouched posture. The posture-weighted committed effective dose was 1.3 × 10−8 Sv Bq−1 134Cs. Body posture has minor influence on organ-level absorbed dose coefficients and committed effective dose for ingestion of soluble 137Cs or 134Cs.
Sunless and Indoor Tanning Among U.S. Non-Hispanic White Women Ages 18–49 Years
Authors: Seidenberg Andrew B. , Julian Anne K. , Hartman Anne M. , Holman Dawn M.
Published: May 2023

The use of indoor ultraviolet tanning devices (also known as “indoor tanning”) has declined in recent years. Less is known about use of dihydroxyacetone-containing products used for tanning (also known as “sunless tanning”). We analyzed data from the 2015 National Health Interview Survey. Analysis was limited to non-Hispanic white women ages 18–49 years. We estimated the proportion of women reporting spray tanning, self-applied lotion tanning, and indoor tanning and used weighted multivariable logistic regression models to examine the relationships between sociodemographic characteristics, skin cancer risk factors, and other cancer risk factors with sunless and indoor tanning. Overall, 17.7% of women reported sunless tanning. Lotion tanning was more common (15.3%) than spray tanning (6.8%), whereas 12.0% of women engaged in indoor tanning. Among sunless tanners, 23.7% also engaged in indoor tanning. Younger age, ever having a skin examination, skin reactions to the sun, binge drinking, and being at a healthy weight were associated with sunless tanning. Although sunless tanning may be less harmful for skin cancer risk than indoor tanning, the frequency with which the two behaviors co-occur suggests that efforts to address societal pressures for women to alter their skin color may have important public health benefits.
The incidence of perioperative lymphatic complications after radical hysterectomy and pelvic lymphadenectomy between robotic and laparoscopic approach : a systemic review and meta-analysis
Authors: Hwang Jong Ha , Kim Bo Wook
Published: May 2023

Background:

Although many studies have reported perioperative complications after radical hysterectomy and pelvic lymph node dissection using robotic and laparoscopic approaches, the risk of perioperative lymphatic complications has not been well identified. The aim of this meta-analysis is to compare the risks of perioperative lymphatic complications after robotic radical hysterectomy and lymph node dissection (RRHND) with laparoscopic radical hysterectomy and lymph node dissection (LRHND) for early uterine cervical cancer.

Materials and methods:

We searched the PubMed, Cochrane Library, Web of Science, ScienceDirect, and Google Scholar databases for studies published up to July 2022 comparing perioperative lymphatic complications after RRHND and LRHND while treating early uterine cervical cancer. Related articles and bibliographies of relevant studies were also checked. Two reviewers independently performed the data extraction.

Results:

A total of 19 eligible clinical trials (15 retrospective studies and 4 prospective studies) comprising 3,079 patients were included in this analysis. Only 107 patients (3.48%) had perioperative lymphatic complications, of which the most common was lymphedema (n=57, 1.85%), followed by symptomatic lymphocele (n=30, 0.97%), and lymphorrhea (n=15, 0.49%). When all studies were pooled, the odds ratio (OR) for the risk of any lymphatic complication after RRHND compared with LRHND was 1.27 (95% confidence interval: 0.86-1.89; P=0.230). In the subgroup analysis, study quality, country of research, and publication year were not associated with perioperative lymphatic complications.

Conclusion:

A meta-analysis of the available current literature suggests that RRHND is not superior to LRHND in terms of perioperative lymphatic complications.
Postmortem Tanning
Authors: Weber Brailyn , Roe Susan , Sens Mary Ann
Published: May 2023

A variety of changes, many predictable and others more aberrant, occur during the postmortem interval. A number of these changes are largely influenced by various environmental conditions. We describe 3 cases of an unusual postmortem change associated with prolonged sunlight exposure in both frozen and nonfrozen individuals. In each case, very well-delineated, dark tanning lines were present where clothing or another object blocked sunlight. This change appears distinct from mummification and scant literature references that describe a tanned skin transformation in cases associated with burials in high salt-containing bogs. Collectively, the cases highlight a novel postmortem phenomenon known as postmortem tanning. The potential mechanism(s) of this change is discussed within the context of known observations. Increased recognition and knowledge of postmortem tanning are exceedingly important in assessing how this change may assist in postmortem scene analysis.
Case Report of Lethal Concentrations of the Over-the-Counter Sleep Aids Diphenhydramine and Melatonin
Authors: Zimmerman Joel T. , Schreiber Sara J. , Huddle Lauren N.
Published: May 2023

Over-the-counter (OTC) medications are not typically considered “drugs of abuse” by the public, yet they are implicated in a portion of overdose cases. Although the toxicity of some OTC medications (such as acetaminophen, aspirin, and diphenhydramine [DPH]) has been extensively reported in the medical literature, the lethality of other substances (including melatonin) has not been well established.

We report the case of a 21-year-old woman who was found deceased within her secure residence. Scene investigation revealed the presence of 5 empty containers of DPH and a partially empty container of melatonin, as well as a handwritten note of apparent suicidal nature. Upon autopsy examination, the gastric mucosa was notable for a green-blue discoloration, and the gastric contents were consisted of a green-tan viscous material with admixed blue particulate material. Further analysis revealed elevated concentrations of both DPH and melatonin within the blood and gastric contents. The death was certified as a suicide by acute combined DPH and melatonin toxicity.

This paper will review the pharmacology of OTC sleep aid medications and provide a brief outline of their documented toxicity, in addition to reinforcing the role of death scene investigation and its correlation with autopsy findings.
Adaptive Clinical Trials in Pediatric Critical Care: A Systematic Review
Authors: Gilholm Patricia , Ergetu Endrias , Gelbart Ben , Raman Sainath , Festa Marino , Schlapbach Luregn J. , Long Debbie , Gibbons Kristen S. ,   on behalf of the Australian and New Zealand Intensive Care Society Paediatric Study Group
Published: May 2023

OBJECTIVES:

This systematic review investigates the use of adaptive designs in randomized controlled trials (RCTs) in pediatric critical care.

DATA SOURCES:

PICU RCTs, published between 1986 and 2020, stored in the www.PICUtrials.net database and MEDLINE, EMBASE, CENTRAL, and LILACS databases were searched (March 9, 2022) to identify RCTs published in 2021. PICU RCTs using adaptive designs were identified through an automated full-text screening algorithm.

STUDY SELECTION:

All RCTs involving children (< 18 yr old) cared for in a PICU were included. There were no restrictions to disease cohort, intervention, or outcome. Interim monitoring by a Data and Safety Monitoring Board that was not prespecified to change the trial design or implementation of the study was not considered adaptive.

DATA EXTRACTION:

We extracted the type of adaptive design, the justification for the design, and the stopping rule used. Characteristics of the trial were also extracted, and the results summarized through narrative synthesis. Risk of bias was assessed using the Cochrane Risk of Bias Tool 2.

DATA SYNTHESIS:

Sixteen of 528 PICU RCTs (3%) used adaptive designs with two types of adaptations used; group sequential design and sample size reestimation. Of the 11 trials that used a group sequential adaptive design, seven stopped early due to futility and one stopped early due to efficacy. Of the seven trials that performed a sample size reestimation, the estimated sample size decreased in three trials and increased in one trial.

CONCLUSIONS:

Little evidence of the use of adaptive designs was found, with only 3% of PICU RCTs incorporating an adaptive design and only two types of adaptations used. Identifying the barriers to adoption of more complex adaptive trial designs is needed.
DYNAMIC METABOLIC CHANGES OBSERVED IN AN LPS-INDUCED SYSTEMIC INFLAMMATION RAT MODEL USING CONTINUOUS LONG-TERM INDIRECT CALORIMETRY EXPERIMENTS
Authors: Murata Satoru , Yamashita Hayato , Kido Satoshi , Harada Daisuke , Ohtsuru Shigeru , Sato Norio
Published: May 2023

Background: Nutritional management is crucial for severely ill patients. Measuring metabolism is believed to be necessary for the acute sepsis phase to accurately estimate nutrition. Indirect calorimetry (IDC) is assumed to be useful for acute intensive care; however, there are few studies on long-term IDC measurement in patients with systemic inflammation. Methods: Rats were categorized into the LPS received or control groups; LPS rats were categorized into underfeeding (UF), adjusted feeding (AF), and overfeeding (OF) groups. Indirect calorimetry measurement was performed until 72 or 144 h. Body composition was measured at −24 and 72 or 144 h, and tissue weight was measured at 72 or 144 h. Results: Low energy consumption and loss of diurnal variation of resting energy expenditure were observed in the LPS group compared with the control group until 72 h, after which the LPS group recovered. The resting energy expenditure in the OF group was higher than that in the UF and AF groups. In the first phase, low energy consumption was observed in all groups. In the second and third phases, higher energy consumption occurred in the OF group than in the UF and AF groups. In the third phase, diurnal variation recovered in all groups. Muscle atrophy caused body weight loss, but fat tissue loss did not occur. Conclusions: We observed metabolic changes with IDC during the acute systemic inflammation phase owing to differences in calorie intake. This is the first report of long-term IDC measurement using the LPS-induced systemic inflammation rat model.
The Impact of Preoperative Pain on Outcomes After Vaginal Reconstructive Surgery and Perioperative Pelvic Floor Muscle Training
Authors: Wang Rui , Tulikangas Paul K. , Sappenfield Elisabeth C.
Published: May 2023

Importance

The impact of preoperative pain on outcomes can guide counseling.

Objective

The objective of this study was to compare outcomes after vaginal reconstructive surgery and pelvic muscle training between women with and without preoperative pain.

Study Design

This is a secondary analysis of the Operations and Pelvic Muscle Training in the Management of Apical Support Loss (OPTIMAL) trial, which randomized patients to a surgical intervention (sacrospinous ligament fixation versus uterosacral vaginal vault suspension) and a perioperative behavioral intervention (pelvic floor muscle training vs usual care). Preoperative pain was defined as a response of “5” or greater on the pain scale or answering “moderately” or “quite a bit” on the Pelvic Floor Distress Inventory question “Do you usually experience pain in the lower abdomen or genital area?”

Results

The OPTIMAL trial included 109 women with preoperative pain and 259 without pain. Although women with pain had worse pain scores and pelvic floor symptoms at baseline and postoperatively, they had greater improvement on pain scores (−2.3 ± 2.4 vs −0.2 ± 1.4, P < 0.001), as well as Pelvic Floor Distress Inventory and Pelvic Floor Impact Questionnaire scores. Among women with pain who underwent a sacrospinous ligament fixation, those who received pelvic floor muscle training had a greater reduction in pain compared with those in the usual care group (−3.0 ± 2.3 vs −1.3 ± 2.1, P = 0.008). Persistent or worsening pain was present at 24 months in 5 (16%) women with preoperative pain.

Conclusions

Women with preoperative pain experience significant improvements in pain and pelvic floor symptoms with vaginal reconstructive surgery. Pelvic floor muscle training perioperatively may be beneficial for select patients.
Pain Catastrophizing and Impact on Pelvic Floor Surgery Experience
Authors: Powell T. Clark , Meyer Isuzu , Redden David T. , Maier Julia , Nguyen Christine , Richter Holly E.
Published: May 2023

Importance

Understanding patients’ perceptions of symptoms and outcomes of urogynecologic surgery is essential for providing high-quality care.

Objective

The aim of the study was to assess association of pain catastrophizing with pelvic floor symptom distress and impact, postoperative pain, and voiding trial in patients undergoing urogynecologic surgery.

Study Design

Individuals whose self-identified gender was female and were undergoing surgery March 2020–December 2021 were included. Participants completed the Pain Catastrophizing Scale (range 0–52), Pelvic Floor Distress Inventory, and Pelvic Floor Impact Questionnaire preoperatively. Pain catastrophizing was score ≥30 and describes the tendency to magnify the overall threat of pain. Voiding trial failure was inability to void ≥2/3 of instilled volume (≤300 mL). The association between pain catastrophizing and symptom distress and impact was assessed with linear regression. A P < 0.05 is significant.

Results

Three hundred twenty patients were included (mean age, 60 years, 87% White). Forty-six of 320 participants (14%) had a pain catastrophizing score ≥30. The pain catastrophizing group had higher body mass index (33 ± 12 vs 29 ± 5), more benzodiazepine use (26% vs 12%), greater symptom distress (154 ± 58 vs 108 ± 60), and greater urogenital (59 ± 29 vs 47 ± 28), colorectal (42 ± 24 vs 26 ± 23), and prolapse (54 ± 24 vs 36 ± 24) subscale scores, all P ≤ 0.02. The pain catastrophizing group had greater impact (153 ± 72 vs 72 ± 64, P < 0.01) and urogenital (60 ± 29 vs 34 ± 28), colorectal (36 ± 33 vs 16 ± 26), and prolapse (57 ± 32 vs 22 ± 27) subscale scores, P < 0.01. Associations remained controlling for confounders (P < 0.01). The pain catastrophizing group had higher 10-point pain scores (8 vs 6, P < 0.01) and was more likely to report pain at 2 weeks (59% vs 20%, P < 0.01) and 3 months (25% vs 6%, P = 0.01). Voiding trial failure did not differ (26% vs 28%, P = 0.98).

Conclusions

Pain catastrophizing is associated with greater pelvic floor symptom distress and impact and postoperative pain but not voiding trial failure.
Bladder Instillation Patterns in a Cohort of Women With Interstitial Cystitis/Bladder Pain Syndrome
Authors: Niino Clarissa A. , Tholemeier Lauren N. , Bresee Catherine , De Hoedt Amanda M. , Barbour Kamil E. , Kim Jayoung , Freedland Stephen J. , Anger Jennifer T.
Published: May 2023

Importance

Interstitial cystitis/bladder pain syndrome (IC/BPS) is a prevalent disorder known to be notoriously difficult to treat.

Objective

The aim of the study was to determine intravesical instillation patterns among women receiving treatment for IC/BPS.

Study Design

This was a retrospective claims-based analysis using the Veterans Affairs Informatics and Computing Infrastructure. Females with an International Classification of Diseases, Ninth Revision, diagnosis of IC/BPS (595.1) were sampled randomly. Patients were considered to have IC/BPS if they had 2 visits with bladder pain in the absence of a positive urine culture 6 weeks or more apart or a history of bladder pain with another visit for bladder pain. Dates of intravesical instillations were extracted. A “course” of instillations was defined as 1 or more instillations made with less than 21 days between visits.

Results

We identified 641 women with a confirmed diagnosis of IC/BPS, 78 of whom underwent a total of 344 intravesical instillations. On average, each woman had 1.5 ± 0.8 courses between October 2004 and July 2016. Each course was an average of 3.1 ± 2.6 instillations. Fifty-five percent of courses consisted of 1 instillation. Only 22% of courses had 6 or more instillations, the number typically recommended to achieve clinical response. Each instillation within a course was an average of 9.4 ± 4.0 days apart. Most instillations (77%) involved a cocktail of 2 or more drugs.

Conclusions

In our cohort, few women with IC/BPS received a recommended treatment course of 6 weekly instillations, with most receiving only 1 per course. Future studies are needed to determine whether instillation courses were altered from the guidelines due to health care provider practice patterns, early improvement, or poor tolerance of instillations.
Impact of Neoadjuvant Paclitaxel/Trastuzumab/Pertuzumab on Breast Tumor Downsizing for Patients with HER2+ Breast Cancer: Single-Arm Prospective Clinical Trial
Authors: Weiss Anna , Li Tianyu , Desai Neelam V , Tung Nadine M , Poorvu Philip D , Partridge Ann H , Nakhlis Faina , Dominici Laura , Sinclair Natalie , Spring Laura M , Faggen Meredith , Constantine Michael , Krop Ian E , DeMeo Michelle , Wrabel Eileen , Alberti Jillian , Chikarmane Sona , Tayob Nabihah , King Tari A , Tolaney Sara M , Winer Eric P , Mittendorf Elizabeth A , Waks Adrienne G
Published: May 2023

BACKGROUND:

The impact of abbreviated neoadjuvant regimens for HER2+ breast cancer on rates of breast conservation therapy (BCT) is unclear. We aimed to determine BCT rates in a single-arm prospective trial of neoadjuvant paclitaxel/trastuzumab/pertuzumab (THP) in patients with stage II or III HER2+ breast cancer.

STUDY DESIGN:

BCT eligibility was prospectively recorded before and after THP. Pre- and posttreatment mammogram and breast ultrasound were required; breast MRI was encouraged. Patients with a large tumor to breast size ratio were eligible for downsizing. Multifocal/multicentric tumors, extensive calcifications, and contraindications to radiation were considered BCT contraindications.

RESULTS:

Overall, 92 patients who received neoadjuvant THP on trial were included. At presentation, 39 (42.4%) were considered eligible for BCT and 53 (57.6%) were not. BCT-eligible patients were older (median 54 vs 47 years, respectively; p = 0.006) and had smaller tumors by palpation (median 2.5 vs 3 cm, respectively; p = 0.004). Of 53 BCT-ineligible patients, 28 were candidates for tumor downsizing, whereas 25 had contraindications to BCT. Overall, 51 (55.4%) patients underwent BCT. Of the 28 patients who were candidates for downsizing, 22 (78.6%) became BCT-eligible after THP and 18 of 22 (81.8%) underwent BCT. In total, 44 of 92 (47.8%) patients experienced breast pathologic complete response (ypT0), including 11 of 25 (44.0%) patients with BCT contraindications at presentation.

CONCLUSIONS:

De-escalated neoadjuvant systemic therapy led to high BCT rates in this cohort. The impact of de-escalated systemic therapy on local therapy and outcomes in early stage HER2+ breast cancer warrants further investigation.
Ornamented species incur higher male mortality in the larval stage
Authors: Moore Michael P.
Published: May 2023

Life-cycle stages are not always capable of evolving independently from each other, but it remains unclear if evolving to meet the demands of one stage actually imposes costs on other stages. Male ornamentation is a useful trait in which to test this potential evolutionary constraint because ornaments improve reproduction in the adult stage but can require the expression of risky traits in the juvenile stage. Here, I compared larval mortality between populations of ornamented and non-ornamented dragonfly species. Since males produce more exaggerated melanin wing ornaments than females, I tested if larval mortality of males is higher in populations of species that have evolved adult male wing ornamentation. My analyses uncover male-biased larval mortality in species that have evolved male ornamentation. These findings indicate that evolving to optimize mating for the adult stage imposes a cost to survival in the larval stage. Thus, this study reveals that evolution in one life-cycle stage can impose fitness costs on other stages that persist over macroevolutionary timescales.
Mechanics of tensegrity cell units incorporating asymmetry and insights into
mollitaxis
Authors: Benvenuti E. , Reho G. A. , Palumbo S. , Fraldi M.
Published: May 2023

The mechanical response of a contractile cell anchored to the substrate through focal adhesions is studied by means of an asymmetric pre-strained tensegrity structure obeying a neo-Hookean stress–strain law. The aim is to assess the influence of overall asymmetric contraction on the cell durotaxis and on the growth of the focal adhesion plaque. The asymmetric kinematics of the system is obtained in two ways, that is by assuming a gradient of the substrate stiffness and through asymmetric buckling. Equivalent springs are purposely considered to represent the stiffness of the ensemble formed by the substrate, the focal adhesion plaque and the integrin ligands. Then, contraction results from elastic strains induced by competing polymerization and actomyosin contraction. The cell mechanical response in terms of durotaxis and its coupling with focal adhesion plaque growth is finally analysed with respect to the effects of asymmetry, gaining some insights into how this asymmetry could participate to redirect cell migration, both in terms of durotaxis and mollitaxis.
A stratified compartmental model for the transmission of
Sparicotyle chrysophrii
(Platyhelminthes: Monogenea) in gilthead seabream (
Sparus aurata
) fish farms
Authors: Stella Elisa , Pastres Roberto , Pasetto Damiano , Kolega Matko , Mejdandžić Danijel , Čolak Slavica , Musmanno Antares , Gustinelli Andrea , Mari Lorenzo , Bertuzzo Enrico
Published: May 2023

The rapid development of intensive fish farming has been associated with the spreading of infectious diseases, pathogens and parasites. One such parasite is
Sparicotyle chrysophrii
(Platyhelminthes: Monogenea), which commonly infects cultured gilthead seabream (
Sparus aurata
)—a vital species in Mediterranean aquaculture. The parasite attaches to fish gills and can cause epizootics in sea cages with relevant consequences for fish health and associated economic losses for fish farmers. In this study, a novel stratified compartmental epidemiological model of
S. chrysophrii
transmission was developed and analysed. The model accounts for the temporal progression of the number of juvenile and adult parasites attached to each fish, as well as the abundance of eggs and oncomiracidia. We applied the model to data collected in a seabream farm, where the fish population and the number of adult parasites attached to fish gills were closely monitored in six different cages for 10 months. The model successfully replicated the temporal dynamics of the distribution of the parasite abundance within fish hosts and simulated the effects of environmental factors, such as water temperature, on the transmission dynamics. The findings highlight the potential of modelling tools for farming management, aiding in the prevention and control of
S. chrysophrii
infections in Mediterranean aquaculture.
Implication of COVID-19 pandemic on the incidence of Clostridioides difficile infection in a Greek tertiary hospital
Authors: Karampatakis Theodoros , Tsergouli Katerina , Kandilioti Eleni , Nikopoulou Anna , Katsifa Helen , Kachrimanidou Melina
Published: May 2023

Introduction.

C. difficile

infection (CDI) represents an important global threat. In the COVID-19 era, the multifactorial nature of CDI has emerged.

Hypothesis – Aim. The aim was to assess the impact of COVID-19 pandemic on the incidence of CDI in a Greek hospital.

Methodology. A retrospective study was performed throughout a 51 month period (January 2018 to March 2022), divided into two periods: pre-pandemic (January 2018 to February 2020) and COVID-19 pandemic (March 2020 to March 2022). The effects of the pandemic compared to the pre-pandemic period on the incidence of CDI [expressed as infections per 10 000 bed days (IBD)] were studied using interrupted time-series analysis.

Results. Throughout the study, there was an increase in the monthly CDI incidence from 0.00 to 11.77 IBD (P<0.001). Interrupted time-series disclosed an increase in CDI incidence during the pre-pandemic period from 0.00 to 3.36 IBD (P<0.001). During the COVID-19 pandemic period the linear trend for monthly CDI rose from 2.65 to 13.93 IBD (P<0.001). The increase rate was higher during the COVID-19 pandemic period (r2 = +0.47) compared to the pre-pandemic period (r1 = +0.16).

Conclusion. A significant increase of CDI incidence was observed, with the rate of the rise being more intense during the COVID-19 pandemic.
Anti-chlamydial effects of azelastine hydrochloride and the impact of the histamine H1 receptor on chlamydial development
Authors: Kuratli Jasmin , Leonard Cory Ann , Schoborg Robert , Borel Nicole
Published: May 2023

Introduction. Azelastine hydrochloride, a second-generation histamine H1 receptor (H1R) antagonist, exhibits anti-chlamydial effects against

Chlamydia trachomatis

(CT) in HeLa cells (genital infection model).

Hypothesis/Gap Statement. Non-antibiotic pharmaceutical interactions with CT are an understudied field and the anti-chlamydial effects of azelastine are a potential interaction requiring further elucidation.

Aim. To explore the underlying anti-chlamydial mechanisms of azelastine.

Methodology. We assessed the specificity of azelastine for the chlamydial species and host cell type, the timing of azelastine application and whether the anti-chlamydial effects could be reproduced with different H1R-modulating compounds.

Results. We observed similar anti-chlamydial azelastine effects for

Chlamydia muridarum

as well as for an ocular CT strain in human conjunctival epithelial cells (ocular infection model). Pre-incubating host cells with azelastine before infection mildly reduced chlamydial inclusion numbers and infectivity. Incubation of cells with azelastine initiated concomitantly with the chlamydial infection, or initiated several hours post-infection, reduced inclusion size, number and infectivity, and altered chlamydial morphology. These effects were strongest when azelastine was added shortly after or with the infection. Azelastine effects were not alleviated by increased concentrations of culture medium nutrients. Additionally, we did not observe anti-chlamydial effects when incubating cultures either with a different H1R antagonist or agonist, indicating that azelastine effects are probably H1R-independent.

Conclusion. Accordingly, we conclude that azelastine anti-chlamydial effects are not restricted to a specific chlamydial species, strain or culture model, and are probably not mediated by H1R antagonism. Thus, it appears likely that off-target mechanisms of azelastine may explain our observations.
Stimulator of interferon genes is required for Toll-Like Receptor-8 induced interferon response
Authors: García-Martínez K. , Chen J. , Jones J. , Woo A. , Aucapina A. , Brito I. , Leifer CA
Published: May 2023

The innate immune system is equipped with multiple receptors to detect microbial nucleic acids and induce type I interferon (IFN) to restrict viral replication. When dysregulated these receptor pathways induce inflammation in response to host nucleic acids and promote development and persistence of autoimmune diseases like Systemic Lupus Erythematosus (SLE). IFN production is regulated by the Interferon Regulatory Factor (IRF) transcription factor family of proteins that function downstream of several innate immune receptors such as Toll-like receptors (TLRs) and Stimulator of Interferon Genes (STING). Although both TLRs and STING activate the same downstream molecules, the pathway by which TLRs and STING activate IFN response are thought to be independent. Here we show that STING plays a previously undescribed role in human TLR8 signaling. Stimulation with the TLR8 ligands induced IFN secretion in primary human monocytes, and inhibition of STING reduced IFN secretion from primary monocytes from 8 healthy donors. We demonstrate that TLR8-induced IRF activity was reduced by STING inhibitors. Moreover, TLR8-induced IRF activity was blocked by inhibition or loss of IKKε, but not TBK1. Bulk RNA transcriptomic analysis supported a model where TLR8 induces transcriptional responses associated with SLE that can be downregulated by inhibition of STING. These data demonstrate that STING is required for full TLR8-to-IRF signaling and provide evidence for a new framework of crosstalk between cytosolic and endosomal innate immune receptors, which could be leveraged to treat IFN driven autoimmune diseases.

Background

High levels of type I interferon (IFN) is characteristic of multiple autoimmune diseases, and while TLR8 is associated with autoimmune disease and IFN production, the mechanisms of TLR8-induced IFN production are not fully understood.

Results

STING is phosphorylated following TLR8 signaling, which is selectively required for the IRF arm of TLR8 signaling and for TLR8-induced IFN production in primary human monocytes.

Conclusion

STING plays a previously unappreciated role in TLR8-induced IFN production

Significance

Nucleic acid-sensing TLRs contribute to development and progression of autoimmune disease including interferonopathies, and we show a novel role for STING in TLR-induced IFN production that could be a therapeutic target.
Synergistic activity of IL-2 mutein with tolerogenic ImmTOR nanoparticles leads to massive expansion of antigen-specific Tregs and protection against autoimmune disease
Authors: Kishimoto Takashi Kei , Fournier Max , Michaud Alicia , Rizzo Gina , Roy Christopher , Capela Teresa , Nukolova Natasha , Li Ning , Doyle Liam , Fu Fen-ni , VanDyke Derek , Traber Peter G. , Spangler Jamie B. , Leung Sheldon S. , Ilyinskii Petr O.
Published: May 2023

Low dose IL-2 therapy and IL-2 molecules engineered to be selective for the high affinity IL-2 receptor have been shown to expand Tregs in vivo, and, in the case of low dose IL-2 therapy, has demonstrated promising therapeutic benefit in autoimmune diseases. One of the potential limitations of IL-2 therapy is the nonselective expansion of pre-existing Treg populations rather than induction of antigen-specific Tregs, as well as potential activation of effector cells. We have recently developed biodegradable nanoparticles encapsulating rapamycin, called ImmTOR, to induce selective immune tolerance to co-administered antigens, such as immunogenic biologic drugs. Unlike Treg-selective IL-2 therapy, ImmTOR alone does not increase total Treg numbers. However, here we demonstrate that the combination of ImmTOR and an engineered Treg-selective IL-2 variant (termed IL-2 mutein) increases the number and durability of total Tregs, as well as inducing a profound synergistic increase in antigen-specific Treg when combined with a target antigen. We demonstrate that the combination of ImmTOR and an IL-2 mutein leads to durable inhibition of antibody responses to co-administered AAV gene therapy capsid, even at sub-optimal doses of ImmTOR, and provides protection in autoimmune models of type 1 diabetes and primary biliary cholangitis. ImmTOR also showed the potential to increase the therapeutic window of engineered IL-2 molecules by mitigating effector T cell expansion typically observed at higher doses of IL-2 and preventing exacerbation of disease in a model of graft-versus-host-disease. At the same time, engineered IL-2 molecules showed potential for dose-sparing of ImmTOR. Overall, these results establish that the combination of ImmTOR and an IL-2 mutein show synergistic benefit on both safety and efficacy to provide durable antigen-specific immune tolerance to mitigate drug immunogenicity and to treat autoimmune diseases.
Global stability and parameter analysis reinforce therapeutic targets of PD-L1-PD-1 and MDSCs for glioblastoma
Authors: Anderson Hannah G. , Takacs Gregory P. , Harris Duane C. , Kuang Yang , Harrison Jeffrey K. , Stepien Tracy L.
Published: May 2023

Glioblastoma (GBM) is an aggressive primary brain cancer that currently has minimally effective treatments. Like other cancers, immunosuppression by the PD-L1-PD-1 immune checkpoint complex is a prominent axis by which glioma cells evade the immune system. Myeloid-derived suppressor cells (MDSCs), which are recruited to the glioma microenviroment, also contribute to the immunosuppressed GBM microenvironment by suppressing T cell functions. In this paper, we propose a GBM-specific tumor-immune ordinary differential equations model of glioma cells, T cells, and MDSCs to provide theoretical insights into the interactions between these cells. Equilibrium and stability analysis indicates that there are unique tumorous and tumor-free equilibria which are locally stable under certain conditions. Further, the tumor-free equilibrium is globally stable when T cell activation and the tumor kill rate by T cells overcome tumor growth, T cell inhibition by PD-L1-PD-1 and MDSCs, and the T cell death rate. Bifurcation analysis suggests that a treatment plan that includes surgical resection and therapeutics targeting immune suppression caused by the PD-L1-PD1 complex and MDSCs results in the system tending to the tumor-free equilibrium. Using a set of preclinical experimental data, we implement the Approximate Bayesian Computation (ABC) rejection method to construct probability density distributions that estimate model parameters. These distributions inform an appropriate search curve for global sensitivity analysis using the extended Fourier Amplitude Sensitivity Test (eFAST). Sensitivity results combined with the ABC method suggest that parameter interaction is occurring between the drivers of tumor burden, which are the tumor growth rate and carrying capacity as well as the tumor kill rate by T cells, and the two modeled forms of immunosuppression, PD-L1-PD-1 immune checkpoint and MDSC suppression of T cells. Thus, treatment with an immune checkpoint inhibitor in combination with a therapeutic targeting the inhibitory mechanisms of MDSCs should be explored.
The ENCODE4 long-read RNA-seq collection reveals distinct classes of transcript structure diversity
Authors: Reese Fairlie , Williams Brian , Balderrama-Gutierrez Gabriela , Wyman Dana , Çelik Muhammed Hasan , Rebboah Elisabeth , Rezaie Narges , Trout Diane , Razavi-Mohseni Milad , Jiang Yunzhe , Borsari Beatrice , Morabito Samuel , Liang Heidi Yahan , McGill Cassandra J. , Rahmanian Sorena , Sakr Jasmine , Jiang Shan , Zeng Weihua , Carvalho Klebea , Weimer Annika K. , Dionne Louise A. , McShane Ariel , Bedi Karan , Elhajjajy Shaimae I. , Upchurch Sean , Jou Jennifer , Youngworth Ingrid , Gabdank Idan , Sud Paul , Jolanki Otto , Strattan J. Seth , Kagda Meenakshi S. , Snyder Michael P. , Hitz Ben C. , Moore Jill E. , Weng Zhiping , Bennett David , Reinholdt Laura , Ljungman Mats , Beer Michael A. , Gerstein Mark B. , Pachter Lior , Guigó Roderic , Wold Barbara J. , Mortazavi Ali
Published: May 2023

The majority of mammalian genes encode multiple transcript isoforms that result from differential promoter use, changes in exonic splicing, and alternative 3’ end choice. Detecting and quantifying transcript isoforms across tissues, cell types, and species has been extremely challenging because transcripts are much longer than the short reads normally used for RNA-seq. By contrast, long-read RNA-seq (LR-RNA-seq) gives the complete structure of most transcripts. We sequenced 264 LR-RNA-seq PacBio libraries totaling over 1 billion circular consensus reads (CCS) for 81 unique human and mouse samples. We detect at least one full-length transcript from 87.7% of annotated human protein coding genes and a total of 200,000 full-length transcripts, 40% of which have novel exon junction chains.

To capture and compute on the three sources of transcript structure diversity, we introduce a gene and transcript annotation framework that uses triplets representing the transcript start site, exon junction chain, and transcript end site of each transcript. Using triplets in a simplex representation demonstrates how promoter selection, splice pattern, and 3’ processing are deployed across human tissues, with nearly half of multitranscript protein coding genes showing a clear bias toward one of the three diversity mechanisms. Evaluated across samples, the predominantly expressed transcript changes for 74% of protein coding genes. In evolution, the human and mouse transcriptomes are globally similar in types of transcript structure diversity, yet among individual orthologous gene pairs, more than half (57.8%) show substantial differences in mechanism of diversification in matching tissues. This initial large-scale survey of human and mouse long-read transcriptomes provides a foundation for further analyses of alternative transcript usage, and is complemented by short-read and microRNA data on the same samples and by epigenome data elsewhere in the ENCODE4 collection.