bluuebunny/crossref_metadata_2025 huggingface dataset:
Outcomes of intralesional osteotomy and distraction osteogenesis for limb length equalization in Ollier’s disease
Authors: Hosny Gamal A. , Elsheikh Ahmed A.
Published: July 2022

Limb length discrepancy and deformities resulting from Ollier’s disease are challenging to treat and have increased complications. We aimed to assess the safety of intralesional osteotomy for distraction osteogenesis and report the results of guided growth as a method of deformity correction in such conditions. We retrospectively reviewed 13 patients (eight boys and five girls), 28 segments (12 femora and 16 tibias), treated using Ilizarov circular ring fixator in one center. Nine patients had an oblique plane deformity, whereas four had a coronal plane deformity. Femoral shortening ranged from three to 11 cm. Tibial shortening ranged from 3.5 to 12 cm. Intralesional osteotomy was carried out in all patients, and guided growth (hemiepiphysiodesis) was used in seven segments (25%). The median age was 11 years (6–14 years) at surgery, with a median follow-up of 4.5 years (3–18 years). The median achieved lengthening in the femur was 7 cm (5–11 cm) and in the tibia was 5 cm (3–9 cm). The average Bone Healing Index (BHI) for the femur was 32 days/cm (28–38 days/cm), and for the tibia was 36 days/cm (28–40 days/cm). Before frame removal, the mechanical axis was restored to the knee joint center in all cases. Normal radiographic bone regeneration was evident in all cases. Hemiepiphysiodesis successfully corrected the angular deformities. Intralesional osteotomy for distraction osteogenesis is well-tolerated and reliable in Ollier’s disease. Radiological normal bone was formed at the distraction site. Guided growth is also a reproducible method for deformity correction in Ollier’s disease, similar to other conditions.
CTLA4, PD-1, PD-L1, PD-L2, TIM-3, TIGIT, and LAG3 DNA Methylation Is Associated With BAP1-Aberrancy, Transcriptional Activity, and Overall Survival in Uveal Melanoma
Authors: de Vos Luka , Carrillo Cano Tzaitel Maria , Zarbl Romina , Klümper Niklas , Ralser Damian Johannes , Franzen Alina , Herr Emmanuelle , Gabrielpillai Jennis , Vogt Timo Jakob , Dietrich Jörn , Strieth Sebastian , Landsberg Jennifer , Dietrich Dimo
Published: July 2022

Uveal melanoma (UM) is an aggressive disease with poor response to oncological treatment, including immunotherapy. Loss of the epigenetic modifier BRCA1-associated protein 1 (BAP1) function drives UM oncogenesis and is associated with an immune-suppressive tumor microenvironment, poor prognosis, and a distinct DNA methylation and gene expression profile. Our study aimed to analyze comprehensively the DNA methylation status of the immune checkpoint genes PD-1, PD-L1, PD-L2, CTLA4, TIM-3 (HAVCR2), TIGIT, and LAG3 and its association with mRNA expression, BAP1-aberrancy, and patients’ survival. We analyzed the DNA methylation landscape of immune checkpoint genes at single CpG resolution in N=80 UM samples provided by The Cancer Genome Atlas. We analyzed CpG methylation levels of the immune checkpoints with regard to their transcriptional signatures and patient outcomes.Methylation of specific CpG sites within the immune checkpoint genes PD-1, PD-L1, PD-L2, CTLA4, TIM-3, TIGIT, and LAG3 correlated strongly with mRNA expression levels, indicating a strong regulation of gene expression through DNA methylation. Moreover, immune checkpoint gene methylation was strongly associated with BAP1-mutation status and associated with overall survival in UM. Our data indicate an epigenetic regulation of immune checkpoints through DNA methylation in UM. Further, our data highlight the prognostic significance of DNA methylation of immune checkpoint genes in UM thereby providing a rationale for methylation testing as predictive biomarkers for immunotherapy response.
Procedure-Related Risk Factors for Surgical Site Infection in Dermatologic Surgery
Authors: Schlager Justin Gabriel , Hartmann Daniela , Ruiz San Jose Virginia , Patzer Kathrin , French Lars E. , Kendziora Benjamin
Published: July 2022

BACKGROUND

Identifying risk factors is essential for preventing surgical site infections (SSIs) in dermatologic surgery.

OBJECTIVE

To analyze whether specific procedure-related factors are associated with SSI.

METHODS

This systematic review of the literature included MEDLINE, EMBASE, CENTRAL, and trial registers. The Newcastle–Ottawa Scale was used for risk bias assessment. If suitable, the authors calculated risk factors and performed meta-analysis using random effects models. Otherwise, data were summarized narratively.

RESULTS

Fifteen observational studies assessing 25,928 surgical procedures were included. Seven showed good, 2 fair, and 6 poor study quality. Local flaps (risk ratio [RR] 3.26, 95% confidence intervall [CI] 1.92–5.53) and skin grafting (RR 2.95, 95% CI 1.37–6.34) were associated with higher SSI rates. Simple wound closure had a significantly lower infection risk (RR 0.34, 95% CI 0.25–0.46). Second intention healing showed no association with SSI (RR 1.82, 95% CI 0.40–8.35). Delayed wound closure may not affect the SSI rate. The risk for infection may increase with the degree of preoperative contamination. There is limited evidence whether excisions >20 mm or surgical drains are linked to SSI.

CONCLUSION

Local flaps, skin grafting, and severely contaminated surgical sites have a higher risk for SSI. Second intention healing and probably delayed wound closure are not associated with postoperative wound infection.
Is There a Smoking Gun for Nicotine? A Review of the Role of Nicotine in Dermatologic Surgery
Authors: Jin Mauricio F. , Campbell Elliott H. , Somani Ally-Khan
Published: July 2022

BACKGROUND

Dermatologic surgeons are faced with a dilemma when counseling actively smoking patients who require dermatologic surgery: recommend total cessation of all nicotine that is associated with extremely high rates of cessation failure or recommend nicotine replacement therapy (NRT).

OBJECTIVE

To determine the safety of NRT in dermatologic surgery.

MATERIALS AND METHODS

PubMed was queried: [(nicotine OR electronic cigarettes) AND (flap OR wound healing)].

RESULTS

Smoking tobacco is detrimental to wound healing, supported by ample evidence (1A). Perioperative smoking cessation reduces risk (1B). Basic science demonstrates both a benefit and detriment of nicotine depending on the factor studied (2A). Human studies suggest no detrimental effect of nicotine on perioperative complications (1B). Nicotine may be detrimental to flaps, but evidence is limited to basic science (2A).

CONCLUSION

Dermatologists should consider recommending nicotine replacement for smokers in the perioperative period. Evidence is lacking to determine safety in flaps. It is presumed based on animal studies that nicotine has a negative effect on flaps; however, it is likely less than tobacco. Weighing the risk of cessation failure without nicotine replacement versus nicotine replacement after flap is challenging. Electronic cigarettes should be discouraged as a means of NRT.
Research Letter: Long-Term Outcomes Following Cognitive Rehabilitation for Mild Traumatic Brain Injury: A 5-Year Follow-Up of a Cohort From the SCORE Randomized Clinical Trial
Authors: Kennedy Jan E. , Cooper Douglas B. , Curtiss Glenn , Shelton Janel L. , Bowles Amy O. , Tate David F. , Eapen Blessen C. , Vanderploeg Rodney D.
Published: July 2022

Objective:

To examine the functioning of military service members 5 years after completing a randomized controlled trial (RCT) of cognitive rehabilitation for mild traumatic brain injury (mTBI).

Setting:

Home-based telephonic interview and internet-based self-ratings.

Participants:

Sixty-nine of the 126 (55%) active-duty service members who were enrolled in a 4-arm RCT of cognitive rehabilitation 3 to 24 months after mTBI and were successfully contacted by phone 5 years later. Original and 5-year follow-up participants in each of 4 RCT treatment arms included: psychoeducation (n = 32 original, n = 17 follow-up), computer (n = 30 original, n = 11 follow-up), therapist-directed (n = 30 original, n = 23 follow-up), integrated (n = 34 original, n = 18 follow-up).

Design:

Inception cohort evaluated 5 years after completion of an RCT of cognitive rehabilitation.

Main Measures:

Postconcussion symptoms (Neurobehavioral Symptom Inventory total score), psychological distress (Symptom Checklist-90-revised Global Severity Index score), and functional cognitive/behavioral symptoms (Key Behaviors Change Inventory total average score).

Results:

Participants' postconcussive symptoms and psychological distress improved at the 5-year follow-up. Functional cognitive/behavioral symptoms were not significantly improved, but therapeutic gains were maintained across time, to 5 years after completing the RCT.

Conclusion:

In this sample of military personnel, postconcussive symptoms and psychological distress significantly improved from posttreatment to 5 years after cognitive rehabilitation, regardless of treatment arm. Functional cognitive/behavioral symptoms significantly improved with treatment while treatment gains were maintained at the 5-year follow-up. Replication of these results with a larger sample and interim data between 18 weeks and 5 years post-treatment is needed.
Is Traumatic Brain Injury Severity in Service Members and Veterans Related to Health-Related Quality of Life in Their Caregivers?
Authors: Brickell Tracey A. , Lippa Sara M. , Wright Megan M. , Varbedian Nicole V. , Tippett Corie E. , Byrd Anice M. , French Louis M. , Lange Rael T.
Published: July 2022

Objective:

To examine the relationship between service member/veteran (SM/V) traumatic brain injury (TBI) severity with caregiver health-related quality of life (HRQOL).

Setting:

Military treatment facility.

Participants:

Caregivers (N = 316) of SM/Vs following a TBI divided into 2 groups based on SM/V TBI severity: (1) caregivers of SM/Vs following an uncomplicated mild TBI (UnMTBI Caregiver group, n = 246), and (2) caregivers of SM//Vs following a complicated mild, moderate, severe, or penetrating TBI (STBI Caregiver group, n = 70). The STBI Caregiver group was further divided into 2 subgroups: Parent (n = 21) versus Intimate Partner (n = 49). The UnMTBI Caregiver group consisted of intimate partners.

Design:

Prospective cohort.

Main Measures:

Caregivers completed 15 HRQOL measures.

Results:

Using analysis of variance and chi-square analysis, the UnMTBI Caregiver group reported worse scores on 12 HRQOL measures and more clinically elevated scores for 6 of 15 comparisons than the STBI Caregiver group. The UnMTBI Caregiver group also reported worse scores on 10 HRQOL measures than intimate partners in the STBI Caregiver group and 5 measures than parents in the STBI Caregiver group. Parents reported worse scores on 3 measures than intimate partners in the STBI Caregiver group. The UnMTBI Caregiver group reported more clinically elevated scores for 7 of 15 comparisons than intimate partners in the STBI Caregiver group.

Conclusion:

Intimate partner caregivers of an SM/V following a remote uncomplicated MTBI reported worse HRQOL than intimate partners and parent caregivers of an SM/V following a more severe TBI, mostly likely due to SM/V physical and mental health comorbidities. Interventions that focus on the SM/V's TBI and other comorbidities, the caregiver's behavioral health problems, and the relationship and family factors that interact with each other will likely have the most success in improving individual and family outcomes for military families.
Contextual Effects of Traumatic Brain Injury on the Connectome: Differential Effects of Deployment- and Non–Deployment-Acquired Injuries
Authors: Rowland Jared A. , Stapleton-Kotloski Jennifer R. , Rogers Emily , Taber Katherine H. , Godwin Dwayne W. , Martindale Sarah L.
Published: July 2022

Objective:

To identify differential effects of mild traumatic brain injury (TBI) occurring in a deployment or nondeployment setting on the functional brain connectome.

Setting:

Veterans Affairs Medical Center.

Participants:

In total, 181 combat-exposed veterans of the wars in Iraq and Afghanistan (n = 74 with deployment-related mild TBI, average time since injury = 11.0 years, SD = 4.1).

Design:

Cross-sectional observational study.

Main Measures:

Mid-Atlantic MIRECC (Mid-Atlantic Mental Illness Research, Education, and Clinical Center) Assessment of TBI, Clinician-Administered PTSD Scale, connectome metrics.

Results:

Linear regression adjusting for relevant covariates demonstrates a significant (P < .05 corrected) association between deployment mild TBI with reduced global efficiency (nonstandardized β = −.011) and degree of the K-core (nonstandardized β = −.79). Nondeployment mild TBI was significantly associated with a reduced number of modules within the connectome (nonstandardized β = −2.32). Finally, the interaction between deployment and nondeployment mild TBIs was significantly (P < .05 corrected) associated with increased mean (nonstandardized β = 9.92) and mode (nonstandardized β = 14.02) frequency at which connections occur.

Conclusions:

These results demonstrate distinct effects of mild TBI on the functional brain connectome when sustained in a deployment versus nondeployment context. This is consistent with findings demonstrating differential effects in other areas such as psychiatric diagnoses and severity, pain, sleep, and cognitive function. Furthermore, participants were an average of 11 years postinjury, suggesting these represent chronic effects of the injury. Overall, these findings add to the growing body of evidence, suggesting the effects of mild TBI acquired during deployment are different and potentially longer lasting than those of mild TBI acquired in a nondeployment context.
Predictors of High School and College Graduation After Sustaining a Moderate-to-Severe Traumatic Brain Injury
Authors: Wright Brittany , Venkatesan Umesh M. , Pinto Shanti M. , Gary Kelli W. , O'Neil-Pirozzi Therese M. , Kajankova Maria , Wilmoth Kristin , Kakkanatt Ashley , Dreer Laura , Juengst Shannon B.
Published: July 2022

Objective:

To identify early predictors of US high school and college graduation after moderate-to-severe traumatic brain injury (TBI).

Setting:

Inpatient rehabilitation and community.

Participants:

TBI Model Systems participants, aged 16 to 24 years, enrolled as high school or college students at time of injury.

Design:

Prospective cohort study.

Main Measures:

Successful graduation was defined as having a diploma (high school) or an associate/bachelor's degree (college) at 1-, 2-, or 5-year follow-up. Predictors were sex, race/ethnicity, urbanicity, preinjury substance abuse, primary rehabilitation payer, and functional independence at inpatient rehabilitation discharge.

Method:

We descriptively characterized differences between those who did and did not graduate high school and college within the first 5 years postinjury and identified early predictors of successful high school and college graduation using 2 binomial logistic regressions.

Results:

Of those with known graduation status, 81.2% of high school and 41.8% of college students successfully graduated. Graduates in both groups were more often White than Black and had more functional independence at discharge. Among high school students, preinjury substance abuse was also a risk factor for not graduating, as was identifying as Hispanic or “other” race.

Conclusions:

Sociodemographic factors and disability influence graduation outcomes, requiring structural, institutional, and personal interventions for success.
Assessing the Effect of the COVID-19 Outbreak on Didactic Education and Mental Health of Physician Assistant Students in the New York City Region
Authors: Kuriakose Shinu , Timko-Swaim Lynn , Loscalzo Carina , L’Eplattenier Mark
Published: July 2022

Introduction

COVID-19 has profoundly affected life throughout the world, and it greatly affected physician assistant (PA) education programs when the virus spread across the New York region 2 years ago. PA programs at Stony Brook University, Hofstra University, and the New York Institute of Technology were located in the epicenter of the pandemic and were forced to transition to online learning during the spring of 2020. The purpose of this study was to explore didactic PA students’ perceptions of virtual learning, their mental health status, and the challenges and unexpected benefits they have faced during this historic time.

Methods

A consent form that linked to an 11-question electronic Qualtrics survey was emailed to all didactic students enrolled in the 3 participating PA programs. The survey data were used to conduct a descriptive analysis and a Spearman’s ρ correlation analysis using SPSS 24 software.

Results

The survey response rate was 39% (89/229). The students perceived it to be more challenging to maintain the same level of academic achievement with virtual learning, although they felt they were able to meet learning objectives and be prepared for clinical clerkships. They reported experiencing greater stress, anxiety, and depression related to decreased socialization and isolation. However, the students said that their PA program provided enough support to assist with student needs, and they noted unexpected benefits of remote learning, including more time to spend with family members, increased schedule flexibility, and lower commuting costs.

Discussion

The PA students’ education and mental health were negatively affected because of the abrupt transition from in-person to virtual learning. At the height of the COVID-19 pandemic, most of the students in the 3 participating PA programs in New York were affected by the change to remote learning and the subsequent lack of socialization. PA students experienced both challenges and benefits during this unscheduled virtual learning period. While students noted increases in mental health issues, they felt supported by faculty members and prepared to start clinical rotations.
Promontory Electrocochleography Recordings to Predict Speech-Perception Performance in Cochlear Implant Recipients
Authors: Walia Amit , Shew Matthew A. , Lee David S. , Lefler Shannon M. , Kallogjeri Dorina , Wick Cameron C. , Durakovic Nedim , Fitzpatrick Douglas C. , Ortmann Amanda J. , Herzog Jacques A. , Buchman Craig A.
Published: July 2022

Objective

1) To determine the relationship of electrocochleography (ECochG) responses measured on the promontory with responses measured at the round window (RW) and various intracochlear sites. 2) To evaluate if promontory ECochG responses correlate with postoperative speech-perception performance using the cochlear implant (CI).

Study Design

Prospective cohort study.

Setting

Tertiary referral center.

Patients and Interventions

Ninety-six adult CI recipients with no cochlear malformations or previous otologic surgery.

Main Outcome Measure(s)

Acoustically evoked ECochG responses were measured intraoperatively at both extracochlear and intracochlear locations. ECochG total response (ECochG-TR), a measure of residual cochlear function, was calculated by summing the fast Fourier transformation amplitudes in response to 250-Hz to 2-kHz acoustic stimuli. Speech-perception performance was measured at 3 months.

Results

There were strong linear correlations for promontory ECochG-TR with the ECochG-TRs measured at the RW (r = 0.95), just inside scala tympani (r = 0.91), and after full insertion (r = 0.83). For an individual subject, the morphology of the ECochG response was similar in character across all positions; however, the response amplitude increased from promontory to RW (~1.6-fold) to just inside scala tympani (~2.6-fold), with the largest response at full insertion (~13.1-fold). Promontory ECochG-TR independently explained 51.8% of the variability (r
2) in consonant-nucleus-consonant at 3 months.

Conclusions

Promontory ECochG recordings are strongly correlated with responses previously recorded at extracochlear and intracochlear sites and explain a substantial portion of the variability in CI performance. These findings are a critical step in supporting translation of transtympanic ECochG into the clinic preoperatively to help predict postoperative CI performance.
Neonatal feeding of an estrogen receptor β agonist induces external adenomyosis-like lesions in ICR mouse
Authors: Cao Yun-Lei , Wang Xi , Liu Xi-Shi , Harada Tasuku , Guo Sun-Wei
Published: July 2022

Objective:

Despite the fact that adenomyosis is a fairly common gynecological disorder, its pathogenesis remains elusive. Several theories on the pathogenesis of adenomyosis have been proposed, but none of them has been proven experimentally. So far, the most used one is the neonatal feeding of tamoxifen (TAM) in Institute of Cancer Research/cryopreserved (ICR/CD-1) mouse. However, its underlying mechanism of action is unknown. To further delineate the mechanism of TAM-induced adenomyosis in ICR/CD-1 mouse with regard to specific estrogen receptor (ER), we conducted an experiment that neonatal mice were fed with either TAM, or 4,4′,4″-(4-propyl-[1H]-pyrazole-1,3,5-triyl) trisphenol (PPT; an ERα agonist), or 2,3-bis(4-hydroxyphenyl)-propionitrile (DPN; an ERβ agonist), or G-1 (a G-protein coupled receptor 30 agonist), or just vehicle, in an attempt to tease out which specific receptor plays a dominant role in the genesis of adenomyosis induced by neonatal feeding of TAM.

Methods:

Forty female neonatal mice were randomly divided into 5 equal-sized groups: CTL (control), TAM, PPT, DPN, and G-1. Three months later, all mice were sacrificed and their uterine horns were harvested, weighed, and processed for histological evaluation.

Results:

All mice in the TAM group developed adenomyosis, so did 4 mice (50%) in the DPN group, a result that should be considered significant given that mice in the CTL group would not develop adenomyosis. No mouse in the PPT or G-1 group developed adenomyosis. Remarkably, all lesions in the DPN group were seen exclusively near the uterine serosa, which are dramatically different from that of TAM mice and reminiscent of extrinsic or external adenomyosis in humans.

Conclusions:

Neonatal feeding of DPN induces adenomyosis, but the adenomyotic lesions appear to be different from those induced by TAM. Thus, the cause of TAM-induced adenomyosis in ICR/CD-1 mouse cannot be attributable to one specific ER alone. This suggests that the extrinsic/external adenomyosis may have a pathogenesis that is different from other sub-types of adenomyosis.
Effect of pre-IVF incubation in maturation medium on oocyte maturity, fertilization, embryonic development, and clinical outcomes following embryo transfer
Authors: Li Jian-Hua , Wang Jian-Ye , Jiao Ting-Ting , Li Min , Wei Yan , Wang Ye , Cheng Yan-Bin , Zhang Shui-Wen , Tian Shuang , Chian Ri-Cheng
Published: July 2022

Objective:

Collected human cumulus-oocyte complexes (COCs) are usually inseminated after 4 to 6 hours in in vitro fertilization (IVF) laboratories. The purpose of this study was to determine the effect of short-term pre-IVF incubation in culture medium on subsequent oocyte maturation, fertilization, and embryonic development, as well as clinical outcomes.

Methods:

Sixty patients were divided randomly into 2 groups, pre-IVF incubation for 5 hours: 1) with (+) the designed oocyte maturation medium; 2) without (−) the designed oocyte maturation medium (transferred directly to fertilization medium for 5 hours before insemination). Oocyte maturation and fertilization were assessed, and the rate of cleavage and good quality embryos were evaluated between the 2 groups on days 2 and 3, respectively. Blastocyst development was based on the remaining number of embryos on day 3, continuously cultured to day 5 after embryo transfer or frozen on day 3, and was compared between the 2 groups. Clinical pregnancy, implantation, and miscarriage rates were also compared.

Results:

Oocyte maturation rates did not differ between groups (85.8 ± 14.1% vs. 90.7 ± 9.1%). However, the range of oocyte maturation rates (58.3%–100.0%) for each patient was significantly higher in the (−) group than in the (+) pre-incubation group (71.4%–100.0%). There were no differences in fertilization rates (89.9 ± 10.0% vs. 86.5 ± 12.2%) and good quality embryos (70.8 ± 19.1% vs. 62.1 ± 23.7%) between groups; however, the blastocyst development rates were significantly different between groups (73.1 ± 20.1% vs. 58.8 ± 18.2%, P <0.05). Nevertheless, clinical pregnancy (62.5% vs. 61.1%) and implantation (46.9% vs. 47.2%) rates did not differ between groups.

Conclusions:

These results indicate that a short pre-IVF incubation time in the designed culture medium promotes oocyte maturation and embryonic development, suggesting that short pre-IVF incubation of COCs in the designed culture medium may be important for subsequent final oocyte maturation and early embryonic development.
A review of guidelines, recommendations, and framework of men’s preconception care
Authors: Rabiei Zeinab , Shariati Mohammad , Mogharabian Naser , Tahmasebi Rahim , Ghiasi Ashraf , Motaghi Zahra
Published: July 2022

The focus of men’s health is within the context of preconception health and primary care, which involves a new method of engaging men’s attention to their preconception and general health. The aim of this review research is to offer health care practitioners a complete framework for men’s preconception care. From 2000 to October 2021, researchers examined electronic databases such as Web of Science, PubMed, Scopus, ScienceDirect, ProQuest, Cochrane, SAGE, Springer, UpToDate, and Google Scholar for published papers on men’s preconception care. Two independent authors assessed the quality of the included studies using techniques suitable for this type of investigation. Only 14 of the 835 studies that were found in the original search matched the inclusion criteria. Individual responsibility across the life span (evaluation of reproductive life plan, acquiring information about contraception) and risk assessment (age, medical and surgical history, medications, family history and genetic risks, social history, sexual health assessment, physical examination, laboratory testing, mental health, and intimate partner violence) are the two main topics of preconception care in men according to a review of studies. Our findings clearly demonstrated the critical components of a comprehensive preconception care approach for men. Therefore, preconception care for men remains a developing concept. Further research is required to develop standards for evaluating males during the preconception period.
Preimplantation genetic testing guidelines of International Society of Reproductive Genetics
Authors: Xu Chen-Ming , Lu Si-Jia , Chen Song-Chang , Zhang Jing-Lan , Xu Cong-Jian , Gao Yuan , Shen Yi-Ping , Cao Yun-Xia , Wu Ling-Qian , Jin Fan , Lin Ge , Liu Ping , Zhu Yi-Min , Wu Yan-Ting , Zhang Dan , Yee Bill , Kushnir Vitaly A. , Yang Zhi-Hong , Liu Jia-Yin , Chen Zi-Jiang , Thornhill Alan , Beltsos Angie N. , Smitz Johan , Frattarelli John , Handyside Alan , Qiao Jie , Huang He-Feng
Published: July 2022

The International Society of Reproductive Genetics (ISRG) assembled a workgroup made up of clinicians, clinical laboratory directors, and scientists for the purpose of creating the guidelines for preimplantation genetic testing (PGT). The most up-to-date information and clinical insights for the optimal PGT practice were incorporated in these guidelines. Recommendations are provided for embryologists, medical geneticists, clinical laboratorians, and other healthcare providers to improve the wellbeing of patients seeking assisted reproductive treatment and their offspring.
Characterization of folic acid, 5-methyltetrahydrofolate and synthetic folinic acid in the high-affinity folate transporters: impact on pregnancy and development
Authors: Palacios Ana M. , Feiner Rachel A. , Cabrera Robert M.
Published: July 2022

Objectives:

Folates are B vitamins that are essential for several molecular, cellular, and biological processes, including nucleotide synthesis, methylation, and methionine cycling. The physiological impacts of these processes on health also extend to cell proliferation, folate deficiency anemia, and reduction of the risk of birth defects during pregnancy. The primary objective of this study was to characterize the binding affinities of different folate forms, folic acid (FA), 5-methyltetrahydrofolate (5MTHF), and folinic acid, to the folate receptors α and β, and to the bovine milk folate binding protein. These three dietary forms of folate are found in enriched grains (FA), various fruits and leafy vegetables (folinic acid), and red blood cells (5MTHF).

Methods:

The half maximal inhibitory concentration values and binding curves of each of these folates for each receptor were determined.

Results:

Our results indicated that FA had the highest affinity for all folate receptors, followed by 5MTHF, and lastly, by folinic acid, examined by several orders of magnitudes.

Conclusion:

These data are expected to provide new insights into the therapeutic applications of the different forms of folate in a variety of diseases.
Donor Simvastatin Treatment Is Safe and Might Improve Outcomes After Liver Transplantation: A Randomized Clinical Trial
Authors: Pagano Duilio , Bosch Jaime , Tuzzolino Fabio , Oliva Elisabetta , Ekser Burcin , Zito Giovanni , Cintorino Davide , di Francesco Fabrizio , Li Petri Sergio , Ricotta Calogero , Bonsignore Pasquale , Calamia Sergio , Magro Bianca , Trifirò Gianluca , Alduino Rossella , Barbara Marco , Conaldi Pier Giulio , Gallo Alessia , Venuti Francesca , Luca Angelo , Gruttadauria Salvatore
Published: July 2022

Background.

The current curative approaches for ischemia/reperfusion injury on liver transplantation are still under debate for their safety and efficacy in patients with end-stage liver disease. We present the SIMVA statin donor treatment before Liver Transplants study.

Methods.

SIMVA statin donor treatment before Liver Transplants is a monocentric, double-blind, randomized, prospective tial aiming to compare the safety and efficacy of preoperative brain-dead donors’ treatment with the intragastric administration of 80 mg of simvastatin on liver transplant recipient outcomes in a real-life setting. Primary aim was incidence of patient and graft survival at 90 and 180 d posttransplant; secondary end-points were severe complications.

Results.

The trial enrolled 58 adult patients (18–65 y old). The minimum follow-up was 6 mo. No patient or graft was lost at 90 or 180 d in the experimental group (n = 28), whereas patient/graft survival were 93.1% (P = 0.016) and 89.66% (P = 0.080) at 90 d and 86.21% (P = 0.041) and 86.2% (P = 0.041) at 180 d in the control group (n = 29). The percentage of patients with severe complications (Clavien-Dindo ≥IIIb) was higher in the control group, 55.2% versus 25.0% in the experimental group (P = 0.0307). The only significant difference in liver tests was a significantly higher gamma-glutamyl transferase and alkaline phosphatase at 15 d (P = 0.017), (P = 0.015) in the simvastatin group.

Conclusions.

Donor simvastatin treatment is safe, and may significantly improve early graft and patient survival after liver transplantation, although further research is mandatory.
Deciphering the consequence of deep intronic variants: a progeroid syndrome caused by aTAPT1mutation is revealed by combined RNA/SI-NET sequencing
Authors: Nabavizadeh Nasrinsadat , Bressin Annkatrin , Chia Poh Hui , Traspas Ricardo Moreno , Escande-Beillard Nathalie , Bonnard Carine , Hojati Zohreh , Drutman Scott , Freier Susanne , El-Khateeb Mohammad , Fathallah Rajaa , Casanova Jean-Laurent , Soror Wesam , Arafat Alaa , Shboul Mohammad , Mayer Andreas , Reversade Bruno
Published: July 2022

Exome sequencing has introduced a paradigm shift for the identification of germline variations responsible for Mendelian diseases. However, non-coding regions, which make up 98% of the genome, cannot be captured. The lack of functional annotation for intronic and intergenic variants makes RNA-seq a powerful companion diagnostic. Here, we illustrate this point by identifying six patients with a recessive Osteogenesis Imperfecta (OI) and neonatal progeria syndrome. By integrating homozygosity mapping and RNA-seq, we delineated a deep intronicTAPT1mutation (c.1237-52G>A) that segregated with the disease. Using patients’ fibroblasts, we document that TAPT1’s nascent transcription was not affected, indicating instead that this variant leads to an alteration of pre-mRNA processing. Predicted to serve as an alternative splicing branchpoint, this mutation causesTAPT1exon 12 skipping, creating a protein-null allele. Additionally, our study reveals dysregulation of pathways involved in collagen and extracellular matrix biology in disease-relevant cells. Overall, our work highlights the power of transcriptomic approaches in deciphering the repercussion of non-coding variants as well as in illuminating the molecular mechanisms and underlying pathways of human diseases.
MCPNet : A parallel maximum capacity-based genome-scale gene network construction framework
Authors: Pan Tony , Chockalingam Sriram P , Aluru Maneesha , Aluru Srinivas
Published: July 2022

Motivation

Gene regulatory network (GRN) reconstruction from gene expression profiles is a compute- and data-intensive problem. Numerous methods based on diverse approaches including mutual information, random forests, Bayesian networks, correlation measures, as well as their transforms and filters such as data processing inequality, have been proposed. However, an effective GRN reconstruction method that performs well in all three aspects of computational efficiency, data size scalability, and output quality remains elusive. Simple techniques such as Pearson correlation are fast to compute but ignore indirect interactions, while more robust methods such as Bayesian networks are prohibitively time consuming to apply to tens of thousands of genes.

Results

We developed MCP Score, a novel maximum-capacity-path based metric to quantify the relative strengths of direct and indirect gene-gene interactions. We further present MCPNet, an efficient, parallelized GRN reconstruction software based on MCP Score, to reconstruct networks in unsupervised and semi-supervised manners. Using synthetic and real S. cervisiae datasets as well as real A. thaliana datasets, we demonstrate that MCPNet produces better quality networks as measured by AUPR, is significantly faster than all other GRN inference software, and also scales well to tens of thousands of genes and hundreds of CPU cores. Thus, MCPNet represents a new GRN inferencing tool that simultaneously achieves quality, performance, and scalability requirements.

Availability

Source code freely available for download at https://doi.org/10.5281/zenodo.6499748 and https://github.com/AluruLab/MCPNet, implemented in C++ and supported on Linux.

Contact

aluru@cc.gatech.edu

Supplementary information

Supplementary data are available at Bioinformatics online.
Molecular and spatial profiling of the paraventricular nucleus of the thalamus
Authors: Gao Claire , Gohel Chiraag A , Leng Yan , Goldman David , Levine Ariel J , Penzo Mario A
Published: July 2022

The paraventricular nucleus of the thalamus (PVT) is known to regulate various cognitive and behavioral processes. However, while functional diversity among PVT circuits has often been linked to cellular differences, the molecular identity and spatial distribution of PVT cell types remains unclear. To address this gap, here we used single nucleus RNA sequencing (snRNA-seq) and identified five molecularly distinct PVT neuronal subtypes. Additionally, multiplex fluorescent in situ hybridization of top marker genes revealed that PVT subtypes are organized by a combination of previously unidentified molecular gradients. Lastly, comparing our dataset with a recently published single-cell sequencing atlas of thalamus yielded novel insight into the PVT's connectivity with cortex, including unexpected innervation of auditory and visual areas. This comparison also revealed that our data contains a largely non-overlapping transcriptomic map of multiple midline thalamic nuclei. Collectively, our findings uncover previously unknown features of the molecular diversity and anatomical organization of the PVT and provide a valuable resource for future investigations.
MicroRNA-mRNA networks are dysregulated in opioid use disorder postmortem brain: further evidence for opioid-induced neurovascular alterations
Authors: Grimm Sandra L. , Mendez Emily F. , Stertz Laura , Meyer Thomas D. , Fries Gabriel R. , Gandhi Tanmay , Kanchi Rupa , Selvaraj Sudhakar , Teixeira Antonio L. , Kosten Tom , Gunaratne Preethi , Coarfa Cristian , Walss-Bass Consuelo
Published: July 2022

To understand mechanisms and identify potential targets for intervention in the current crisis of opioid use disorder (OUD), postmortem brains represent an under-utilized resource. To refine previously reported gene signatures of neurobiological alterations in OUD from the dorsolateral prefrontal cortex (Brodmann Area 9, BA9), we explored the role of microRNAs (miRNA) as powerful epigenetic regulators of gene function. Building on the growing appreciation that miRNAs can cross the blood-brain barrier, we carried out miRNA profiling in same-subject postmortem samples from BA9 and blood tissues. miRNA-mRNA network analysis showed that even though miRNAs identified in BA9 and blood were fairly distinct, their target genes and corresponding enriched pathways were highly overlapping, with tube development and morphogenesis, and pathways related to endothelial cell function and vascular organization, among the dominant enriched biological processes. These findings point to robust, redundant, and systemic opioid-induced miRNA dysregulation with potential functional impact on transcriptomic changes. Further, using correlation network analysis we identified cell-type specific miRNA targets, specifically in astrocytes, neurons, and endothelial cells, associated with OUD transcriptomic dysregulation. Our refined miRNA-mRNA networks enabled identification of novel pharmaco-chemical interventions for OUD, particularly targeting the TGF beta-p38MAPK signaling pathway. Finally, leveraging a collection of control brain transcriptomes from the Genotype-Tissue Expression (GTEx) project, we identified correlation of OUD miRNA targets with TGF beta, hypoxia, angiogenesis, coagulation, immune system and inflammatory pathways. These findings support previous reports of neurovascular and immune system alterations as a consequence of opioid abuse.
“FDA-approved carbonic anhydrase inhibitors reduce Amyloid β pathology and improve cognition, by ameliorating cerebrovascular health and glial fitness”
Authors: Canepa Elisa , Parodi-Rullan Rebecca , Vazquez-Torres Rafael , Gamallo-Lana Begona , Guzman-Hernandez Roberto , Lemon Nicole L. , Angiulli Federica , Debure Ludovic , Ilies Marc A. , Østergaard Leif , Wisniewski Thomas , Gutiérrez-Jiménez Eugenio , Mar Adam C. , Fossati Silvia
Published: July 2022

Alzheimer’s disease (AD) is a devastating neurodegenerative disorder with no effective cure. Cerebrovascular and neurovascular pathology are early and causal hallmarks of AD, where cerebral amyloid angiopathy (CAA), the deposition of amyloid β (Aβ) at the cerebral vasculature, is present in about 90% of cases. Our previous work has uncovered the protective effect of carbonic anhydrase (CA) inhibition against Aβ-mediated mitochondrial dysfunction, production of reactive oxygen species (ROS) and apoptosis in vascular, glial and neuronal cells in culture. Here, we tested for the first time in a transgenic model of AD and cerebrovascular amyloidosis, the TgSwDI mice, a therapeutic regimen employing the FDA-approved CA inhibitors (CAIs), methazolamide (MTZ) and acetazolamide (ATZ). These drugs are used in humans for glaucoma, high altitude sickness, and other disorders, and can cross the blood-brain barrier. We found that both CAIs were non- toxic, significantly reduced cerebral amyloidosis, vascular, microglial and astrocytic Aβ accumulation, and ameliorated cognition. MTZ and ATZ treatment prevented caspase-3 activation in endothelial cells, microglia and astrocytes, reverted capillary constriction and microhemorrhages, reduced gliosis, and induced glial pro-clearance pathways, which are likely responsible for the reduction of Aβ deposition. Notably, we unveiled a critical new druggable target, revealing that the mitochondrial isozyme CA-VB is specifically upregulated in TgSwDI mouse brains, as well as in human brains of CAA and AD (with CAA) patients. Importantly, Aβ challenge induced CA-VB overexpression in human cerebral endothelial cells, and CA-VB silencing, mimicking CAIs effects, reduced Aβ-mediated endothelial apoptosis. This work paves the way for the application of CAIs in clinical trials for AD and CAA and uncovers CA-VB as a mediator of cerebral amyloid toxicity.
Cis-inhibition suppresses basal Notch signalling during sensory organ precursor selection
Authors: Troost Tobias , Binshtok Udi , Sprinzak David , Klein Thomas
Published: July 2022

The emergence of the sensory organ precursor (SOP) from the proneural equivalence group in Drosophila melanogaster is a paradigm for studying single cell fate specification through the process of lateral inhibition. Classical lateral inhibition models describing this selection process are based on a transcriptional feedback mechanism where inhibitory signals between neighbouring cells, mediated by Notch pathway, are coupled to an intracellular circuit regulating the expression of the Notch ligand Delta (Dl). It was previously shown that in addition to its ability to trans-activate Notch in neighbouring cells, Dl can also cis-inhibit Notch in the same cell. However, it remains unclear what role does cis-inhibition play during SOP selection, and how it contributes to the selection of only one SOP. Here we address these questions using the unexpected observation that the mammalian ligand Delta-like 1 (Dll1) can trans-activate but not cis-inhibit Notch in Drosophila. We develop a mathematical model for SOP selection, termed the two-channel SOP (TCS) model, where Dl activity, but not its expression, is regulated by two channels associated with the two E3 ubiquitin ligases Neuralized (Neur) and Mindbomb1 (Mib1). While the Neur-dependent channel is regulated by Notch signalling, the Mib1-dependent channel is not, leading to tissue-wide basal inhibitory activity. We show theoretically and experimentally that cis-inhibition is required for suppressing Mib1-dependent basal Notch activity. Thus, our results highlight the trade-off between basal Notch activity and cis-inhibition as a mechanism for singling out an SOP from the proneural equivalence group.
Bulb growth potential is independent of leaf longevity for the spring ephemeralErythronium americanumKer-Gawl
Authors: Bertrand Hugo , Lapointe Line
Published: July 2022

Growth in most spring ephemerals is decreased under warmer temperatures. Although photosynthetic activities are improved at warmer temperatures, leaves senesce earlier, which prevents the bulb from reaching a larger size. A longer leaf life duration during a warm spring, therefore, may improve bulb mass. We tested this hypothesis by modulating leaf life span ofErythronium americanumthrough the application of Promalin® (PRO; cytokinins and gibberellins) that prolonged, or silver thiosulphate (STS) that reduced leaf duration. Gas exchange and chlorophyll fluorescence were measured along with leaf and bulb carbohydrate concentrations. Plants were also pulse labelled with13CO2to monitor sugar transport to the bulb. Lower photosynthetic rates and shorter leaf life span of STS plants reduced the quantity of C that they assimilated during the season, resulting in a smaller bulb compared to Control plants. PRO plants maintained their photosynthetic rates for a longer period than Control plants, yet final bulb biomass did not differ between them. We conclude that seasonal growth forE. americanumis not limited by leaf life duration under warm growing conditions, but rather by limited sink growth capacity. Under global warming, spring geophytes might be at risk of being reduced in size and eventually, reproducing less frequently.

Highlight

Warmer springs negatively affect trout lily growth and delaying leaf senescence in this spring ephemeral does not translate into a larger bulb if temperatures remain high during springtime.
NeuronBridge: an intuitive web application for neuronal morphology search across large data sets
Authors: Clements Jody , Goina Cristian , Hubbard Philip M. , Kawase Takashi , Olbris Donald J. , Otsuna Hideo , Svirskas Robert , Rokicki Konrad
Published: July 2022

Neuroscience research in Drosophila is benefiting from large-scale connectomics efforts using electron microscopy (EM) to reveal all the neurons in a brain and their connections. In order to exploit this knowledge base, researchers target individual neurons and study their function. Therefore, vast libraries of fly driver lines expressing fluorescent reporter genes in sets of neurons have been created and imaged using confocal light microscopy (LM). However, creating a fly line for driving gene expression within a single neuron found in the EM connectome remains a challenge, as it typically requires identifying a pair of fly lines where only the neuron of interest is expressed in both. This task and other emerging scientific workflows require finding similar neurons across large data sets imaged using different modalities. Here, we present NeuronBridge, a web application for easily and rapidly finding putative morphological matches between large datasets of neurons imaged using different modalities. We describe the functionality and construction of the NeuronBridge service, including its user-friendly GUI, data model, serverless cloud architecture, and massively parallel image search engine. NeuronBridge is openly accessible at http://neuronbridge.janelia.org/.
Mechanistic insights into RNA surveillance by the canonical poly(A) polymerase Pla1 of the MTREC complex
Authors: Soni Komal , Sivadas Anusree , Horváth Attila , Dobrev Nikolay , Hayashi Rippei , Kiss Leo , Simon Bernd , Wild Klemens , Sinning Irmgard , Fischer Tamás
Published: July 2022

The S. pombe orthologue of the human PAXT complex, Mtl1-Red1 Core (MTREC), is an eleven-subunit complex which targets cryptic unstable transcripts (CUTs) to the nuclear RNA exosome for degradation. It encompasses the canonical poly(A) polymerase Pla1, responsible for polyadenylation of nascent RNA transcripts as part of the cleavage and polyadenylation factor (CPF/CPSF). In this study we identified and characterised the interaction between Pla1 and the MTREC complex core component Red1 and analysed the functional relevance of this interaction in vivo. Our crystal structure of the Pla1-Red1 complex showed that a 58-residue fragment in Red1 binds to the RNA recognition motif domain of Pla1 and tethers it to the MTREC complex. Structure-based Pla1-Red1 interaction mutations showed that Pla1, as part of MTREC complex, hyper-adenylates CUTs for their efficient degradation. Interestingly, the Red1-Pla1 interaction was also required for the efficient assembly of the fission yeast facultative heterochromatic islands. Together, our data suggest a complex interplay between the RNA surveillance and 3’-end processing machineries.