bluuebunny/crossref_metadata_2025 huggingface dataset:
COMBINATION OF VITRECTOMY AND INTENTIONAL MACULAR DETACHMENT IS ASSOCIATED WITH A FASTER EDEMATOUS REGRESSION THAN VITRECTOMY ALONE IN THE TREATMENT OF REFRACTORY DIABETIC MACULAR EDEMA
Authors: Yan Ying , Zhu Li , Zeng Miao , Huang Zhijian , Ding Qin , Liu Yang , Gao Chengyuan , Yu Doudou , Chen Xiao
Published: June 2022

Purpose:

To compare clinical outcomes in eyes with refractory diabetic macular edema managed by vitrectomy combined with and without intentional macular detachment (IMD).

Methods:

This is a retrospective cohort study. Forty-one eyes with diabetic macular edema that were previously poorly responsive to at least 5 monthly anti–vascular endothelial growth factor and at least twice switch therapy previously were included in this study. All eyes underwent pars plana vitrectomy with internal limiting membrane peeling, 21 of which were combined with an IMD procedure (assigned to an IMD group) and 20 of which did not have IMD performed (nMD group). Macular morphologic and visual acuity changes were analyzed from baseline through the endpoint (24 weeks) postprocedure, and were compared between groups.

Results:

All patients completed at least six months of follow-up, with a mean of 29.7 weeks (24–56 weeks). The mean central retinal thickness reduction was greater in the IMD group than that in the nMD group at 1 week (P = 0.001), 2 weeks (P = 0.008), and 4 weeks (P = 0.004), but there was no statistically significant difference at 12 weeks (P = 0.051) or 24 weeks (P = 0.056). There were no significant differences in the mean changes of best-corrected visual acuity from baseline to the 24 weeks endpoint in either group (P = 0.83).

Conclusion:

Vitrectomy can release macular edema in the eyes with refractory diabetic macular edema. Combined with IMD technical, patients seemed to achieve a faster central retinal thickness decrease but neither the final morphologic outcome nor the visual acuity was affected.
Peripapillary and Macular Vascular Density in Patients With Preperimetric and Early Primary Open Angle Glaucoma
Authors: Oba Turker , Solmaz Nilgun , Onder Feyza
Published: June 2022

Précis:

Decreased circumpapillary vascular density (cpVD) and average retinal nerve fiber layer (RNFL) thickness were detected at different locations in eyes with preperimetric glaucoma (PPG). Although RNFL loss was more prominent in preperimetric eyes, in early glaucoma, both cpVD and RNFL thickness showed comparable diagnostic ability.

Purpose:

To evaluate changes in circumpapillary and macular vascular density and investigate correlations between vascular and structural parameters in PPG and early glaucoma.

Method:

This cross-sectional study included a total of 27 patients with PPG in 1 eye and early primary open angle glaucoma in the fellow eye, as well as a control group consisting of 27 eyes of 27 healthy volunteers. All subjects underwent optical coherence tomography angiography (OCTA) imaging. RNFL and macular ganglion cell complex measurements were obtained simultaneously with vascular parameters by AngioVue OCTA using the single-scan protocol. cpVD was examined in 8 sectors. Diagnostic accuracy was evaluated using the area under the receiver operating characteristic curve.

Results:

In preperimetric eyes, average RNFL thickness and whole-image vessel density had comparable diagnostic performance (area under the receiver operating characteristic curve =0.853 and 0.753, respectively). Compared with the control group, PPG eyes had significantly lower RNFL thickness in all quadrants (P<0.001–0.003) except for the temporal quadrant, whereas cpVD differed only in the nasal inferior and nasal superior sectors (P=0.001 and 0.041, respectively). In early glaucoma eyes, cpVD differed significantly from controls in all sectors except for the inferotemporal, temporal inferior, and temporal superior sectors, whereas perifoveal macular vascular parameters differed in all quadrants (all P<0.05). cpVD was strongly correlated with RNFL thickness in the superior, nasal, and temporal quadrants (r=0.664, 0.698, and 0.649, respectively, P<0.001) and moderately correlated in the inferior quadrant (r=0.450, P<0.001).

Conclusion:

Although RNFL involvement is valuable in the diagnosis and follow-up of PPG, the change in nasal cpVD has an important place in these patients. The role of macular vascular parameters and macular ganglion cell complex in glaucoma follow-up becomes important in early glaucoma. Longitudinal studies are needed to determine the place of OCTA in the diagnosis and follow-up of glaucoma.
Acute Cognitive Effects of the Dual Orexin Receptor Antagonist Lemborexant Compared With Suvorexant and Zolpidem in Recreational Sedative Users
Authors: Landry Ishani , Hall Nancy , Alur Jagadeesh , Filippov Gleb , Reyderman Larisa , Setnik Beatrice , Henningfield Jack , Moline Margaret
Published: June 2022

Purpose/Background

As part of a human abuse potential (HAP) study of lemborexant (LEM), the effects of therapeutic (LEM 10 mg), and supratherapeutic doses of LEM 20 mg and LEM 30 mg on cognition and psychomotor performance were compared with placebo (PBO) and supratherapeutic doses of zolpidem (ZOL) 30 mg and suvorexant (SUV) 40 mg. Subjects (n = 32) were healthy, nondependent, recreational sedative users able to discriminate the effects of both SUV and ZOL from PBO on subjective drug measures.

Methods/Procedures

The human abuse potential study was a single-dose, randomized, double-blind, PBO-controlled, 6-way crossover study. Eligible subjects admitted to the treatment phase completed the choice reaction test (CRT) and divided attention test. The CRT included measurements of recognition reaction time (RRT) and motor reaction time.

Findings/Results

Recognition reaction time and mean maximum change from baseline (CFBmax) scores were significantly increased (slower performance) versus PBO for all LEM doses (all P < 0.001), ZOL (P < 0.001), and SUV (P = 0.004), and LEM (all doses) was not statistically different from ZOL or SUV. Motor reaction time and mean CFBmax versus PBO were significantly increased for all LEM doses (all P < 0.001), and ZOL (P < 0.001) and SUV (P < 0.001). All LEM doses showed significantly decreased (better performance) mean CFBmax versus ZOL (all P < 0.001), but not SUV. Notably, all cognitive effects in the CRT and divided attention test were limited to the main treatment phase (up to 8 hours postdose).

Implications/Conclusions

All active doses of LEM, ZOL, and SUV generally increased reaction time and reduced divided attention capabilities versus PBO. However, at therapeutic/supratherapeutic doses, LEM led to significantly less cognitive impairment than supratherapeutic doses of ZOL in some measures.
Internal Operational Metrics and Center for Medicare and Medicaid Services Hospital Compare Quality Ratings
Authors: Thornton Michele , Bonzo Sarah , Khan Raihan , Souza Leah
Published: June 2022

The Center for Medicare and Medicaid Services (CMS) has made several refinements to their model for calculating hospital quality star ratings (Hospital Compare) amidst criticism and evidence of bias against some institutions. We argue that the CMS model does align with important internal quality metrics and encourage a measured approach to redesign, potentially using categorizations or tiers, rather than a complete abandonment of the ratings system. We find that institutional characteristics (available resources, average severity of illness, and academic affiliation) are associated with internal quality metrics related to patient flow. Furthermore, regression results from the original and revised CMS star rating methodologies suggest that patient flow metrics (discharges before noon [p < .01] and weekend discharges [p < .001]) have a positive relationship with the Hospital Compare rating. Hospitals with better patient flow, as measured by higher levels of discharges before noon and weekend discharges, are associated with higher CMS quality ratings. These findings suggest that CMS star ratings do reflect key aspects of operational performance, specifically efforts to improve patient flow, but the ranking system should consider hospital characteristics that influence internal operations as we move toward a system capable of quality and price transparency for consumers.
The influence of age and sex in sarcoidosis
Authors: Singha Arindam , Kirkland Marina , Drake Wonder , Crouser Elliott D
Published: June 2022

Purpose of review

This review aims to describe how the clinical manifestations of sarcoidosis may be shaped by the effects of sex hormones and by age dependent changes in immune functions and physiology This review is intended to highlight the need to consider the effects of sex and sex in future studies of sarcoidosis

Recent findings

The clinical manifestations of sarcoidosis differ based on sex and gender There is emerging evidence that female and male hormones and X-linked genes are important determinants of immune responses to environmental antigens, which has important implications for granuloma formation in the context of sarcoidosis Furthermore, sex hormone levels predictably change throughout adolescence and adulthood, and this occurs in parallel with the onset immune senescence and changes in physiology with advanced age

Recent studies indicate that sex and age are important variables shaping the immune response of humans to environmental antigens We posit herein that sex and age are important determinants of sarcoidosis clinical phenotypes Many gaps in our understanding of the roles played by sex and gender in sarcoidosis, and these need to be considered in future studies
Usefulness of simulation in optimizing imaging settings for pediatric technetium-99m-dimercaptosuccinic acid single-photon emission computed tomography
Authors: Kurosawa Yuji , Kanzaki Takao , Higuchi Tetsuya , Suto Takayuki , Tsushima Yoshito
Published: June 2022

Purpose

Technetium-99m (99mTc) dimercaptosuccinic acid (DMSA) single-photon emission computed tomography (SPECT) has been used to diagnose renal scarring. The Japanese Society of Nuclear Medicine recently revised the ‘Consensus Guidelines for Pediatric Nuclear Medicine Examination.’ In this study, we compared simulation data with actual data obtained using a pediatric phantom for 99mTc-DMSA examinations and evaluated the usefulness of simulations in determining the optimal acquisition conditions for SPECT images.

Methods

A SPECT quality assurance (QA) phantom study produced images with a renal-to-background 99mTc ratio of 283:1 kBq/ml. The projection data for the simulation were simulated using the simulation of imaging nuclear detectors. To compare the actual measurements and simulations, recovery factors were used for the SPECT QA phantom for image quality assessment. Defect contrast and visual evaluation using Scheffe’s method of pairwise comparison were used for the pediatric kidney phantom.

Results

The optimal imaging settings using a kidney phantom required an acquisition time of more than 8 min. The maximum difference in the recovery coefficient between the simulation and actual measurement using the SPECT QA phantom was 6%.

Conclusion

We showed that an acquisition time of more than 8 min was necessary for DMSA-SPECT. In addition, phantom simulations were approximately equivalent to the actual measurement data and the adaptability of simulations was confirmed.
Hepatic superscan on fluorine-18 fluorodeoxyglucose PET/computed tomography imaging: a specific manifestation for diagnosing lymphoma or leukemia involvement
Authors: Wang Lijuan , Jiang Yanping , Zhang Yin , Zhou Wenlan , Li Hongsheng , Wu Hubing
Published: June 2022

Objective

To explore whether the markedly fluorine-18 fluorodeoxyglucose (18F-FDG) uptake in the liver (named hepatic superscan) is a specific manifestation of malignant involvement.

Methods

From January 2014 to June 2019, 23 patients with such presentations were retrospectively reviewed. 18F-FDG uptake was semiquantified using maximal standardized uptake value (SUVmax), liver to cerebellum (L/C) ratio, liver to mediastinum (L/M) ratio, mean standardized uptake value (SUVmean), peak standardized uptake value (SUVpeak), metabolic tumor volume (MTV) and total lesion glycolysis (TLG). Some related laboratory examinations were also collected and analyzed. For comparison, 37 patients with mildly and moderately uptake in the liver were selected as the control group.

Results

The hepatic SUVmax, L/C ratio, L/M ratio, SUVmean, MTV and TLG of the superscan group were significantly higher than that of mild- or moderate-uptake group (P < 0.005). Malignant hematological tumors accounted for 91.3% of the superscan group, which was significantly higher than 51.4% of mild- or moderate-uptake group (P = 0.004). β2-microglobulin was observed to be significantly higher in the superscan group compared with mild- or moderate-uptake group (P < 0.001), but not lactate dehydrogenase (LDH) (P = 0.409). On the contrary, C-reactive protein (CRP) was significantly higher in mild- or moderate-uptake group than that in the superscan group (P < 0.001).

Conclusion

Our study demonstrates that hepatic superscan is a strong indicator of malignant hematological tumors invading the liver.
Decoding germ cell tumours for clinicians
Authors: Haider Aiman , Verrill Clare , Alifrangis Constantine , Berney Daniel Maurice
Published: June 2022

Purpose of review

Germ-cell tumours of the testis affect predominantly younger males aged between 15 and 40 years, with nearly 74,500 new cases estimated globally in 2020. Their rarity and the complex morphology, mean that, in nonexpert hands, there is a significant risk of misdiagnosis of both type and staging of these neoplasms.

Recent findings

There have been significant changes in the 2016 WHO classification of Testicular tumours that need to be understood by both pathologists and clinicians for streamlining management. Standardised structured reporting guidelines and discussion at the multidisciplinary-team meetings lead to subsequently better health outcomes and patient safety.

Therefore, communication with high-quality reports and understanding of clinicians of what constitutes an adequate report, is the key to ensure proper management of these patients. We attempt to discuss the key updates and pathological features that influence management and need to be communicated with clarity and precision.
Sex cord stromal tumors and tumors of the paratestis: new and old entities in a landscape of rare tumors
Authors: Colecchia Maurizio , Raspollini Maria Rosaria , Bremmer Felix , Pini Giacomo Maria
Published: June 2022

Purpose of review

The 5th edition of WHO classification incorporates the most relevant new data available in the literature regarding tumors of the male genitourinary tract. In this review, the authors summarize and critically discuss the most relevant new information regarding tumors occurring in the stromal testis and in the paratestis that will be reported in the new edition of WHO classification of tumors of the male genitourinary tract.

Recent findings

Signet-ring stromal tumors (SRST) and myoid gonadal stromal tumors (MGST) are two new entities brought in the 5th WHO classification of testicular tumors. All cases of SRST and MGST reported so far have behaved in a benign fashion after resection and whenever possible a conservative surgery is recommended. A future perspective is to aim at creating large multiinstitutional case series to link different morphologic patterns and molecular bases to the biologic behavior of these neoplasms. Another innovation in WHO consists in the inclusion in the group of Sertoli cell tumors of the sertoliform cystadenoma. The sertoliform cystadenoma is localized in the rete testis and it is of unknown origin. It was included in the group of gonadal stromal tumors because of a high morphological and immunohistochemical similarity to the Sertoli cell tumor.

Although further studies with long-term follow-up are needed to estimate the main oncologic outcomes in patients with rare gonadal stromal tumors, we highlight the importance of an accurate characterization by molecular and immunohistochemical assays of these entities.
Electromagnetic-guided puncture: a tool or a tale?
Authors: Tsaturyan Arman , Liatsikos Evangelos , Faitatziadis Solon , Kallidonis Panagiotis
Published: June 2022

Purpose of review

The puncture technique and site of the puncture can impact the clinical outcome and the development of postoperative adverse events following percutaneous nephrolithotomy (PCNL). The aim of the current review was to discuss the available puncture guidance approaches and outline the potential role of the recently introduced electromagnetic-guided method.

Recent findings

The puncture and PCNL tract establishment is usually performed using fluoroscopic or ultrasound guidance or a combination of two approaches. Electromagnetic-guided puncture is one of the most recent advancements of technology. The puncture navigation to the renal collecting system is available after placing a special wire with an electromagnetic tracking sensor into the desired calyx through the flexible ureterorenoscope. The available experimental and clinical studies have shown a high first puncture rate, decreased median time for obtaining a puncture, and shorter learning curves for beginners.

Fluoroscopic and ultrasound guidance are the main approaches used by urologists. However, these modalities require a steep learning curve, approximately 60 cases for reaching competency. The initial data on electromagnetic navigation have shown the feasibility and potential promising outcomes of this novel approach. New studies are required to investigate its potential implementation opportunities in the daily practice of urologists.
Maternal Distress in Disclosing a Nonlethal Fetal Anomaly Diagnosis to Family and Friends
Authors: Tucker Janet Adams , Christian Becky J.
Published: June 2022

Purpose:

To describe experiences of women disclosing a nonlethal fetal anomaly diagnosis to family and friends from initial prenatal diagnosis through postpartum.

Study Design and Methods:

A descriptive, qualitative approach was used to explore women's perceptions of nonlethal fetal anomaly diagnosis in a high-risk obstetric clinic. In-depth interviews were conducted with 10 pregnant women, followed by postpartum interviews with 8 women. Data were analyzed using thematic analysis.

Results:

Analysis of semistructured interviews revealed an overarching theme, Pregnancy Forever Changed, which captured the experience when expectant women first heard the news about their fetus. Prenatal themes were News of a Diagnosis, No Going Back; A Mother's Response: Managing Information; and Words from Others Matter. Women's struggles continued into postpartum, The Journey Continues: Echoing Past Concerns; and Not the Journey We Planned.

Clinical Implications:

Women with a nonlethal fetal anomaly diagnosis experienced distress and stigma about disclosure of the diagnosis to others. Distress with disclosure continued throughout the pregnancy and extended into postpartum. Women described negative responses from others and ongoing management of information as stressful and painful. Clinicians are aware disclosing a lethal diagnosis is distressing for women but may not understand the experience of women with a nonlethal diagnosis. An appreciation of women's distress on disclosure of nonlethal fetal anomaly diagnoses can guide practice for maternity, neonatal, and pediatric nurses providing interventions that include information and anticipatory guidance.
Infant Safe Sleep Initiative in a Small Volume Maternity Service
Authors: Patterson Kimberly J. , Adams Ellise D. , Ramieh Charlotte
Published: June 2022

Purpose:

Despite the 2016 American Academy of Pediatrics recommendations for preventing sudden unexpected infant death, there are approximately 3,400 sudden unexpected infant deaths annually in the United States. Modeling of safe sleep practices by nurses in the hospital influences parents' practice at home; however, safe sleep practices are not consistently modeled during the childbirth hospitalization.

Methods:

A quality improvement project was conducted to implement a safe sleep initiative based on the 2016 American Academy of Pediatrics recommendations for nurses caring for hospitalized infants after birth. Evaluation included testing of nurses' knowledge, infant crib audits, and nurses' evaluation of the intervention.

Results:

A significant improvement was found in overall nurse education scores. Crib audits demonstrated a significant improvement in the following elements: use of multiple blankets, swaddling of the infant, and parent teaching. Nursing surveys reported an increase in confidence to practice safe sleep recommendations and educate and redirect parents.

Clinical Implications:

Implementing a safe sleep initiative can increase nurses' knowledge, improve adherence to recommendations with modeling safe sleep practices, and increase parent awareness of safe sleep recommendations, potentially positively affecting adherence after discharge.
Prominent Pseudoacini in Focal Nodular Hyperplasia
Authors: Wang Donghai , González Iván A. , Russo Pierre A. , Jain Dhanpat , Zhang Xuchen
Published: June 2022

Pseudoacini are generally a morphologic feature of hepatocellular carcinoma (HCC), being absent or rare in benign hepatocytic tumors, such as hepatocellular adenoma. However, rarely these can be seen in focal nodular hyperplasia (FNH) and may pose diagnostic challenges, especially when prominent. The study was aimed to evaluate the occurrence of pseudoacini in FNH and their clinicopathologic correlations. A total of 95 FNH cases diagnosed from 2005 to 2020 were included in the study. A pseudoacinus was defined as a circular arrangement of hepatocytes around a central dilated lumen present within the lobular parenchyma of the lesion with or without inspissated bile. Among the 95 FNH cases, 28 (29.5%) showed pseudoacini, which were prominent in 12 (12.6%) cases. Of these 3 occurred in patients above 50 years old. The pseudoacini were numerous in 3 cases, leading to an initial consideration of HCC in the differential diagnosis, and 1 case was diagnosed as well-differentiated hepatocellular neoplasm on initial biopsy. All 12 cases showed map-like staining pattern for glutamine synthetase. The hepatocytes forming the pseudoacini were positive for CK7 and HepPar1, while the inner lumina were highlighted by CD10 and bile salt export pump immunostains similar to adjacent canaliculi. The presence of prominent pseudoacini was not significantly associated with any clinical or pathologic features. The findings suggest that pseudoacini are likely manifestation of hepatocyte biliary transdifferentiation associated with chronic cholestasis in the lesion. This feature may pose a potential diagnostic pitfall especially on needle biopsies and awareness is needed to avoid misdiagnosing this as HCC.
Thoracic spine deformation may predict prosthetic rehabilitation outcome
Authors: Kim Mindae
Published: June 2022

Background:

A considerable number of patients require prosthetic ambulation, which necessitates improvements in the success rate of prosthetics.

Objective:

This study aimed to determine the association between the presence of thoracic spinal osteophyte on imaging and the patient’s ability to walk with lower leg prosthetics.

Study design:

Retrospective cohort study.

Methods:

This study included 15 patients with lower leg amputations who underwent prosthetic rehabilitation. Medical records and spine radiographs of patients with lower leg amputations between 2013 and 2019 at a private rehabilitation hospital were reviewed. The primary outcome was achieving prosthetic ambulation with a single T-cane or without a walking aid.

Results:

Poor outcomes were associated with the presence of thoracic spinal deformation (P = 0.007) and the lower Berg Balance Scale score at admission (P = .067) and discharge (P = .033) groups. Monte Carlo simulation results showed a ≥33% difference in walking achieving rate between patients with and without thoracic spinal deformity. In addition, an 18% probability was found for randomly selected persons with an amputation to show a difference of ≥1 point in Berg Balance Scale scores.

Conclusion:

Thoracic spinal deformity on radiography and Berg Balance Scale score at admission are potentially associated with successful prosthetic rehabilitation. These findings potentially affect the indications for prosthetic limbs.
Fibular hemimelia and risk of patellar dislocations: A case series
Authors: Isaacs-Itua Alifa , Sedki Imad
Published: June 2022

The likelihood of patellar instability and consequently, risk of patellar dislocations is higher in those with anatomical abnormalities. Fibular hemimelia is a congenital disorder resulting in partial or full absence of the fibula, often with absence of the lateral and cruciate ligaments, although this patient group rarely undergoes ligament reconstruction. There is potential for adverse outcomes, in the longer term, including, possible increased risk of patellar dislocation and pain in the knee and hip. We aim to investigate the potential risk of spontaneous, unprovoked patellar dislocation among patients with fibular hemimelia, through a review of medical records and radiological investigations. All patients with a diagnosis of fibular hemimelia were included (n = 25), regardless of ultimate approach to management. Tibiofemoral angle measurement and Caton-Deschamps indices were calculated where suitable radiology was available, to better establish extent of potential patellar instability. All the patients with normal Caton-Deschamps indices had only partial fibular absence, although this does not detract from absence or hypoplasia of the anterior cruciate ligament, as a risk factor for patellar dislocation by predisposing to anterior tibial translation. Notably, of the three patients with increased Caton-Deschamps indices, two had complete fibular absence and underwent definitive amputation surgery at age 18 months and 3 years, respectively. Ultimately, this was a young patient group and on-going follow-up might yield better understanding of knee stability. Maintaining a well-aligned lower limb throughout growth might be protective even in the presence of anatomical abnormalities. This article mainly aims to raise awareness among prosthetic and orthotic professionals regarding the increased risk of patella dislocations.
Extracellular Vesicles Released During Normothermic Machine Perfusion Are Associated With Human Donor Kidney Characteristics
Authors: Woud Wouter W. , Arykbaeva Asel S. , Alwayn Ian P.J. , Baan Carla C. , Minnee Robert C. , Hoogduijn Martin J. , Boer Karin
Published: June 2022

Background.

Extracellular vesicles (EVs) are tissue-specific particles released by cells containing valuable diagnostic information in the form of various biomolecules. The characterization of EVs released by kidney grafts during normothermic machine perfusion (NMP) may present a promising avenue to assess graft status before transplantation.

Methods.

We phenotyped and determined the concentrations of EVs in the perfusate of 8 discarded expanded-criteria donor human kidneys during 6 h of NMP. Perfusate samples were taken at 0/60/180/360 min and examined with nanoparticle tracking analysis and imaging flow cytometry (IFCM). Using IFCM, EVs were identified by their expression of common EV markers CD9, CD63, and CD81 (tetraspanins) in combination with either platelet endothelial cell adhesion molecule (CD31), pan-leukocyte protein (CD45), or carboxyfluorescein succiminidyl ester (CFSE) fluorescence.

Results.

Nanoparticle tracking analysis measurements revealed the release of nanoparticles <400 nm into the perfusate during NMP. With IFCM, tetraspanin protein signatures of the released nanoparticles were characterized, and the majority (~75%) of CFSE+ EVs were found to be CD81+, whereas ~16% were CD9+ and ~8% CD63+. Correlation analysis of concentrations of identified EV subsets with crude donor characteristics and NMP viability characteristics revealed significant correlations with cold ischemia time, donor age, and renal flow.

Conclusions.

Our findings demonstrate that discarded expanded-criteria donor kidney grafts release distinct EV subsets during NMP. Because these subsets correlate with well-established indicators of transplant outcome, EVs might represent new potential candidates for assessment of kidney graft quality.
Cancer related subarachnoid hemorrhage: a multicenter retrospective study using propensity score matching analysis
Authors: K Senthil
Published: June 2022

Objective

To investigate the clinical features, risk factors and underlying pathogenesis of cancer related subarachnoid hemorrhage (SAH).

Methods

Clinical data of SAH in patients with active cancer from January 2010 to December 2020 at four centers were retrospectively reviewed. Patients with active cancer without SAH were matched to SAH patients with active cancer group. Logistic regression was applied to investigate the independent risk factors of SAH in patients with active cancer, after a 1:1 propensity score matching. A receiver operator characteristic curve was configured to calculate the optimal cut-off value of the joint predictive factor for cancer related SAH.

Results

A total of 82 SAH patients with active cancer and 309 patients with active cancer alone were included. Most SAH patients with cancer had poor outcomes, with thirty-day mortality of 41.5%, and with ninety-day mortality of 52.0%. The propensity score matching yielded 75 pairs of study participants. Logistic regression revealed that a decrease in platelet and prolonged prothrombin time were the independent risk factors of cancer related SAH. In addition, receiver operator characteristic curve of the joint predictive factor showed the largest AUC of 0.8131, with cut-off value equaling to 11.719, with a sensitivity of 65.3% and specificity of 89.3%.

Conclusions

Patients with cancer related SAH often have poor outcomes. The decrease in platelet and prolonged prothrombin time are the independent risk factors of cancer related SAH, and the joint predictive factor with cutoff value equal to 11.719 should hence serve as a novel biomarker of cancer related SAH.
HNRNPA2B1 controls an unfolded protein response-related prognostic gene signature in prostate cancer
Authors: Foster John G , Gea Esteban , Labiba Mosammat A , Anene Chinedu A , Stockley Jacqui , Philippe Celine , Cereda Matteo , Rouault-Pierre Kevin , Leung Hing , Bessant Conrad , Rajan Prabhakar
Published: June 2022

HNRNPA2B1 is associated with prostate cancer (PC) disease aggressiveness and underlies pro-tumourigenic cellular stress responses. By analysing >500 PC transcriptomes, we reveal that HNRNPA2B1 over-expression is associated with poor patient prognosis and stress response pathways. These include the “protein processing in the endoplasmic reticulum” (ER) pathway, which incorporates the unfolded protein response (UPR). By RNA-sequencing of HNRNPA2B1-depleted cells PC cells, we identified HNRNPA2B1-mediated down-regulation of UPR genes including the master ER-stress sensor IRE1, which induces ER proteostasis. Consistent with IRE1 down-regulation in HNRNPA2B1-depleted cells, we observed reduced splicing of the IRE1-target and key UPR effector XBP1s. Furthermore, HNRNPA2B1 depletion up-regulates expression of the IRE1-dependent decay (RIDD) target gene BLOC1S1, which is degraded by activated IRE1. We identify a HNRNPA2B1-IRE1-XBP1-controlled four gene prognostic biomarker signature (HIX) which classifies a subgroup of primary PC patients at high risk of disease relapse. Pharmacological targeting of IRE1 attenuated HNRNAPA2-driven PC cell growth. Taken together, our data reveal a putative novel mechanism of UPR activation in PC by HNRNPA2B1, which may promote an IRE1-dependent yet potentially-targetable recurrent disease phenotype.
EZH2 inhibition remodels the inflammatory senescence-associated secretory phenotype to potentiate pancreatic cancer immune surveillance
Authors: Chibaya Loretah , Murphy Katherine C. , Lopez-Diaz Yvette , DeMarco Kelly D. , Liu Haibo , Gopalan Sneha , Faulkner Melissa , Li Junhui , Morris John P. , Ho Yu-jui , Simon Janelle , Luan Wei , Kulick Amanda , de Stanchina Elisa , Simin Karl , Zhu Lihua Julie , Fazzio Thomas G. , Lowe Scott W. , Ruscetti Marcus
Published: June 2022

T cell-activating immunotherapies that produce durable and even curative responses in some malignancies have failed in pancreatic ductal adenocarcinoma (PDAC) due to rampant immune suppression and poor tumor immunogenicity. We and others have demonstrated that induction of cellular senescence and its accompanying senescence-associated secretory phenotype (SASP) can be an effective approach to activate not only T cell but also cytotoxic Natural Killer (NK) cell-mediated anti-tumor immunity. Here we found that the pancreas tumor microenvironment (TME) suppresses NK and T cell surveillance following therapy-induced senescence through EZH2-mediated repression of pro-inflammatory SASP genes. Genetic or pharmacological inhibition of EZH2 or its methyltransferase activity stimulated the production of pro-inflammatory SASP chemokines CCL2 and CXCL9/10 that led to enhanced NK and T cell infiltration and tumor eradication in preclinical PDAC mouse models. EZH2 activity was also associated with suppression of SASP-associated inflammatory chemokines and cytotoxic lymphocyte immunity and reduced overall survival in a PDAC patient cohort. These results demonstrate that EZH2 mediates epigenetic repression of the pro-inflammatory SASP in the pancreas TME, and that EZH2 blockade in combination with senescence-inducing therapies could be a powerful means to potentiate NK and T cell surveillance in PDAC to achieve immune-mediated tumor control.
New Hydra genomes reveal conserved principles of hydrozoan transcriptional regulation
Authors: Cazet Jack F. , Siebert Stefan , Little Hannah Morris , Bertemes Philip , Primack Abby S. , Ladurner Peter , Achrainer Matthias , Fredriksen Mark T. , Moreland R. Travis , Singh Sumeeta , Zhang Suiyuan , Wolfsberg Tyra G. , Schnitzler Christine E. , Baxevanis Andreas D. , Simakov Oleg , Hobmayer Bert , Juliano Celina E.
Published: June 2022

The epithelial and interstitial stem cells of the freshwater polyp Hydra are the best characterized stem cell systems in any cnidarian, providing valuable insight into cell type evolution and the origin of stemness in animals. However, little is known about the transcriptional regulatory mechanisms that determine how these stem cells are maintained and how they give rise to their diverse differentiated progeny. To address such questions, a thorough understanding of transcriptional regulation in Hydra is needed. To this end, we generated extensive new resources for characterizing transcriptional regulation in Hydra, including new genome assemblies for Hydra oligactis and the AEP strain of Hydra vulgaris, an updated whole-animal single-cell RNA-seq atlas, and genome-wide maps of chromatin interactions, chromatin accessibility, sequence conservation, and histone modifications. These data revealed the existence of large chromatin interaction domains in the Hydra genome that likely influence transcriptional regulation in a manner distinct from topologically associating domains in bilaterians. We also uncovered the transcriptomic profiles of two previously molecularly uncharacterized cell types, isorhiza-containing nematocytes and somatic gonad ectoderm. We identified novel candidate regulators of cell-type-specific transcription, several of which have likely been conserved at least since the divergence of Hydra and the jellyfish Clytia hemisphaerica over 200 million years ago. The resources generated in this study, which collectively represent the most comprehensive characterization of transcriptional regulation in a cnidarian to date, are accessible through a newly created genome portal, available at research.nhgri.nih.gov/HydraAEP/.
A call for improving the Key Biodiversity Areas framework
Authors: Farooq Harith , Antonelli Alexandre , Faurby Søren
Published: June 2022

Eight percent of all land surface has been designated as “Key Biodiversity Areas” (KBAs). Since these areas were established based on only two percent of all terrestrial species estimated to exist, we ask what would happen if we used all species on Earth to identify additional KBAs. We explore this question at a global scale by using data from 64,110 species of animals and plants to identify how many areas could qualify as KBAs under current criteria. We find that between 26% and 68% of the world’s terrestrial areas can be classified as KBAs, depending on the spatial resolution. The total area from potential KBAs increases drastically as more species are assessed, suggesting that if all species were included, virtually all land surface could eventually meet the biological requirements for becoming a KBA. In addition, KBAs lack a data-driven ranking system, thus assuming that all KBAs are equally worthy protection. KBAs are intended to be areas which are both of biological importance and manageable but the current approach largely sidesteps the biological component. We make an urgent call for stricter criteria in the KBA methodology or alternative methodologies that allow for biologically robust area prioritization, help secure evidence-based investments, and support progress towards the targets under the new Global Biodiversity Framework.
The integrated LIM-peptidase domain of the CSA1/CHS3 paired immune receptor detects changes in DA1 family peptidase inhibitors to confer Albugo candida resistance in Arabidopsis
Authors: Gu Benguo , Parkes Toby , Smith Caroline , Lu Fu-Hao , McKenzie Neil , Dong Hui , Jones Jonathan D. G. , Cevik Volkan , Bevan Michael W.
Published: June 2022

White blister rust, caused by the oomycete Albugo candida, is a widespread disease of Brassica crops. The Arabidopsis CSA1/DAR4 (also known as CSA1/CHS3) paired immune receptor carries an Integrated Domain (ID) with homology to the DA1 family of peptidases. Using domain swaps with DA1 family members, we show that the DAR4 ID acts as an integrated decoy for DAR3, which interacts with and inhibits the peptidase activities of DA1, DAR1 and DAR2 family members. Albugo infection rapidly lowered DAR3 levels and activates DA1 peptidase activity. This promotes endoreduplication of host tissues to support pathogen growth. We propose that DAR4/CSA1 senses the actions of a putative Albugo effector that reduces DAR3 levels and initiates defense.
DHFR metabolic activity controls neurogenic transitions in the developing Human and mouse neocortex
Authors: Saha Sulov , Jungas Thomas , Ohayon David , Audouard Christophe , Ye Tao , Fawal Mohamad-Ali , Davy Alice
Published: June 2022

One-carbon/folate (1C) metabolism supplies methyl groups required for DNA and histone methylation, and is involved in the maintenance of self-renewal in stem cells. Dihydrofolate reductase (DHFR), a key enzyme in 1C metabolism, is highly expressed in Human and mouse neural progenitors at the early stages of neocortical development. Here, we investigated the role of DHFR in the developing neocortex and report that reducing its activity in Human cerebral organoids and mouse embryonic neocortex accelerates indirect neurogenesis, a hallmark of mammalian brain evolution, thereby affecting neuronal composition of the neocortex. Further, we show that decreasing DHFR activity in neural progenitors leads to a reduction in One-carbon/folate metabolites and correlates with modifications of H3K4me3 methylation. Our findings reveal an unanticipated role for DHFR in controlling specific steps of neocortex development and indicate that variations in 1C metabolic cues impact cell fate transitions.
SUMO Activated Target Traps (SATTs) enable the identification of a comprehensive E3-specific SUMO proteome
Authors: Salas-Lloret Daniel , van der Meulen Coen , Nagamalleswari Easa , Gracheva Ekaterina , de Ru Arnoud H. , Marie Otte H. Anne , van Veelen Peter A. , Pichler Andrea , Goedhart Joachim , Vertegaal Alfred C.O. , González-Prieto Román
Published: June 2022

Ubiquitin and ubiquitin-like conjugation cascades consist of dedicated E1, E2 and E3 enzymes with E3s providing substrate specificity. Mass spectrometry-based approaches have enabled the identification of more than 60,000 acceptor sites for ubiquitin and 40,000 acceptor sites for SUMO2/3. However, E3-to-target wiring is poorly understood. The limited number of SUMO E3s provides the unique opportunity to systematically study E3-substrate wiring. We developed SUMO Activated Target Traps (SATTs) and systematically identified substrates for eight different SUMO E3s, PIAS1, PIAS2, PIAS3, PIAS4, NSMCE2, ZNF451, LAZSUL(ZNF451-3) and ZMIZ2. SATTs enabled us to identify 590 SUMO1 and 1195 SUMO2/3 targets in an E3-specific manner. We found pronounced E3 substrate preference, even at the substrate isoform level. Quantitative proteomics enabled us to measure substrate specificity of E3s, quantified using the SATT index. Furthermore, we developed the Polar SATTs web-based tool (https://amsterdamstudygroup.shinyapps.io/PolaRVolcaNoseR/) to browse the dataset in an interactive manner, increasing the accessibility of this resource for the community. Overall, we uncover E3-to-target wiring of 1681 SUMO substrates, highlighting unique and overlapping sets of substrates for eight different SUMO E3 ligases.
A CRISPR-engineered Isogenic Model Reveals Altered Neuronal Phenotypes of the 22q11.2 A-B Syndromic Deletion
Authors: Paranjape Neha , Lin Yu-Hsiu T. , Flores-Ramirez Quetzal , Sarin Vishesh , Johnson Amanda Brooke , Chu Julia , Paredes Mercedes , Wiita Arun P.
Published: June 2022

The 22q11.2 deletion syndrome (22q11.2DS), associated with congenital and neuropsychiatric anomalies, is the most common copy number variant (CNV)-associated syndrome. Patient-derived, induced pluripotent stem cell (iPS) models have provided important insight into the mechanisms of phenotypic features of this condition. However, patient-derived iPS models may harbor underlying genetic heterogeneity that can confound analysis of pathogenic CNV effects. Furthermore, the ∼1.5 Mb “A-B” deletion at this locus is inherited at higher frequency than the more common ∼3 Mb “A-D” deletion, but remains under-studied due to lack of relevant models. To address these issues, here we leveraged a CRISPR-based strategy in Cas9-expressing iPS cells to engineer novel isogenic models of the 22q11.2 “A-B” deletion. After in vitro differentiation to excitatory neurons, integrated transcriptomic and cell surface proteomics identified deletion-associated alterations in surface adhesion and cell signaling. Furthermore, implantation of iPS-derived neuronal progenitor cells into the cortex of neonatal mice found accelerated neuronal maturation within a relevant microenvironment. Taken together, our results suggest pathogenic mechanisms of the 22q11.2 “A-B” deletion in driving neuronal and neurodevelopmental phenotypes, both in vitro and in vivo. We further propose that the isogenic models generated here will provide a unique resource to study this less-common variant of the 22q11.2 microdeletion syndrome.
Large-scale genetic screens identify BET-1 as a cytoskeleton regulator promoting actin health and lifespan
Authors: Garcia Gilberto , Bar-Ziv Raz , Dutta Naibedya , Moaddeli Darius , Averbukh Maxim , Torres Toni Castro , Alcala Athena , Tsui C. Kimberly , Moehle Erica A. , Shalem Ophir , Thorwald Max A. , Higuchi-Sanabria Ryo
Published: June 2022

The actin cytoskeleton is a three-dimensional scaffold of proteins that is a regulatory, energy-consuming network with dynamic properties to shape the structure and function of the cell. Proper actin function is required for many cellular pathways, including cell division, autophagy, chaperone function, endocytosis, and exocytosis. Deterioration of these processes manifests during aging and exposure to stress, which is in part due to the breakdown of the actin cytoskeleton. However, the regulatory mechanisms involved in preservation of cytoskeletal form and function are not well understood. Here, we performed a multi-pronged, cross-organismal screen combining a whole-genome CRISPR-Cas9 screen in human fibroblasts with in vivo C. elegans synthetic lethality screening. We identified the bromodomain protein, BET-1, as a key regulator of actin health and longevity. Overexpression of bet-1 preserves actin health at late age and promotes lifespan and healthspan in C. elegans. These beneficial effects are mediated through actin preservation by the transcriptional regulator function of BET-1. Together, our discovery assigns a key role for BET-1 in cytoskeletal health, highlighting regulatory cellular networks promoting cytoskeletal homeostasis.
A Single Anodal Transcranial Direct Current Stimulation Session to Enhance Sport-Specific Performance in Trained Individuals? A Systematic Review and Meta-Analysis
Authors: Maudrich Tom , Ragert Patrick , Perrey Stephane , Kenville Rouven
Published: June 2022

Background

Transcranial direct current stimulation (tDCS) has emerged as a promising and feasible method to improve motor performance in healthy and clinical populations. However, the potential of tDCS to enhance sport-specific motor performance in athletes remains elusive.

Objective

We aimed at analyzing the acute effects of a single anodal tDCS session on sport-specific motor performance changes in athletes compared to sham.

Methods

A systematic review and meta-analysis was conducted in the electronic databases PubMed, Web of Science, and SPORTDiscus with publication dates through April 2022. The meta-analysis was performed using an inverse variance method and a random-effects model. Additionally, two subgroup analyses were conducted (1) depending on the stimulated brain areas (i.e., primary motor cortex (M1), temporal cortex (TC), prefrontal cortex (PFC), cerebellum (CB)), and (2) studies clustered in subgroups according to different sports performance domains (endurance, strength, and visuomotor skill).

Results

A total number of 18 studies enrolling a sample size of 245 athletes were deemed eligible for inclusion. Across all included studies, a significant moderate standardized mean difference (SMD) favoring anodal tDCS to enhance sport-specific motor performance could be observed (SMD = 0.27, 95%CI [0.10, 0.44], p = 0.002). Subgroup analysis depending on cortical target areas of tDCS indicated non-significant moderate to high SMD in favor of anodal tDCS compared to sham for M1 (SMD = 0.24, 95%CI [-0.01, 0.49], p = 0.06), TC (SMD = 0.40, 95%CI [-0.10, 0.89], p = 0.12), PFC (SMD = 0.23, 95%CI [-0.04, 0.50], p = 0.09) and CB (SMD = 0.89, 95%CI [-0.15, 1.94], p = 0.09). Performance domain subgroup analysis revealed non-significant moderate SMD favoring anodal tDCS compared to sham: endurance domain (SMD = 0.23, 95%CI [-0.01, 0.47], p = 0.06), strength domain (SMD = 0.44, 95%CI [-0.14, 1.01], p = 0.14, Chi2 = 0.31) and visuomotor skill domain (SMD = 0.30, 95%CI [-0.03, 0.62], p = 0.07).

Conclusion

A single anodal tDCS session leads to performance enhancement in athletes in sport-specific motor tasks. Although no conclusions can be drawn regarding the modes of action as a function of performance domain or stimulation site, these results imply intriguing possibilities concerning sports performance enhancement. Furthermore, this study highlights the need to investigate tDCS applications under real-life conditions rather than in highly controlled laboratory settings to uncover the true potential of non-invasive brain stimulation as a performance enhancement not only in sports but also in the context of prevention or rehabilitation of neurological diseases.