bluuebunny/crossref_metadata_2025 huggingface dataset:
Monitoring Drug Safety in Pregnancy with Scan Statistics: A Comparison of Two Study Designs
Authors: Suarez Elizabeth A. , Nguyen Michael , Zhang Di , Zhao Yueqin , Stojanovic Danijela , Munoz Monica , Liedtka Jane , Anderson Abby , Liu Wei , Dashevsky Inna , DeLuccia Sandra , Menzin Talia , Noble Jennifer , Maro Judith C.
Published: October 2022

Background:

Traditional surveillance of adverse infant outcomes following maternal medication exposures relies on pregnancy exposure registries, which are often underpowered. We characterize the statistical power of TreeScan, a data mining tool, to identify potential signals in the setting of perinatal medication exposures and infant outcomes.

Methods:

We used empirical data to inform background incidence of major congenital malformations and other birth conditions. Statistical power was calculated using two probability models compatible with TreeScan, Bernoulli and Poisson, while varying the sample size, magnitude of the risk increase, and incidence of a specified outcome. We also simulated larger referent to exposure matching ratios when using the Bernoulli model in the setting of fixed N:1 propensity score matching. Finally, we assessed the impact of outcome misclassification on power.

Results:

The Poisson model demonstrated greater power to detect signals than the Bernoulli model across all scenarios and suggested a sample size of 4,000 exposed pregnancies is needed to detect a twofold increase in risk of a common outcome (approximately 8 per 1,000) with 85% power. Increasing the fixed matching ratio with the Bernoulli model did not reliably increase power. An outcome definition with high sensitivity is expected to have somewhat greater power to detect signals than an outcome definition with high positive predictive value.

Conclusions:

Use of the Poisson model with an outcome definition that prioritizes sensitivity may be optimal for signal detection. TreeScan is a viable method for surveillance of adverse infant outcomes following maternal medication use.
Tranexamic Acid Dosing in Craniosynostosis Surgery: A Systematic Review with Meta-analysis
Authors: O’Donnell Devon B. , Vazquez Sima , Greisman Jacob D. , Uddin Anaz , Graifman Gillian , Dominguez Jose F. , Zellner Elizabeth , Muh Carrie R.
Published: October 2022

Objective:

This study aimed to compare operative time, blood loss, and transfusion requirement in patients receiving a high tranexamic acid (TXA) dose of greater than 10 mg/kg versus those receiving a low dose of 10 mg/kg or less.

Methods:

PubMed, Cochrane Central, and Embase were queried to perform a systematic review with meta-analysis. Studies reporting outcomes of TXA use in craniosynostosis surgery were included. TXA dosing, operative time, blood loss, and transfusion requirement were the primary outcomes studied. Other variables studied included age and types of craniosynostosis.

Results:

In total, 398 individuals in the included articles received TXA for craniosynostosis surgery. TXA loading doses ranged from 10 mg/kg to 50 mg/kg. Overall, administration of TXA was not associated with changes in operative time, but was associated with decreased blood loss and transfusion requirement on meta-analysis. Comparison of high dose TXA (>10 mg/kg) versus low dose (10 mg/kg or less) showed no statistical differences in changes in operative time, blood loss, or transfusion requirement.

Conclusions:

Overall, TXA reduced blood loss and transfusion requirement in patients undergoing surgery for craniosynostosis. There was no difference in outcomes between high dose and low dose regimens amongst those receiving TXA. Low dose TXA appears adequate to achieve clinical efficacy with a low adverse event rate.
Dermal Micro-coring for the Treatment of Moderate to Severe Facial Wrinkles
Authors: Gfrerer Lisa , Kilmer Suzanne L. , Waibel Jill S. , Geronemus Roy G. , Biesman Brian S.
Published: October 2022

Background:

Micro-coring technology (MCT) removes cores of skin without formation of scars, thereby tightening skin and reducing skin wrinkling. The purpose of this study was to evaluate the safety and efficacy of MCT with the dermal micro-coring device for the treatment of facial wrinkles.

Methods:

This prospective, multicenter clinical trial included fifty-one subjects who underwent MCT treatments of the mid to lower face. The primary study endpoint was change in the Lemperle Wrinkle Severity Scale. Secondary study endpoints were change in Global Aesthetic Improvement Scale (GAIS), participant satisfaction, and evaluation of treatment outcome by an independent review panel. All study endpoints were evaluated at 1, 7, 30, 60, and 150 or 180 days after treatment. Procedure bleeding, pain, and early healing profile were also captured.

Results:

The mean Lemperle Wrinkle Severity Scale change was 1.3 grades. Improvement in the GAIS was reported for 89.7% (87/97) of treated sites, and average improvement of GAIS was 1.5. Participants reported satisfaction with 85.6% of treatment sites. The independent review panel correctly identified 84.2% of the post-treatment photographs as post-treatment. Procedure bleeding and pain was mild with good healing responses and patient-reported average down time of 3 days.

Conclusions:

The results of this study demonstrate the safety and efficacy of MCT with the dermal micro-coring device for the treatment of moderate to severe facial wrinkles. MCT led to significant improvement of facial wrinkles with high patient satisfaction and fast recovery time and should be considered in patients who are seeking minimally invasive treatment for wrinkles of the face.
Chronic temporomandibular disorders are associated with higher propensity to develop central sensitization: a case–control study
Authors: Cayrol Timothée , van den Broeke Emanuel N. , Gerard Eve , Meeus Mira , Mouraux André , Roussel Nathalie , Pitance Laurent
Published: October 2022

Temporomandibular disorders (TMD) include a group of musculoskeletal disorders that may involve increased responsiveness of nociceptive neurons in the central nervous system (ie, central sensitization). To test this hypothesis further, this study examined whether, as compared with healthy subjects, patients with chronic TMD have a greater propensity to develop secondary mechanical hyperalgesia—a phenomenon that can be confidently attributed to central sensitization. In this case–control study, we assessed the area of secondary mechanical hyperalgesia induced experimentally by delivering high-frequency electrical stimulation (HFS) to the volar forearm skin in 20 participants with chronic TMD and 20 matched healthy controls. High-frequency electrical stimulation consisted in 12 trains of constant-current electrical pulses (5 mA) delivered at 42 Hz. The area of secondary mechanical hyperalgesia was evaluated 30 minutes after applying HFS. The area of secondary mechanical hyperalgesia induced by HFS was on average 76% larger in the chronic TMD group (M = 67.7 cm2, SD = 28.2) than in the healthy control group (M = 38.4 cm2, SD = 14.9; P = 0.0003). Regarding secondary outcomes, there was no group difference in the intensity of secondary mechanical hyperalgesia, but allodynia to cotton after HFS was more frequent in the chronic TMD group. To the best of our knowledge, this is the first study to show that individuals with chronic TMD have an increased propensity to develop secondary hyperalgesia in a site innervated extratrigeminally. Our results contribute to a better understanding of the pathophysiology of chronic TMD.
Adenosine causes short-lasting vasodilation and headache but not migraine attacks in migraine patients: a randomized clinical trial
Authors: Thuraiaiyah Janu , Al-Karagholi Mohammad Al-Mahdi , Elbahi Fatima Azzahra , Zhuang Zixuan Alice , Ashina Messoud
Published: October 2022

Migraine is a common disabling disease with a complex pathophysiology. Headache is a frequent side effect after intravenous adenosine administration, although adenosine receptor antagonist, caffeine, relieves migraine headache. These observations suggest a possible involvement of adenosine signaling in headache and migraine pathophysiology. In a randomized, double-blinded, placebo-controlled, crossover study, 18 participants diagnosed with migraine without aura received 120 µg/kg per minute adenosine or placebo over 20 minutes. Headache intensity, migraine-associated symptoms, vital signs, the diameter of the superficial temporal artery (STA), blood flow velocity in the middle cerebral artery (VMCA), and facial skin blood flow were measured at baseline and every 10 minutes until 2 hours after infusion start. The primary end point was the difference in the incidence of migraine attacks after adenosine infusion compared with placebo. Eighteen participants completed the study. We found no difference in the incidence of migraine after adenosine infusion (7 of 18, 39%) compared with placebo (3 of 18, 17%) (P = 0.29). Fourteen participants reported headache after adenosine infusion (14 of 18, 78%) compared with placebo (6 of 18, 33%) (P < 0.01). Adenosine increased heart rate (P < 0.001), facial skin blood flow (P < 0.05), and STA diameter (AUCT0-20min, P = 0.01) and decreased VMCA (AUCT0-20min, P < 0.001) compared with placebo. Adenosine induced headache accompanied by a short-lasting (<30 minutes) dilation of intracerebral and extracerebral arteries. The nonsignificant migraine induction might be because of the presence of several adenosine receptors with counteracting signaling, highlighting the need of more selective modulators to dissect the implication of adenosine in migraine.
Better Approaches to Derisking Psychiatric Drug Development are Needed, Not New Funding Mechanisms
Authors: Potter William Z.
Published: October 2022

Background

The pulling back of large pharma from psychiatric drug development over the last 15 years has been a cause of concern. The uncertainty of success with any novel mechanism raises questions concerning whether current funding mechanisms for the various components of drug development need to be revisited. Alternatively, advances in neuroscience and translational methods may provide a sufficient incentive for continued private sector investment.

Method

Narrative commentary drawing on personal positions in both NIH and Industry devoted to translation of CNS compounds from bench to bedside coupled with specific examples of efforts to improve the selection of compounds to take into large clinical trials.

Results

Strategies for increasing R&D productivity in the field of CNS drugs articulated over a decade ago have been implemented over the same period with pre-competitive consortia involved in developing the tools needed to show that before being taken into large trials adequate evidence of postulated brain effects are required. In parallel, the field and the FDA have focused much more on the search for domain specific treatments rather than those depending on traditional measures of efficacy in DSM disorders. NIMH programs such as RDoC and the “Fast-Fail” initiative are provided as efforts which influence and involve partnerships with industry.

Conclusions

The evolution of the field over the last decade is such that there is a shared focus across sources of funding in the public sector, especially NIH brain institutes, on the tools needed to de-risk psychiatric drug development to the degree needed to encourage private sector investment in the clinical trials needed to advance potential new treatments for areas of greatest need. Expansion of funding for translational tool development will have the highest impact on delivering novel treatments.
Detecting Sarcopenic Obesity in Survivors of Pediatric Acute Lymphoblastic Leukemia: An Exploration of Body Mass Index and Triponderal Mass Index as Potential Surrogate Markers
Authors: Guolla Louise , Thabane Lehana , Barr Ronald D.
Published: October 2022

Survivors of pediatric acute lymphoblastic leukemia (ALL) often have altered body composition secondary to treatment effects, including sarcopenic obesity (SO), which increases the risk of both metabolic complications and frailty. SO is difficult to detect without using advanced imaging techniques to which access is often limited. To explore whether common clinical indices can reliably identify the presence of SO in a cohort of long-term survivors of ALL, the discriminatory capacity of body mass index (BMI) or triponderal mass index (TMI, kg/m3) for detecting SO was assessed. Thresholds of BMI and TMI associated with overweight or obesity status had poor sensitivity (<50%) and specificity for detecting SO. Total misclassification rates at these thresholds exceeded 50% and positive likelihood ratios were nonsignificant. Notably, TMI is more strongly correlated with elevated adiposity than is BMI in this survivor population (R
2=0.73 vs. 0.57), suggesting further exploration is warranted. Our study is limited by the sample size, precluding detailed regression analysis. This study highlights the challenges of identifying SO in survivors of pediatric ALL using common clinical indices. Prospective evaluation of additional potential surrogate markers in survivors, in conjunction with the component features of SO, should be a key focus of future research.
The Relationship Between Practice Environment Variables and Nurse Manager Perceptions of Workplace Mistreatment to Identify Factors Amenable to Change
Authors: Tarasenko Lindsey Marie , Weston Marla J. , Jones Jacqueline
Published: October 2022

OBJECTIVE

To examine the relationships between practice environment factors and nurse manager (NM) perceptions of workplace mistreatment (WPM).

BACKGROUND

NMs have a unique perspective of business operations and care delivery and can offer insight into how WPM manifests in clinical settings at the leadership level.

METHODS

Researchers used a cross-sectional correlational design using a nonexperimental causal technique. A convenience sample of 139 NMs completed a survey regarding their perceptions of organizational change, the practice environment, and WPM.

RESULTS

NMs reported experiencing incivility (98%) and bullying (90%). Approximately 20% variance explained mistreatment by relationships with supervisors and budgeted resources (F
4,134 = 9.16, P = 0.000).

CONCLUSIONS

Modifiable factors can be identified to prevent or reduce WPM.
Workplace Exposures and Prescription Drug Misuse Among Nurses
Authors: Trinkoff Alison M. , Selby Victoria L. , Baek Hyang , Storr Carla L. , Steele Jenell , Han Kihye
Published: October 2022

OBJECTIVE

This study examined the association between workplace exposure and prescription drug misuse in nurses.

BACKGROUND

Studies have found RNs and other health providers have higher rates of prescription misuse than the general population and have suggested that workplace exposures along with excessive job demands create circumstances fostering misuse.

METHODS

Survey data from 1170 RNs on workplace exposures (availability, frequency of administration, knowledge of substances, and workplace controls) were described by workplace, position, and specialty. Exposures were then related to prescription drug misuse using logistic regression.

RESULTS

Each workplace exposure was associated with past year prescription drug misuse. An index combining all exposures was significantly related to misuse (P = 0.001), and odds of misuse increased by 38% for each point increase in the exposure index.

CONCLUSIONS

Consideration of the health and well-being of nurses at higher odds of exposure to prescription drugs with misuse potential is warranted. Workplace support to help nurses maintain and restore their health should be a priority.
Using Deep Learning to Predict Final HER2 Status in Invasive Breast Cancers That are Equivocal (2+) by Immunohistochemistry
Authors: Rasmussen Sean A. , Taylor Valerie J. , Surette Alexi P. , Barnes Penny J. , Bethune Gillian C.
Published: October 2022

Invasive breast carcinomas are routinely tested for HER2 using immunohistochemistry (IHC), with reflex in situ hybridization (ISH) for those scored as equivocal (2+). ISH testing is expensive, time-consuming, and not universally available. In this study, we trained a deep learning algorithm to directly predict HER2 gene amplification status from HER2 2+ IHC slides. Data included 115 consecutive cases of invasive breast carcinoma scored as 2+ by IHC that had follow-up HER2 ISH testing. An external validation data set was created from 36 HER2 IHC slides prepared at an outside institution. All internal IHC slides were digitized and divided into training (80%), and test (20%) sets with 5-fold cross-validation. Small patches (256×256 pixels) were randomly extracted and used to train convolutional neural networks with EfficientNet B0 architecture using a transfer learning approach. Predictions for slides in the test set were made on individual patches, and these predictions were aggregated to generate an overall prediction for each slide. This resulted in a receiver operating characteristic area under the curve of 0.83 with an overall accuracy of 79% (sensitivity=0.70, specificity=0.82). Analysis of external validation slides resulted in a receiver operating characteristic area under the curve of 0.79 with an overall accuracy of 81% (sensitivity=0.50, specificity=0.82). Although the sensitivity and specificity are not high enough to negate the need for reflexive ISH testing entirely, this approach may be useful for triaging cases more likely to be HER2 positive and initiating treatment planning in centers where HER2 ISH testing is not readily available.
Use of Cephalic Vein in DIEP Breast Reconstruction Does Not Increase Risk of Lymphedema of the Ipsilateral Arm – a Cohort Study with Nine Years of Follow-up
Authors: Svee Andreas , Falk-Delgado Alberto , Folkvaljon Folke , Cederland Christoffer , Wallenius Imke , Audolfsson Thorir , Drazan Lubos , Mani Maria
Published: October 2022

Flap failure is a rare but devastating complication in deep inferior epigastric perforator flap (DIEP) reconstructions. Common causes of partial or complete flap failure are related to venous congestion. Although cephalic vein is usually a safe and reliable recipient vein for additional venous outflow, there is a hypothesized risk of donor-arm lymphedema secondary to lymphatic vessel damage in the vicinity of the cephalic vein or related to scarring and reduced venous backflow of the arm. The aim was to assess if the cephalic vein as an additional recipient vessel, via the superficial inferior epigastric vein in DIEP breast reconstruction, was associated with long-term volume changes of the arm and/or symptoms of lymphedema.

Arm volume was assessed preoperatively in patients scheduled to undergo unilateral delayed DIEP breast reconstruction at Uppsala University hospital, Sweden, between 2001-2007. Long-term postoperative assessments were made in 2015-2016. Water displacement and circumferential measurement were assessed preoperatively and postoperatively by the same lymphedema therapists. Patients were divided into two groups; DIEP reconstruction with cephalic vein or without. Fifty-four patients fulfilled the inclusion criteria and completed the study with a mean follow-up time of 136 months. There was no increased occurrence of lymphedema in the group undergoing DIEP with a cephalic vein as extra venous drainage, based on an analysis of change from baseline in arm volume difference.

This study shows that the cephalic vein can be used for secondary venous outflow in DIEP breast reconstruction without long-term risk of ipsilateral arm volume increase or symptoms of lymphedema.
Health Care Utilization in Systemic Lupus Erythematosus in the Community
Authors: Chevet Baptiste , Figueroa-Parra Gabriel , Valenzuela-Almada Maria O. , Hocaoglu Mehmet , Vallejo Sebastian , Osei-Onomah Shirley-Ann , Giblon Rachel E. , Dabit Jesse Y. , Chamberlain Alanna M. , Cornec Divi , Greenlund Kurt J. , Barbour Kamil E. , Crowson Cynthia S. , Duarte-García Alí
Published: October 2022

Objective

The aim of this study was to determine inpatient health care utilization in an incident cohort of patients with systemic lupus erythematosus (SLE) compared with the general population.

Methods

This was a population-based cohort study in the upper Midwest, United States. We included patients fulfilling the European League Against Rheumatism/American College of Rheumatology SLE classification criteria between 1995 and 2018. They were 1:1 age-, sex-, county-matched with individuals without SLE. All hospital admissions and emergency department (ED) visits were electronically retrieved for 1995–2020. Rates for hospital admission, length of stay, readmission, ED visits, and discharge destination were compared between groups.

Results

Three hundred forty-one patients with SLE and 341 comparators without SLE were included (mean age, 48.6 years at diagnosis; 79.2% female). Rates of hospitalization for patients with SLE and comparators were 29.8 and 9.9 per 100 person-years, respectively. These differences were present across sexes and age groups. Hospitalization rates were higher in patients with SLE after diagnosis and remained higher than comparators for the first 15 years of the disease. Patients with SLE were more likely than comparators to visit the ED (hazard ratio, 2.71; 95% confidence interval, 2.05–3.59). Readmission rates (32% vs. 21%, p = 0.017) were higher in patients with SLE. Length of stay and discharge destination were similar between both groups.

Conclusion

Patients with SLE were more likely to be hospitalized and to visit the ED than individuals without SLE, highlighting important inpatient care needs. Increased hospitalization rates were observed in both male and female patients and all age groups.
Therapeutic strategies for pseudoaneurysm following blunt liver and spleen injuries: a multicenter cohort study in the pediatric population.
Authors: Katsura Morihiro , Kondo Yutaka , Yasuda Hideto , Fukuma Shingo , Matsushima Kazuhide , Shiraishi Atsushi , Tsuchiya Asuka , Kuriyama Akira , Gima Masafumi , Hayashida Kazuyuki , Miura Naoya , Sugiura Kenta , Toma Keiichiro , Yasumatsu Hiroshi , Kushimoto Shigeki ,   SHIPPs Study Group*
Published: October 2022

Background

Little guidance exists for the treatment of pseudoaneurysm following pediatric blunt liver and/or spleen injuries (BLSI). We aimed to describe the incidence of delayed pseudoaneurysm development and the subsequent clinical course of pseudoaneurysm in pediatric BLSI.

Methods

This multicenter retrospective cohort study from Japan included pediatric patients (≤16 years old) who sustained BLSI from 2008 to 2019. The cohort was divided into four groups based on hemostatic intervention within 48 hours of admission, namely non-operative management (NOM), NOM with interventional radiology (IR), operative management (OM), and combined IR/OM. Descriptive statistics were used to describe the incidence of delayed pseudoaneurysm among the groups and to characterize the clinical course of any pseudoaneurysms.

Results

A total of 1,407 children (median age, 9 years) from 83 institutions were included. The overall number (incidence) of cases of delayed pseudoaneurysm formation was 80 (5.7%), and the number with delayed pseudoaneurysm rupture was 16 (1.1%) cases in the entire cohort. Patients treated with NOM (1056), NOM with IR (276), OM (53), and combined IR/OM (22) developed 43 (4.1%), 32 (12%), 2 (3.8%), and 3 (14%) delayed pseudoaneurysms, respectively. Among patients who developed any pseudoaneurysms, 39% of patients underwent prophylactic IR for unruptured pseudoaneurysm, while 13% required emergency angioembolization for delayed pseudoaneurysm rupture, with one ruptured case requiring total splenectomy. At least 45% of patients experienced spontaneous resolution of pseudoaneurysm without any interventions.

Conclusion

Our results suggest that the risk of delayed pseudoaneurysm still exists even after acute phase IR as an adjunct to NOM for BLSI in children, indicating the necessity of a period of further observation. While endovascular interventions are usually successful for pseudoaneurysm management, including rupture cases, given the high incidence of spontaneous resolution, the ideal management of pseudoaneurysm remains to be investigated in future studies.

Level of evidence

Level 4; Therapeutic/Care management
Association of Maternal and Neonatal Birth Outcomes With Subsequent Pediatric Transplants
Authors: Côté-Corriveau Gabriel , Luu Thuy Mai , Bilodeau-Bertrand Marianne , Auger Nathalie
Published: October 2022

Background.

We identified maternal and neonatal birth characteristics that were associated with organ or tissue transplants during childhood.

Methods.

We designed a retrospective cohort study of the population of children born between 2006 and 2019 in Quebec, Canada. The exposure included birth complications such as congenital anomaly, neonatal blood transfusion, and oligohydramnios. The main outcome measure was organ or tissue transplantation before 14 y of age. We categorized transplants according to type (major organs versus superficial tissues). To determine the association of birth characteristics with risk of pediatric transplant, we estimated hazard ratios (HRs) and 95% confidence intervals (CIs) using Cox proportional hazards models adjusted for potential confounders.

Results.

The cohort comprised 1 038 375 children with 7 712 678 person-years of follow-up, including 436 children who had transplants before 14 y of age. Birth complications were predominantly associated with major organ transplants. Congenital anomaly was associated with heart or lung (HR, 10.41; 95% CI, 5.33-20.33) and kidney transplants (HR, 13.69; 95% CI, 7.48-25.06), compared with no anomaly. Neonatal blood transfusion was associated with all major organ transplants, compared with no transfusion. Maternal complications were not as strongly associated with the risk of childhood transplant, although oligohydramnios was associated with 16.84 times (95% CI, 8.09-35.02) the risk of kidney transplant, compared with no oligohydramnios.

Conclusions.

Adverse birth outcomes such as congenital anomaly, neonatal blood transfusion, and maternal oligohydramnios are associated with a greater risk of transplantation before 14 y of age. Maternal and neonatal birth outcomes may be useful predictors of transplantation.
miR-128-3p inhibits the inflammation by targeting MAPK6 in penicillin-induced astrocytes
Authors: Pang Yuejiu , Luo Dingzhen , Wang Shuhua
Published: October 2022

Objective

Epilepsy causes physical and mental damage to patients. As well known, microRNAs (miRNAs) provide therapeutic target potentials for patients with epilepsy. miR-128-3p was previously reported to be downregulated in temporal lobe epilepsy (TLE) patients, however, its detailed function in epilepsy is unknown.

Methods

Astrocytes function in epilepsy, penicillin-induced astrocytes can be used as a model for seizures in vitro. Currently, the expression levels of mitogen-activated protein kinase 6 (MAPK6), interleukin-1 beta (IL-1β) and tumor necrosis factor-alpha (TNF-α) were determined by western blot and reverse transcription-quantitative PCR analyses (RT-qPCR). The expression level of miR-128-3p was evaluated by RT-qPCR. TargetScan 7.1 and dual luciferase reporter assay were used for prediction and verification of interaction between miR-128-3p and MAPK6 3′ untranslated region (UTR). Cell viability was detected by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) assay.

Results

We found that penicillin-induced decrease in cell viability, and increase of TNF-α/IL-1β in primary astrocytes. There were lower miR-128-3p and higher MAPK6 in penicillin-treated primary astrocytes. miR-128-3p overexpression rescued penicillin-induced reduction of cell viability, and upregulation of TNF-α/IL-1β, which was partially abolished by MAPK6 overexpression.

Conclusion

Altogether, miR-128-3p attenuates penicillin-induced cell injury and inflammation in astrocytes by targeting MAPK6, thus providing a protective role in epilepsy.
Alternative mammalian strategies leading towards gastrulation: losing polar trophoblast (Rauber's layer) or gaining an epiblast cavity
Authors: Pfeffer Peter L.
Published: October 2022

Using embryological data from 14 mammalian orders, the hypothesis is presented that in placental mammals, epiblast cavitation and polar trophoblast loss are alternative developmental solutions to shield the central epiblast from extraembryonic signalling. It is argued that such reciprocal signalling between the edge of the epiblast and the adjoining polar trophoblast or edge of the mural trophoblast or with the amniotic ectoderm is necessary for the induction of gastrulation.

This article is part of the theme issue ‘Extraembryonic tissues: exploring concepts, definitions and functions across the animal kingdom’.
Validation of the names Cyanobacterium and Cyanobacterium stanieri, and proposal of Cyanobacteriota phyl. nov.
Authors: Oren Aharon , Mareš Jan , Rippka† Rosmarie
Published: October 2022

The decision by the International Committee on Systematics of Prokaryotes (ICSP) to place the rank of phylum under the rules of the International Code of Nomenclature of Prokaryotes (ICNP), with phylum names ending in –ota based on the name of a type genus, enables the valid publication of the phylum name Cyanobacteriota with

Cyanobacterium

as the type genus. The names

Cyanobacterium

and its type species Cyanobacterium stanieri were effectively published in 1983 by Rippka and Cohen-Bazire, but the names were not validly published under the rules of the ICNP (then named the International Code of Nomenclature of Bacteria) or the rules of the ICN (International Code of Nomenclature for algae, fungi, and plants, then named the International Code of Botanical Nomenclature). We here propose the names

Cyanobacterium

gen. nov and Cyanobacterium stanieri sp. nov. for valid publication under the provisions of the ICN. Upon validation these names are also validly published under the ICNP according to General Consideration 5 and Rule 30. We also propose the phylum name Cyanobacteriota phyl. nov. under the rules of the ICNP.
Development of an affinity-enhanced clinical candidate TCR targeting NY-ESO-1 with optimal potency and high specificity
Authors: Ou Yusheng , Liu Min , Zhan Kai , Wu Wanli , Huang Jiao , Sun Hanli , Zheng Hongjun , Yu Xiaohong , Gong Haiping , Han Zhaosheng , Chen Aiyuan , Liao Youping , Lin Yanmei , Liu Ge , Liu Qiuping , Ma Ruijuan , Mei Yingyi , Tang Xianqing , Weng Zhiming , Wu Jieyi , Ye Yun , Zhang Tingting , Chen Jiehong , Chen Lin , Ding Qingfeng , Fan Hui , Hu Jiajia , Huang Jinhua , Huang Lihong , Li Qiaowei , Li Siyun , Liu Min , Shi Jia , Tan Xiangpeng , Wang Xiaoling , Xiang Ruirui , Yan Qingjia , Zhang Jianbin , Zheng Wenjing , Zhong Shi
Published: October 2022

The clinical success of T-cell receptor (TCR)-based immunotherapy depends on the efficacy and specificity of TCRs. Naturally occurring TCRs have limited anti-tumor potency due to their low affinity for tumor antigens. Affinity enhancement is a promising strategy to generate highly potent TCRs. However, it is concerned that affinity-enhanced TCRs are prone to lose specificity. We isolated low affinity TCRs specific for NY-ESO-1157-165/HLA-A*02:01 from peripheral blood mononuclear cells of healthy donors. An affinity-enhanced TCR candidate with optimal affinity and specificity was generated using phage display and an extensive set ofin vitroandin vivoassays. Alanine scanning mutagenesis showed that the TCR candidate retained specificity by making extensive contacts to the side chains of NY-ESO-1157-165peptide. Adoptive transfer of T cells engineered with this candidate (termed TAEST16001) significantly inhibited tumor growth in subcutaneous, metastatic, and patient-derived xenograft (PDX) mouse tumor models. This study demonstrates that sophisticated engineering and screening techniques can be utilized to generate a clinical candidate TCR with potent anti-tumor activity without losing specificity. TAEST16001 was approved by the Center for Drug Evaluation (CDE) as the first TCR-based immunotherapy clinical trial in China (ClinicalTrials.govIdentifier:NCT03159585).
Prioritizing prognostic-associated subpopulations and individualized recurrence risk signatures from single-cell transcriptomes of colorectal cancer
Authors: Tong Mengsha , Lin Yuxiang , Yang Wenxian , Song Jinsheng , Zhang Zheyang , Xie Jiajing , Tian Jingyi , Luo Shijie , Liang Chenyu , Huang Jialiang , Yu Rongshan
Published: October 2022

Colorectal cancer (CRC) is one of the most common gastrointestinal malignancies. There are few recurrence risk signatures for CRC patients. Single-cell RNA-sequencing (scRNA-seq) provides a high resolution platform for prognostic signature detection. However, scRNA-seq is not practical in large cohorts due to its high cost and most single-cell experiments lack clinical phenotype information. Few studies have been reported to use external bulk transcriptome with survival time to guide the detection of key cell subtypes in scRNA-seq data. We proposed a data analysis framework to prioritize prognostic-associated subpopulations based on relative expression orderings (REOs). Cell type specific gene pairs (C-GPs) were identified to evaluate prognostic value for each cell type. We found REOs-based signatures could accurately classify most cell subtypes. C-GPs achieves higher precision compared with four current methods. Moreover, we developed single-cell gene pair signatures to predict recurrence risk for patients individually. Fibro_SGK1 cells and IgA+ IGLC2+ B cells were novel prognostic-associated subpopulations. A user-friendly toolkit, scRankXMBD(https://github.com/xmuyulab/scRank-XMBD), was developed to enable implementation of this framework. Our work facilitate the application of the rank-based method in scRNA-seq data for prognostic biomarker discovery and precision oncology.
Adiponectin/leptin ratio - a marker of insulin sensitivity in pre-eclampsia and fetal growth
Authors: de Knegt Victoria Elizabeth , Hedley Paula L. , Eltvedt Anna K. , Placing Sophie , Wøjdemann Karen , Shalmi Anne-Cathrine , Rode Line , Kanters Jørgen , Sundberg Karin , Tabor Ann , Lausten-Thomsen Ulrik , Christiansen Michael
Published: October 2022

The serum adiponectin-leptin ratio (A/L ratio) is a surrogate marker of insulin sensitivity. Pre-eclampsia (PE) is associated with maternal metabolic syndrome and occasionally impaired fetal growth. We assessed whether the A/L ratio in first-trimester maternal serum was associated with PE and/or birth weight. Adiponectin and leptin were quantitated in first-trimester blood samples (gestational week 10+3-13+6) from 126 women who later developed PE with proteinuria, (98 mild PE; 21 severe PE; 7 HELLP syndrome), and 297 controls, recruited from the Copenhagen First-Trimester Screening Study. The A/L ratio was reduced in PE pregnancies, median 0.17 (IQR: 0.12-0.27) compared to controls, median 0.32 (IQR: 0.19-0.62), (p<0.001). A multiple logistic regression showed that PE was negatively associated with A/L ratio independent of maternal BMI (odds ratio = 0.08, 95% CI = 0.0322 to 0.214). Adiponectin (AUC = 0.632) and PAPP-A (AUC = 0.605) were negatively, and leptin (AUC = 0.712) was positively associated with PE. However, the A/L ratio was a better predictor of PE (AUC = 0.737). No significant association was found between A/L ratio and clinical severity of pre-eclampsia or preterm birth. PE was associated with significantly lower relative birth weight, (p<0.001). A significant negative correlation was found between relative birth weight and A/L ratio in controls but not in PE pregnancies, (β= −0.144, 95% CI = −9.944 to −0.093), independent of maternal BMI. After correction for maternal BMI, leptin was significantly associated with relative birth weight, (β= 0.197, 95 % CI = 2.361 to 14.353), while adiponectin was not significantly associated. Our findings suggest that an impairment of the A/L ratio (as seen in metabolic syndrome) in first-trimester is characteristic of PE, while aberrant fetal growth in PE is not dependent on insulin sensitivity but rather on leptin associated pathways.
Elucidating a locus coeruleus-hippocampal dopamine pathway for operant reinforcement
Authors: Petter Elijah A. , Fallon Isabella P. , Hughes Ryan N. , Watson Glenn D. R. , Meck Warren H. , Ulloa Severino Francesco Paolo , Yin Henry H.
Published: October 2022

Animals can learn to repeat behaviors to earn desired rewards, a process commonly known as reinforcement learning. While previous work has implicated the ascending dopaminergic projections to the basal ganglia in reinforcement learning, little is known about the role of the hippocampus. Here we report that a specific population of hippocampal neurons and their dopaminergic innervation contribute to operant self-stimulation. These neurons are located in the dentate gyrus, receive dopaminergic projections from the locus coeruleus, and express D1 dopamine receptors. Activation of D1+ dentate neurons is sufficient for self-stimulation: mice will press a lever to earn optogenetic activation of these neurons. A similar effect is also observed with selective activation of the locus coeruleus projections to the dentate gyrus, and blocked by D1 receptor antagonism. Calcium imaging of D1+ dentate neurons revealed significant activity at the time of action selection, but not during passive reward delivery. These results reveal the role of dopaminergic innervation of the hippocampus in supporting operant reinforcement.
Physiological Condition Dependent Changes in Ciliary GPCR Localization in the Brain
Authors: Brewer Kathryn M. , Engle Staci E. , Bansal Ruchi , Brewer Katlyn K. , Jasso Kalene R. , McIntyre Jeremy C. , Vaisse Christian , Reiter Jeremy F. , Berbari Nicolas F.
Published: October 2022

Primary cilia are small immotile cellular appendages which mediate diverse types of singling and are found on most mammalian cell types including throughout the central nervous system. Cilia are known to localize certain G protein-coupled receptors (GPCRs) and are critical for mediating the signaling of these receptors. Several of these neuronal GPCRs have recognized roles in feeding behavior and energy homeostasis. Heterologous cell line and model systems likeC. elegansandChlamydomonashave implicated both dynamic GPCR cilia localization and cilia length and shape changes as key for signaling. However, it is unclear if mammalian ciliary GPCRs utilize similar mechanismsin vivoand under what physiological conditions these processes may occur. Here, we use the ciliary GPCRs, melanin concentrating hormone receptor 1 (MCHR1) and neuropeptide-Y receptor 2 (NPY2R) as model ciliary receptors to determine if dynamic localization to cilia occurs. We tested physiological conditions in which these GPCRs have been implicated such as feeding behavior, obesity, and circadian rhythm. Cilia were imaged using confocal microscopy and analyzed with a computer assisted approach allowing for unbiased and high throughput analysis of cilia. We analyzed GPCR positive cilia, cilia frequency as well as cilia length and receptor occupancy. Interestingly we observed changes in ciliary length, receptor occupancy, and cilia frequency under different conditions, but no consistent theme across GPCRs or brain nuclei was observed. A better understanding of the subcellular localization dynamics of ciliary GPCRs could reveal unrecognized molecular mechanisms regulating behaviors like feeding.

Significance Statement

Often, primary cilia localize specific G protein-coupled receptors (GPCRs) for subcellular signaling. Cell lines and model systems have indicated that cilia deploy dynamic GPCR localization and change their shape or length to modulate signaling. We used mice to assess neuronal cilia GPCRs under physiological conditions associated with both the receptors’ known functions and ciliopathy clinical features like obesity. We show that certain cilia with specific GPCRs appear to dynamically alter their length while others appear relatively stable under these conditions. These results implicate multiple themes across cilia GPCR mediated signaling and indicate that not all cilia modulate GPCR signaling using the same mechanisms. These data will be important for potential pharmacological approaches to target cilia GPCR-mediated signaling.
Spatial heterogeneity of T cell repertoire across NSCLC tumors, tumor edges, adjacent and distant lung tissues
Authors: Hu Qikang , Gao Yang , Frank Meredith , Ji Liyan , Peng Muyun , Chen Chen , Wang Bin , Hu Yan , Wu Zeyu , Li Jina , Shu Lu , He Qiongzhi , Zhang Yingqian , Xia Xuefeng , Zhang Jianjun , Yi Xin , Reuben Alexandre , Yu Fenglei
Published: October 2022

Background

A better understanding of the T cells in lung cancer and their distribution across tumor-adjacent lungs and the peripheral blood is needed to improve efficacy and minimize toxicity from immunotherapy to lung cancer patients.

Methods

Here, we performed CDR3β TCR sequencing of 143 samples from 21 patients with early-stage NSCLC including peripheral blood mononuclear cells, tumor, tumor edges (<1cm from tumor), as well as adjacent lungs 1cm, 2cm, 5cm, and 10cm away from the tumor to gain insight into the spatial heterogeneity of T cells across the lungs in patients with NSCLC. PD-L1, CD4 and CD8 expression was assessed by immunohistochemical staining and genomic features were derived by targeted sequencing of 1,021 cancer related genes.

Results

Our study reveals a decreasing gradient in TIL homology with the tumor-edge, adjacent lungs, and peripheral blood but no discernible distance-associated patterns of T cell trafficking within the adjacent lung itself. Furthermore, we show a decrease in pathogen-specific TCRs in regions with high T cell clonality and PD-L1 expression.

Conclusions

The exclusion in T cells at play across the lungs of patients with NSCLC may be potentially the mechanism for lung cancer occurrence.
Exploring the causal role of the human gut microbiome in colorectal cancer: Application of Mendelian randomization
Authors: Hatcher Charlie , Richenberg George , Waterson Samuel , Nguyen Long H. , Joshi Amit D. , Carreras-Torres Robert , Moreno Victor , Chan Andrew T. , Gunter Marc , Lin Yi , Qu Conghui , Song Mingyang , Casey Graham , Figueiredo Jane C , Gruber Stephen B , Hampe Jochen , Hampel Heather , Jenkins Mark A , Keku Temitope O , Peters Ulrike , Tangen Catherine M , Wu Anna H , Hughes David A , Rühlemann Malte C , Raes Jeroen , Timpson Nicholas J. , Wade Kaitlin H.
Published: October 2022

Aim

The role of the human gut microbiome in colorectal cancer (CRC) is unclear as most studies on the topic are unable to discern correlation from causation. We apply two-sample Mendelian randomization (MR) to estimate the causal relationship between the gut microbiome and CRC.

Materials and methods

We used summary-level data from independent genome-wide association studies to estimate the causal effect of 14 microbial traits (n=3,890 individuals) on overall CRC (55,168 cases, 65,160 controls) and site-specific CRC risk, conducting several sensitivity analyses to understand the nature of results.

Results

Initial MR analysis suggested that a higher abundance ofBifidobacteriumand presence of an unclassified group of bacteria within theBacteroidalesorder in the gut increased overall and site-specific CRC risk. However, sensitivity analyses suggested that instruments used to estimate relationships were likely complex and involved in many potential horizontal pleiotropic pathways, demonstrating that caution is needed when interpreting MR analyses with gut microbiome exposures. In assessing reverse causality, we did not find strong evidence that CRC causally affected these microbial traits.

Conclusions

Whilst our study initially identified potential causal roles for two microbial traits in CRC, importantly, further exploration of these relationships highlighted that these were unlikely to reflect causality.
Assessment of Added Activity of An Antitumor Agent
Authors: Chen Cong , Sun Linda Zhiping , Ren Yixin , Rubin Eric H. , Weinstock David M. , Schmidt Emmett V.
Published: October 2022

An unprecedented number of novel oncology drugs are under preclinical and clinical development, and nearly all are developed in combinations. With an over-reliance on biological hypotheses, there is less effort to establish single agent activity before initiating late clinical development. This may be contributing to a decreased success rate going from phase 1 to approval in the immunotherapy era. Growing evidence in clinical trial data shows that the treatment benefit from most approved combination therapies can be explained by the independent drug action model. Using this working model, we develop a simple index to measure the added antitumor activity of a new drug based on mean response duration, an endpoint that naturally combines both response status and duration information for all patients, which is shown to be highly predictive of clinical benefit of FDA-approved anti-PD-(L)1 immunotherapies. This index sheds light on challenges and opportunities in contemporary oncology drug development and provides a practical tool to assist with decision-making.
Neuronal Morphology Enhances Robustness to Perturbations of Channel Densities
Authors: Zang Yunliang , Marder Eve
Published: October 2022

Biological neurons show significant cell-to-cell variability but have the striking ability to maintain their key firing properties in the face of unpredictable perturbations and stochastic noise. Using a population of multi-compartment models consisting of soma, neurites, and axon for the lateral pyloric (LP) neuron in the crab stomatogastric ganglion, we explored how rebound bursting is preserved when the 14 channel conductances in each model are all randomly varied. The soma-axon coupling is critical for the ability of the axon to spike during bursts and consequently determines the set of successful solutions. When the coupling deviates from a biologically realistic range, the neuronal tolerance of conductance variations is significantly lessened. Thus, the gross morphological features of these neurons enhance their robustness to perturbations of channel densities and expands the space of individual variability that can maintain a desired output pattern.
Ethnicity-Specific Effects on Cardiac Arrest During the COVID-19 Pandemic: A Two-Year Prospective Evaluation in a North American Community
Authors: Chugh Harpriya S , Sargsyan Arayik , Nakamura Kotoka , Uy-Evanado Audrey , Dizon Bernadine , Norby Faye L , Young Christopher , Hadduck Katy , Jui Jonathan , Shepherd Daniel , Salvucci Angelo , Chugh Sumeet S , Reinier Kyndaron
Published: October 2022

Background

Out-of-hospital sudden cardiac arrest (SCA) is a major public health problem with mortality >90%, and incidence has increased during the COVID-19 pandemic. Information regarding ethnicity-specific effects on SCA incidence and survival is lacking.

Methods

In a prospective, population-based study of Ventura County, CA residents (2020 Pop. 843,843; 44.1% Hispanic), we compared SCA incidence and outcomes during the first two years of the COVID-19 pandemic to the prior four years, overall and by ethnicity (Hispanic vs non-Hispanic).

Findings

Of 2,222 OHCA cases identified, 907 occurred during the pandemic (March 2020 - Feb 2022) and 1315 occurred pre-pandemic (March 2016 - Feb 2020). Overall age-standardized annual SCA incidence increased from 38.9/100,000 [95% CI 36.8-41.0] pre-pandemic to 53.8/100,00 [95% CI 50.3 - 57.3, p<0.001] during the pandemic. Among Hispanics, incidence increased by 77%, from 38.2/100,00 [95% CI 33.8-42.5] to 67.7/100,00 [95% CI 59.5- 75.8, p<0.001]. Among non-Hispanics, incidence increased by 26% from 39.4/100,000 [95% CI 36.9-41.9, p<0.001] to 49.8/100,00 [95% CI 45.8-53.8]. SCA incidence rates closely tracked COVID-19 infection rates. During the pandemic, SCA survival was significantly reduced (15.3% to 10.0%, p<0.001) and Hispanics were less likely than non-Hispanics to have bystander CPR (44.6% vs. 54.7%, p=0.005) and shockable rhythm (15.3% vs. 24.1%, p=0.003).

Interpretation

Hispanic residents experienced higher SCA rates during the pandemic with less favorable resuscitation profiles. These findings implicate potential ethnicity-specific barriers to acute care and represent an urgent call to action at the community and health-system levels.

Funding

National Heart Lung and Blood Institute Grants R01HL145675 and R01HL147358.