bluuebunny/crossref_metadata_2025 huggingface dataset:
Lactate as a mediator of prehospital plasma mortality reduction in hemorrhagic shock
Authors: Canton Stephen P. , Lutfi Waseem , Daley Brian J. , Miller Richard S. , Harbrecht Brian G. , Claridge Jeffrey A. , Phelan Herb A. , Guyette Francis X. , Sperry Jason L. , Brown Joshua B.
Published: April 2021

BACKGROUND

Prehospital plasma transfusion in trauma reduces mortality. However, the underlying mechanism remains unclear. Reduction in shock severity may play a role. Lactate correlates with physiologic shock severity and mortality after injury. Our objective was to determine if prehospital plasma reduces lactate and if this contributes to the mortality benefit of plasma.

METHODS

Patients in the Prehospital Air Medical Plasma trial in the upper quartile of injury severity (Injury Severity Score, >30) were included to capture severe shock. Trial patients were randomized to prehospital plasma or standard care resuscitation (crystalloid ± packed red blood cells). Regression determined the associations between admission lactate, 30-day mortality, and plasma while adjusting for demographics, prehospital crystalloid, time, mechanism, and injury characteristics. Causal mediation analysis determined what proportion of the effect of plasma on mortality is mediated by lactate reduction.

RESULTS

A total of 125 patients were included. The plasma group had a lower adjusted admission lactate than standard of care group (coefficient, −1.64; 95% confidence interval [CI], −2.96 to −0.31; p = 0.02). Plasma was associated with lower odds of 30-day mortality (odds ratio [OR], 0.27; 95% CI, 0.08–0.90; p = 0.03). When adding lactate to this model, the effect of plasma on 30-day mortality was no longer significant (OR, 0.36; 95% CI, 0.07–1.88; p = 0.23), while lactate was associated with mortality (OR, 1.74 per 1 mmol/L increase; 95% CI, 1.10–2.73; p = 0.01). Causal mediation demonstrated 35.1% of the total effect of plasma on 30-day mortality was mediated by the reduction in lactate among plasma patients.

CONCLUSION

Prehospital plasma is associated with reduced 30-day mortality and lactate in severely injured patients. More than one third of the effect of plasma on mortality is mediated by a reduction in lactate. Thus, reducing the severity of hemorrhagic shock appears to be one mechanism of prehospital plasma benefit. Further study should elucidate other mechanisms and if a dose response exists.

LEVEL OF EVIDENCE

Therapeutic, level II.
Choosing wisely: A prospective study of direct to operating room trauma resuscitation including real-time trauma surgeon after-action review
Authors: Martin Matthew J. , Johnson Amelia , Rott Michael , Kuchler Andrea , Cole Frederick , Ramzy Ameen , Barbosa Ronald , Long William B.
Published: April 2021

INTRODUCTION

Although several centers have direct to operating room (DOR) resuscitation programs, there are no published prospective studies on optimal patient selection, interventions, outcomes, or real-time surgeon assessments.

METHODS

Direct to operating room cases for 1 year were prospectively enrolled. Demographics, injury types/severity, triage criteria, interventions, and outcomes including Glasgow Outcome Scale score were collected. Detailed time-to-event and sequence data on initial lifesaving interventions (LSIs) or emergent surgeries were analyzed. A structured real-time attending surgeon assessment tool for each case was collected. Direct to operating room activation criteria were grouped into categories: mechanism, physiology, injury pattern, or emergency medical services (EMS) suspicion.

RESULTS

There were 104 DOR cases: male, 84%; penetrating, 80%; and severely injured (Injury Severity Score, >15), 39%. The majority (65%) required at least one LSI (median of 7 minutes from arrival), and 41% underwent immediate emergent surgery (median, 26 minutes). Blunt patients were more severely injured and more likely to undergo LSI (86% vs. 59%) but less likely to require emergent surgery (19% vs. 47%, all p < 0.05). Analysis of DOR criteria categories showed unique patterns in each group for interventions and outcomes, with EMS suspicion associated with the lowest need for DOR. Surgeon assessment tool results found that DOR was indicated in 84% and improved care in 63%, with a small subset identified (9%) where DOR had a negative impact.

CONCLUSION

Direct to operating room resuscitation facilitated timely emergent interventions in penetrating truncal trauma and a select subset of critically ill blunt patients. Unique intervention/outcome profiles were identified by activation criteria groups, with little utility among activations for EMS suspicion. Real-time surgeon assessment tool identified high- and low-yield DOR groups.

LEVEL OF EVIDENCE

Prospective observational study, level III.
Effects of nonselective internal iliac artery angioembolization on pelvic venous flow in the swine model
Authors: Sherman Nathan C. , Williams Keneeshia N. , Hennemeyer Charles T. , Devis Paola , Chehab Mohamad , Joseph Bellal , Tang Andrew L.
Published: April 2021

BACKGROUND

Pelvic angioembolization (AE) is a mainstay in the treatment algorithm for pelvic hemorrhage from pelvic fractures. Nonselective AE refers to embolization of the bilateral internal iliac arteries (IIAs) proximally rather than embolization of their tributaries distally. The aim of this study was to quantify the effect of nonselective pelvic AE on pelvic venous flow in a swine model. We hypothesized that internal iliac vein (IIV) flow following IIA AE is reduced by half.

METHODS

Nine Yorkshire swine underwent nonselective right IIA gelfoam AE, followed by left. Pelvic arterial and venous diameter, velocity, and flow were recorded at baseline, after right IIA AE and after left IIA AE. Linear mixed-effect model and signed rank test were used to evaluate significant changes between the three time points.

RESULTS

Eight swine (77.8 ± 7.1 kg) underwent successful nonselective IIA AE based on achieving arterial resistive index of 1.0. One case was aborted because of technical difficulties. Compared with baseline, right IIV flow rate dropped by 36% ± 29% (p < 0.05) and 54% ± 29% (p < 0.01) following right and left IIA AE, respectively. Right IIA AE had no initial effect on left IIV flow (0.37% ± 99%, p = 0.95). However, after left IIA AE, left IIV flow reduced by 54% ± 27% (p < 0.01). Internal iliac artery AE had no effect on the external iliac arterial or venous flow rates and no effect on inferior vena cava flow rate.

CONCLUSION

The effect of unilateral and bilateral IIA AE on IIV flow appears to be additive. Despite bilateral IIA AE, pelvic venous flow is diminished but not absent. There is abundant collateral circulation between the external and internal iliac vascular systems. Arterial embolization may reduce venous flow and improve on resuscitation efforts in those with unstable pelvic fractures.

LEVEL OF EVIDENCE

Prognostic, level IV.
Developing a tool to assess competence in resuscitative endovascular balloon occlusion of the aorta: An international Delphi consensus study
Authors: Engberg Morten , Hörer Tal , Rasmussen Todd E. , Taudorf Mikkel , Nayahangan Leizl Joy , Rasmussen Niklas K. , Russell Lene , Konge Lars , Lönn Lars
Published: April 2021

BACKGROUND

Resuscitative endovascular balloon occlusion of the aorta (REBOA) is an emergency procedure that is potentially lifesaving in major noncompressible torso hemorrhage. It may also improve outcome in nontraumatic cardiac arrest. However, the procedure can be technically challenging and requires the immediate presence of a qualified operator. Thus, evidence-based training and assessment of operator skills are essential for successful implementation and patient safety. A prerequisite for this is a valid and reliable assessment tool specific for the procedure. The aim of this study was to develop a tool for assessing procedural competence in REBOA based on best-available knowledge from international experts in the field.

METHODS

We invited international REBOA experts from multiple specialties to participate in an anonymous three-round iterative Delphi study to reach consensus on the design and content of an assessment tool. In round 1, participants suggested items to be included. In rounds 2 and 3, the relevance of each suggested item was evaluated by all participants to reach consensus. Interround data processing was done systematically by a steering group.

RESULTS

Forty panelists representing both clinical and educational expertise in REBOA from 16 countries (in Europe, Asia, and North and South America) and seven different specialties participated in the study. After 3 Delphi rounds and 532 initial item suggestions, the panelists reached consensus on a 10-item assessment tool with behaviorally anchored rating scales. It includes assessment of teamwork, procedure time, selection and preparation of equipment, puncture technique, guidewire handling, sheath handling, placement of REBOA catheter, occlusion, and evaluation.

CONCLUSION

We present the REBOA-RATE assessment tool developed systematically by international experts in the field to optimize content validity. Following further studies of its validity and reliability, this tool represents an important next step in evidence-based training programs in REBOA, for example, using mastery learning.

LEVEL OF EVIDENCE

Therapeutic, level V.
High resuscitative endovascular balloon occlusion of the aorta procedural volume is associated with improved outcomes: An analysis of the AORTA registry
Authors: Gorman Elizabeth , Nowak Brittany , Klein Michael , Inaba Kenji , Morrison Jonathan , Scalea Thomas , Seamon Mark , Fox Charles , Moore Laura , Kauvar David , Spalding Marshall , Dubose Joseph , DiMaggio Charles , Livingston David H. , Bukur Marko ,   the AAST AORTA Study Group
Published: April 2021

BACKGROUND

The use of resuscitative endovascular balloon occlusion of the aorta (REBOA) is controversial. We hypothesize that REBOA outcomes are improved in centers with high REBOA utilization.

METHODS

We examined the Aortic Occlusion in Resuscitation for Trauma and Acute Care Surgery registry over a 5-year period (2014–2018). Resuscitative endovascular balloon occlusion of the aorta outcomes were analyzed by stratifying institutions into low-volume (<10), average-volume (11–30), and high-volume (>30) deployment centers. A multivariable model adjusting for volume group, mechanism of injury, signs of life, systolic blood pressure at initiation, operator level, device type, zone of placement, and hemodynamic response to aortic occlusion was created to analyze REBOA mortality and REBOA-related complications.

RESULTS

Four hundred ninety-five REBOA placements were included. High-volume centers accounted for 63%, while low accounted for 13%. High-volume institutions were more likely to place a REBOA in the emergency department (81% vs. 63% low volume, p = 0.003), had a lower mean systolic blood pressure at insertion (53 ± 38 vs. 64 ± 40, p = 0.001), and more Zone I deployments (64% vs. 55%, p = 0.002). Median time from admission to REBOA placement was significantly less in patients treated at high-volume centers (15 [7–30] minutes vs. 35 [20–65] minutes, p = 0.001). Resuscitative endovascular balloon occlusion of the aorta mortality was significantly higher at low-volume centers (67% vs. 57%; adjusted odds ratio, 1.29; adj p = 0.040), while average- and high-volume centers were similar. Resuscitative endovascular balloon occlusion of the aorta complications were less frequent at high-/average-volume centers, but did not reach statistical significance (adj p = 0.784).

CONCLUSION

Resuscitative endovascular balloon occlusion of the aorta survival is increased at high versus low utilization centers. Increased experience with REBOA may be associated with earlier deployment and subsequently improved patient outcomes.

LEVEL OF EVIDENCE

Therapeutic/Care Management, level IV.
The effect of prolonged antibiotics on postoperative complications for common bile duct stones: A post hoc analysis of an EAST multicenter study
Authors: Tracy Brett M. , Paterson Cameron W. , Torres Denise M. , Young Katelyn , Saxe Jonathan M. , Kinstedt Daniel P. , Zielinski Martin D. , Camazine Maraya , Yeh D Dante , Gelbard Rondi B. ,   on behalf of the EAST Retained Common Bile Duct Stones Study Group*
Published: April 2021

BACKGROUND

Antimicrobial guidance for common bile duct (CBD) stones is limited. We sought to examine the effect of antibiotic duration on infectious complications in patients with choledocholithiasis and/or gallstone pancreatitis.

METHODS

We performed a post hoc analysis of a prospective, observational, multicenter study of patients undergoing same admission cholecystectomy for choledocholithiasis and gallstone pancreatitis between 2016 and 2019. We excluded patients with cholangitis and/or cholecystitis. Patients were divided into groups based on duration of antibiotics: prophylactic (<24 hours) or prolonged (≥24 hours). We analyzed these two groups in the preoperative and postoperative periods. Outcomes included infectious complications, acute kidney injury (AKI), and hospital length of stay (LOS).

RESULTS

There were 755 patients in the cohort. Increasing age, CBD diameter, and a preoperative endoscopic retrograde cholangiopancreatography (odds ratio, 1.91; 95% confidence interval, 1.34–2.73; p < 0.001) significantly predicted prolonged preoperative antibiotic use. Increasing age, operative duration, and a postoperative endoscopic retrograde cholangiopancreatography (odds ratio, 4.8; 95% confidence interval, 1.85–13.65; p < 0.001) significantly predicted prolonged postoperative antibiotic use. Rates of infectious complications were similar between groups, but LOS was 2 days longer for patients receiving overall prolonged antibiotics (p < 0.0001). Patients with AKI received two more days of overall antibiotic therapy (p = 0.02) compared with those without AKI.

CONCLUSION

Rates of postoperative infectious complications were similar among patients treated with a prolonged or prophylactic course of antibiotics. Prolonged antibiotic use was associated with a longer LOS and AKI.

LEVEL OF EVIDENCE

Therapeutic, Level IV.
D-Day to December 1944: The odyssey of the third auxiliary surgical group in World War II
Authors: Burney Richard E.
Published: April 2021

As a Major in the US Army Medical Corps, Darrell A. Campbell, MD, led Team 13 of the Third Auxiliary Surgical Group in Europe in World War II. The team began work on June 7, 1944, in a clearing station tent near the beach at Normandy. Subsequently, over the next 7 months, it was assigned to mobile hospitals in 15 different locations in France, Belgium, Luxembourg, and Germany. Major Campbell kept the log books used to record all of the operations done by his team during this time and brought them home where three were discovered more than 70 years later. These log books contain descriptions of more than 500 consecutive operations done by Team 13. They provide a unique insight into the activities of the surgeons who worked to save lives on the front lines of battle in the European Theater of Operations between June and December 1944 and form the basis for this historical perspective.

This is an article on the history of surgery.
Hospital-based intervention is rarely needed for children with low-grade blunt abdominal solid organ injury: An analysis of the Trauma Quality Improvement Program registry
Authors: Evans Lauren L. , Williams Regan F. , Jin Chengshi , Plumblee Leah , Naik-Mathuria Bindi , Streck Christian J. , Jensen Aaron R.
Published: April 2021

BACKGROUND

Children with low-grade blunt solid organ injury (SOI) have historically been admitted to an inpatient setting for monitoring, but the evidence supporting the necessity of this practice is lacking. The purpose of this study was to quantify the frequency and timing of intervention for hemorrhage and to describe hospital-based resource utilization for low-grade SOI in the absence of other major injuries (OMIs).

METHODS

A cohort of children (aged <16 years) with blunt American Association for the Surgery of Trauma grade 1 or 2 SOI from the American College of Surgeons Trauma Quality Improvement Program registry (2007–2017) was analyzed. Children were excluded if they had confounding factors associated with intervention for hemorrhage (comorbidities, OMIs, or extra-abdominal surgical procedures). Outcomes included frequency and timing of intervention (laparotomy, angiography, or transfusion) for hemorrhage, as well as hospital-based resource utilization.

RESULTS

A total of 1,019 children were identified with low-grade blunt SOI and no OMIs. Nine hundred eighty-six (96.8%) of these children were admitted to an inpatient unit. Admitted children with low-grade SOI had a median length-of-stay of 2 days and a 23.9% intensive care unit admission rate. Only 1.7% (n = 17) of patients with low-grade SOI underwent an intervention, with the median time to intervention being the first hospital day. No child who underwent angiography was transfused or had an abnormal initial ED shock index.

CONCLUSION

Children with low-grade SOI are routinely admitted to the hospital and often to the intensive care unit but rarely undergo hospital-based intervention. The most common intervention was angiography, with questionable indications in this cohort. These data question the need for inpatient admission for low-grade SOI and suggest that discharge from the emergency room may be safe. Prospective investigation into granular risk factors to identify the rare patient needing hospital-based intervention is needed, as is validation of the safety of ambulatory management.

LEVEL OF EVIDENCE

Prognostic and epidemiological, level III.
Stress-related changes in the gut microbiome after trauma
Authors: Kelly Lauren S. , Apple Camille G. , Gharaibeh Raad , Pons Erick E. , Thompson Chase W. , Kannan Kolenkode B. , Darden Dijoia B. , Efron Philip A. , Thomas Ryan M. , Mohr Alicia M.
Published: April 2021

Background

The gut microbiome protects the host from infection by promoting epithelial integrity and providing basal immunologic stimulation. Disruption of this delicate ecosystem is linked to morbidity and mortality among critically ill patients, but the impact of traumatic injury on the gut microbiome is poorly understood. This study sought to identify alterations in gut microbiota following trauma and persistent stress in rodents without confounding antibiotics.

Methods

Male Sprague-Dawley rats aged 9 weeks to 11 weeks were randomized to naive, lung contusion with hemorrhagic shock (LCHS), and LCHS plus either 7 (LCHS/CS 7/7) or 14 days (LCHS/CS 14) of restraint cylinder stress for 2 hours daily. Stool was collected on Days 0, 3, 7, and 14 for bacterial whole genome DNA isolation. Alpha diversity, or the number and relative abundance of unique bacterial species within each cohort, was assessed using Chao1 indices. Beta diversity, or the measure of differences in biodiversity across cohorts, was assessed by principle coordinate analysis. False discovery rate correction was applied to all statistical analyses and corrected for cohousing effects.

Results

Rodent groups subject to restraint stress demonstrated a progressive increase in alpha diversity over time. These microbiota changes resolved after cessation of stress (LCHS/CS 7/7) but continued to increase among rats subjected to ongoing stress (LCHS/CS 14). The LCHS/CS 7/7 also demonstrated reductions in class Actinobacteria and increased abundance of the genus Bacteroides by Day 7, which resolved by Day 14. Increased abundance of Bacteroides was also noted in the LCHS/CS 14 cohort, suggesting the role of chronic stress in its destabilization.

Conclusion

This study points to persistent stress as a potential source of the destabilization of microbial diversity seen after trauma. This lack of microbiota stability could be associated with worse long-term outcomes in critically ill trauma patients. Further studies are warranted to elucidate mechanistic pathways and potential therapeutic modalities.
A comparison of efficacy, efficiency, and durability in novel tourniquet designs
Authors: Treager Christopher , Lopachin Tyler , Mandichak Sally , Kinney Bradley , Bohan Megan , Boboc Michael , Go Christian , Friedrich Emily , Stuart Sean
Published: April 2021

BACKGROUND

Exsanguination due to extremity hemorrhage is a major cause of preventable traumatic deaths. Extremity tourniquet use has been shown to be safe and improve survival. The purpose of this study was to compare the efficacy, efficiency, and durability of the Generation 7 Combat Application Tourniquet (CAT; North American Rescue, Greer, SC), the Tactical Mechanical Tourniquet (TMT; Combat Medical Systems, Harrisburg, NC), and the SOF Tactical Tourniquet—Wide (SOFTT-W; Tactical Medical Solutions, Anderson, SC).

METHODS

This study was a three-phase randomized, cross-over trial. In successive trials, subjects were timed during the application of each tourniquet to the upper and lower extremity. Following successful lower extremity application, subjects low crawled 25 ft and then were dragged 25 ft, after which effectiveness was reassessed, as defined by the cessation of distal pulses by Doppler ultrasound.

RESULTS

In arm application, both the CAT and TMT had significantly less failure rates than the SOFTT-W (5.56%, 19.44%, 58.33%), with the CAT being the fastest tourniquet when compared with TMT and SOFTT-W (37.8 seconds, 65.01 seconds, 63.07 seconds). In leg application, the CAT had significantly less rates of failure when compared with the SOFTT-W, but there was no other significant difference between the tourniquets (27.78%, 44.44%, 61.11%). In addition, the CAT was significantly faster than both the TMT and SOFTT-W when applied to the leg (8.33 seconds, 40.96 seconds, 34.5 seconds). There was no significant difference in tourniquet failure rates between the three tourniquets after subject maneuvers in phase 3 (34.29%, 42.86%, 45.45%).

DISCUSSION

The CAT is as effective as the TMT and significantly more effective than the SOFTT-W. In addition, the CAT demonstrated shorter application times than either the TMT or SOFTT-W. However, there was no significant difference between the three tourniquets in their ability to maintain pulselessness after subject maneuvers.

LEVEL OF EVIDENCE

Care management, level II.
T-cell Immunometabolism: Therapeutic Implications in Organ Transplantation
Authors: Tran Danh T. , Sundararaj Kamala , Atkinson Carl , Nadig Satish N.
Published: April 2021

Although solid-organ transplantation has evolved steadily with many breakthroughs in the past 110 y, many problems remain to be addressed, and advanced therapeutic strategies need to be considered. T-cell immunometabolism is a rapidly advancing field that has gathered much attention recently, providing ample mechanistic insight from which many novel therapeutic approaches have been developed. Applications from the field include antitumor and antimicrobial therapies, as well as for reversing graft-versus-host disease and autoimmune diseases. However, the immunometabolism of T cells remains underexplored in solid-organ transplantation. In this review, we will highlight key findings from hallmark studies centered around various metabolic modes preferred by different T-cell subtypes (categorized into naive, effector, regulatory, and memory T cells), including glycolysis, glutaminolysis, oxidative phosphorylation, fatty acid synthesis, and oxidation. This review will discuss the underlying cellular signaling components that affect these processes, including the transcription factors myelocytomatosis oncogene, hypoxia-inducible factor 1-alpha, estrogen-related receptor alpha, and sterol regulatory element-binding proteins, along with the mechanistic target of rapamycin and adenosine monophosphate–activated protein kinase signaling. We will also explore potential therapeutic strategies targeting these pathways, as applied to the potential for tolerance induction in solid-organ transplantation.
Kidney Transplantation in Small Children: Association Between Body Weight and Outcome—A Report From the ESPN/ERA-EDTA Registry
Authors: Boehm Michael , Bonthuis Marjolein , Aufricht Christoph , Battelino Nina , Bjerre Anna , Edvardsson Vidar O. , Herthelius Maria , Hubmann Holger , Jahnukainen Timo , de Jong Huib , Laube Guido F. , Mattozzi Francesca , Molchanova Elena A. , Muñoz Marina , Noyan Aytul , Pape Lars , Printza Nikoleta , Reusz George , Roussey Gwenaelle , Rubik Jacek , Spasojevic'-Dimitrijeva Brankica , Seeman Tomas , Ware Nicholas , Vidal Enrico , Harambat Jérôme , Jager Kitty J. , Groothoff Jaap
Published: April 2021

Background.

Many centers accept a minimum body weight of 10 kg as threshold for kidney transplantation (Tx) in children. As solid evidence for clinical outcomes in multinational studies is lacking, we evaluated practices and outcomes in European children weighing below 10 kg at Tx.

Methods.

Data were obtained from the European Society of Paediatric Nephrology/European Renal Association and European Dialysis and Transplant Association Registry on all children who started kidney replacement therapy at <2.5 y of age and received a Tx between 2000 and 2016. Weight at Tx was categorized (<10 versus ≥10 kg) and Cox regression analysis was used to evaluate its association with graft survival.

Results.

One hundred of the 601 children received a Tx below a weight of 10 kg during the study period. Primary renal disease groups were equal, but Tx <10 kg patients had lower pre-Tx weight gain per year (0.2 versus 2.1 kg; P < 0.001) and had a higher preemptive Tx rate (23% versus 7%; P < 0.001). No differences were found for posttransplant estimated glomerular filtration rates trajectories (P = 0.23). The graft failure risk was higher in Tx <10 kg patients at 1 y (graft survival: 90% versus 95%; hazard ratio, 3.84; 95% confidence interval, 1.24-11.84), but not at 5 y (hazard ratio, 1.71; 95% confidence interval, 0.68-4.30).

Conclusions.

Despite a lower 1-y graft survival rate, graft function, and survival at 5 y were identical in Tx <10 kg patients when compared with Tx ≥10 kg patients. Our results suggest that early transplantation should be offered to a carefully selected group of patients weighing <10 kg.
Quetiapine for Bipolar Depressive Episode in Obsessive-Compulsive Disorder Patients Maintained on Selective Serotonin Reuptake Inhibitor Treatment
Authors: Poyurovsky Michael , Weizman Abraham
Published: April 2021

Objectives

A meaningful proportion of patients with obsessive-compulsive disorder (OCD) develop symptoms of bipolar depression (BP-D). In the present investigation, we aimed to determine whether quetiapine is efficacious in OCD patients who despite continuous treatment with a selective serotonin reuptake inhibitor developed an acute episode of BP-D.

Methods

We analyzed 68 charts of Diagnostic and Statistical Manual of Mental Disorders Fifth Edition OCD patients from our outpatient clinic and identified 15 patients who in addition met Diagnostic and Statistical Manual of Mental Disorders Fifth Edition criteria for bipolar II disorder, depressive episode. Eleven (7 men and 4 women, aged 24–54 years) patients for whom quetiapine was added to treat the index episode of BP-D were included. Treatment response was assessed retrospectively and defined as a score of “much improved” or “very much improved” on the Clinical Global Impression—Improvement scale.

Results

Quetiapine was added for treatment of BP-D in a dose range of 150 to 400 mg (mean, 273 mg). Eight (73%) of the 11 study patients fulfilled the criterion of response, that is a score of “much improve” (4 patients) and “very much improved” (4 patients) on the Clinical Global Impression—Improvement scale. Notably, quetiapine was associated with additional improvement of OCD symptoms in 6 of 8 study responders. Quetiapine was well tolerated. The most frequently detected side effects were drowsiness (5 patients), constipation (4 patients), and orthostatic hypotension (2 patients).

Conclusions

The revealed beneficial effect of quetiapine addition for acute episode of BP-D in OCD patients maintained on selective serotonin reuptake inhibitor treatment merits further controlled investigation.
Electroconvulsive Therapy Applications on Children in the 1940s
Authors: Sirgiovanni Elisabetta
Published: April 2021

The existence of pediatric applications of electroconvulsive therapy (ECT) in the 1940s in Italy has been neglected by international literature. However, 2 case reports by Ferdinando Accornero and Mario Anderson, both assistants of Ugo Cerletti at the Sapienza Clinic for Nervous and Mental Diseases, should be brought to the attention of historians of ECT. The work presented therein began in Rome in September 1940, approximately at the same time of the first reported ECT administration on a child in Bristol, United Kingdom. The 2 reports described applications on 19 children and adolescents during 3 different sessions (1940–1941, 1944–1947, and 1947–1949), with a 3-year-long interruption due to the circumstances of World War II. Unfortunately, this research appeared belatedly in 2 articles from 1948 and 1950, respectively, in an Italian journal with limited distribution, when more extensive research contributions on pediatric ECT had already received international exposure. The Italian reports may cast light on the progress made by the early generation of ECT researchers in the 1940s toward the refinement of ECT techniques and the subsequent identification of diagnostic indicators for ECT among children.
Repeated stimulation of the HPA axis alters white blood cell counts without increasing oxidative stress or inflammatory cytokines in fasting elephant seal pups
Authors: Ensminger David C. , Crocker Daniel E. , Lam Emily K. , Kaitlin N. Allen , Vázquez-Medina José Pablo
Published: April 2021

The hypothalamic-pituitary-adrenal (HPA) axis controls the release of glucocorticoids, which regulate immune and inflammatory function by modulating cytokines, white blood cells (WBCs), and oxidative stress via glucocorticoid receptor (GR) signaling. Although the response to HPA activation is well characterized in many species, little is known about the impacts of HPA activation during extreme physiological conditions in marine mammals. Hence, we challenged 18 simultaneously fasting and developing elephant seal pups with daily intramuscular injections of adrenocorticotropin (ACTH), a GR antagonist (RU486), or a combination (ACTH+RU486) for four days (4d). We collected blood at baseline, two hours (2h), and 4d after the beginning of treatment. ACTH and ACTH+RU486 elevated serum aldosterone and cortisol at 2h, with effects diminishing at 4d. RU486 alone induced a compensatory increase in aldosterone, but not cortisol, at 4d. ACTH decreased neutrophils at 2h while decreasing lymphocytes and increasing neutrophil:lymphocyte ratio at 4d. These effects were abolished by RU486. Despite alterations in WBCs, there was no effect of ACTH or RU486 on transforming growth factor-β or interleukin-6 levels; however, both cytokines decreased with the 4-d fasting progression. Similarly, ACTH did not impact protein oxidation, lipid peroxidation, or antioxidant enzymes, but plasma isoprostanes and catalase activity decreased while glutathione peroxidase increased with fasting progression. These data demonstrate differential acute (2h) and chronic (4d) modulatory effects of HPA activation on WBCs and that the chronic effect is mediated, at least in part, by GR. These results also underscore elephant seals’ resistance to potential oxidative stress derived from repeated HPA activation.

Summary statement

Many species experience oxidative stress and inflammation after repeated activation of the hypothalamic-pituitary-adrenal axis. We show that simultaneously fasting and developing elephant seals are resistant to repeated hypothalamic-pituitary-adrenal axis activation.
Region-specific effects of early-life status epilepticus on the adult hippocampal CA3 – medial entorhinal cortex circuitryin vitro: focus on interictal spikes and concurrent high-frequency oscillations
Authors: Lisgaras Christos Panagiotis , Mikroulis Apostolos , Psarropoulou Caterina
Published: April 2021

Convulsive status epilepticus (SE) in immature life is often associated with lasting neurobiological changes. We provoked SE by pentylenetetrazole in postnatal day 20 rat pups and examined communication modalities between the temporal hippocampus and medial entorhinal cortex (mEC)in vitro. After a minimum of 40 days post-SE, we prepared combined temporal hippocampal - medial entorhinal cortex (mEC) slices from conditioned (SE) and naïve (N) adult rats and recorded 4-aminopyridine-induced spontaneous epileptiform interictal-like discharges (IED) simultaneously from CA3 and mEC layer V-VI. We analyzed IED frequency and high frequency oscillations (HFOs) in intact slices and after surgical separation of hippocampus from mEC, by two successive incisions (Schaffer collateral cut, Parasubiculum cut). In all slices, IED frequency was higher in CA3 vs mEC and Raster plots indicated no temporal coincidence between them either in intact or in CA1-cut slices. IED frequency was significantly higher in SE mEC, but similar in SE and N CA3, independently of connectivity state. Ripples (R) and Fast Ripples (FR) coincided with IEDs and their power differed between SE and N intact slices, both in CA3 and mEC. CA3 FR/R ratios were higher in the absence of mEC. Moreover, SE (vs N) slices showed significantly higher FR/R ratios independently of the presence of mEC. Taken together, these findings suggest lasting effects of immature SE in network dynamics governing hippocampal-entorhinal communication which may impact adult cognitive, behavioral and/or seizure threshold sequalae.

HIGHLIGHTS

Early-life Status Epilepticus (SE) impacts on the adult hippocampal – entorhinal communication in thein vitro4-AP model

Post-SE CA3 output decreases in HFO power with no change in interictal discharge frequency

Post-SE mEC output increases both in HFO power and interictal discharge frequency

Interictal HFO dynamics in CA3-mEC change upon the connectivity state of the two areas and priorhistory of early-life SE
Fungicide resistance characterised across seven modes of action inBotrytis cinereaisolated from Australian vineyards
Authors: Harper Lincoln A. , Paton Scott , Hall Barbara , McKay Suzanne , Oliver Richard P. , Lopez-Ruiz Francisco J.
Published: April 2021

BACKGROUND

Botrytis bunch rot, caused byBotrytis cinerea, is an economically important disease of grapes in Australia and across grape growing regions worldwide. Control of this disease relies on canopy management and the application of fungicides. Fungicide application can lead to the selection of resistantB. cinereapopulations, which has an adverse effect on management of the disease. Characterising the distribution and severity of resistantB. cinereapopulations is needed to inform resistance management strategies.

RESULTS

In this study, 725 isolates were sampled from 75 Australian vineyards during 2013 – 2016 and were screened against seven fungicides with different modes of action (MOAs). The resistance frequencies for azoxystrobin, boscalid, fenhexamid, fludioxonil, iprodione, pyrimethanil and tebuconazole were 5, 2.8, 2.1, 6.2, 11.6, 7.7 and 2.9% respectively. Nearly half of the resistant isolates (43.8%) were resistant to more than one of the fungicides tested. The frequency of vineyards with at least one isolate simultaneously resistant to 1, 2, 3, 4 or 5 fungicides was 19.5, 7.8, 6.5, 10.4 and 2.6%. Resistance was associated with previously published genotypes inCytB(G143A),SdhB(H272R/Y),Erg27(F412S),Mrr1(D354Y),Bos1(I365S, N373S + Q369P, I365S + D757N) andPos5(V273I, P319A, L412F/V). Novel genotypes were also described inMrr1(S611N, D616G)Pos5(V273L) andCyp51(P347S). Expression analysis was used to characterise fludioxonil resistant isolates exhibiting overexpression (6.3-9.6-fold) of the ABC transporter geneAtrB(MDR1 phenotype).

CONCLUSION

Resistance frequencies were lower when compared to most previously published surveys ofB. cinerearesistance in grape and other crops. Nevertheless, continued monitoring of critical MOAs used in Australian vineyards is recommended.
A simple assay for quantification of plant-associative bacterial nitrogen fixation
Authors: Haskett Timothy L , Poole Philip S
Published: April 2021

Accurate quantification of plant-associative bacterial nitrogen (N) fixation is crucial for selection and development of elite diazotrophic inoculants that could be used to supply cereal crops with nitrogen in a sustainable manner. Because a low oxygen environment that may not be conducive to plant growth is essential for optimal stability and function of the N-fixing catalyst nitrogenase, quantification of N fixation is routinely carried out on “free-living” bacteria grown in the absence of a host plant. Such experiments may not divulge the true extent of N fixation occurring in the rhizosphere where the availability and forms of nutrients such as carbon and N, which are key regulators of N fixation, may vary widely. Here, we present a modifiedin plantaacetylene reduction assay, utilising the model cereal barley as a host, to quantify associative N fixation by diazotrophic bacteria. The assay is rapid, highly reproducible, applicable to a broad range of diazotrophs, and can be performed with simple equipment commonly found in most laboratories that investigate plant-microbe interactions.

Importance

Exploiting “nitrogen-fixing” bacteria that reduce atmospheric dinitrogen into ammonia as inoculants of cereal crops has great potential to alleviate current inputs of environmentally deleterious fertiliser nitrogen and drive more sustainable crop production. Accurately quantifying plant-associative bacterial nitrogen fixation is central to the development of such inoculant bacteria, but most assays fail to adequately reproduce the conditions of plant root systems. In this work, we have validated and optimised a simplein plantaassay to accurately quantify N fixation in bacteria occupying the root and surrounding soil of the model cereal barley. This assay represents a benchmark for quantification of plant-associative bacterial N fixation.
RNA-controlled nucleocytoplasmic shuttling of mRNA decay factors regulates mRNA synthesis and initiates a novel mRNA decay pathway
Authors: Chattopadhyay Shiladitya , Garcia-Martinez Jose , Haimovich Gal , Khwaja Aya , Barkai Oren , Ghosh Ambarnil , Chuarzman Silvia Gabriela , Schuldiner Maya , Elran Ron , Rosenberg Miriam , Bohnsack Katherine , Bohnsack Markus , Perez-Ortin Jose E , Choder Mordechai
Published: April 2021

mRNA level is controlled by factors that mediate both mRNA synthesis and decay, including the exonuclease Xrn1 - a major mRNA synthesis and decay factor. Here we show that nucleocytoplasmic shuttling of Xrn1 and of some of its associated mRNA decay factors plays a key role in determining both mRNA synthesis and decay. Shuttling is regulated by RNA-controlled binding of the karyopherin Kap120 to two nuclear localization sequences (NLSs) in Xrn1. The decaying RNA binds and masks NLS1, establishing a link between mRNA decay and Xrn1 shuttling. Mutations in the two NLSs, which prevent Xrn1 import, compromise transcription and, unexpectedly, also the cytoplasmic decay of ∼50% of the cellular mRNAs - comparably to Xrn1 deletion. These findings uncover a cytoplasmic mRNA decay pathway that begins in the nucleus. Interestingly, Xrn1 shuttling is required for proper adaptation to environmental changes, in particular to ever changing environmental fluctuations.
Novel zebrafish mutants reveal new roles for Apolipoprotein B during embryonic development and pathological conditions
Authors: Templehof Hanoch , Moshe Noga , Avraham-Davidi Inbal , Yaniv Karina
Published: April 2021

Apolipoprotein B (ApoB) is the primary protein of chylomicrons, VLDLs and LDLs and is essential for their assembly. Defects in ApoB synthesis and secretion result in several human diseases, including abetalipoproteinemia and familial hypobetalipoproteinemia. Conversely, high levels of APOB in plasma are associated with increased risk for coronary heart disease and atherosclerosis.

The involvement of APOB in lipid metabolism and atherogenesis prompted the generation of several mutant mice. However, as APOB is required for supplying nutrients to the developing embryo,ApoBnull mice are embryonic lethal, thereby precluding the study of the roles of this protein during development.

Here, we established novel zebrafish mutants for twoapoBgenes:apoBaandapoBb.1. Double-mutant embryos display clear hallmarks of human hypolipidemia-related diseases, including intestinal defects and fatty liver, as well as profound vascular defects. We further use these models to identify the domains within ApoB responsible for its functions. By assessing the ability of different truncated forms of human APOB to rescue the mutant phenotypes, we demonstrate the benefits of this model for prospective therapeutic screens. Overall, our novel zebrafish models uncover new functions of ApoB in organ development and morphogenesis and shed new light on the mechanisms underlying hypolipidemia-related diseases.
Single-Cell Multiomics Reveals Distinct Cell States at the Top of the Human Hematopoietic Hierarchy
Authors: Sommarin Mikael N.E. , Dhapola Parashar , Safi Fatemeh , Warfvinge Rebecca , Ulfsson Linda Geironson , Erlandsson Eva , Konturek-Ciesla Anna , Thakur Ram Krishna , Böiers Charlotta , Bryder David , Karlsson Göran
Published: April 2021

The advent of single cell (Sc) genomics has challenged the dogma of haematopoiesis as a tree-like structure of stepwise lineage commitment through distinct and increasingly restricted progenitor populations. Instead, analysis of ScRNA-seq has proposed that the earliest events in human hematopoietic stem cell (HSC) differentiation are characterized by only subtle molecular changes, with hematopoietic stem and progenitor cells (HSPCs) existing as a continuum of low-primed cell-states that gradually transition into a specific lineage (CLOUD-HSPCs). Here, we combine ScRNA-seq, ScATAC-seq and cell surface proteomics to dissect the heterogeneity of CLOUD-HSPCs at different stages of human life. Within CLOUD-HSPCs, pseudotime ordering of both mRNA and chromatin data revealed a bifurcation of megakaryocyte/erythroid and lympho/myeloid trajectories immediately downstream a subpopulation with an HSC-specific enhancer signature. Importantly, both HSCs and lineage-restricted progenitor populations could be prospectively isolated based on correlation of their molecular signatures with CD35 and CD11A expression, respectively. Moreover, we describe the changes that occur in this heterogeneity as hematopoiesis develops from neonatal to aged bone marrow, including an increase of HSCs and depletion of lympho-myeloid biased MPPs. Thus, this study dissects the heterogeneity of human CLOUD-HSPCs revealing distinct HSPC-states of relevance in homeostatic settings such as ageing.
IRC3regulates mitochondrial translation in response to metabolic cues inSaccharomyces cerevisiae
Authors: Kaur Jaswinder , Datta Kaustuv
Published: April 2021

Mitochondrial oxidative phosphorylation (OXPHOS) enzymes are made up of dual genetic origin. Mechanism regulating expression of nuclear encoded OXPHOS subunits in response to metabolic cues (glucose vs. glycerol), is significantly understood while regulation of mitochondrially encoded OXPHOS subunits is poorly defined. Here, we show thatIRC3a DEAD/H box helicase, previously implicated in mitochondrial DNA maintenance, is central to integrating metabolic cues with mitochondrial translation. Irc3 associates with mitochondrial small ribosomal subunit in cells consistent with its role in regulating translation elongation based on Arg8mreporter system. Glucose grownΔirc3ρ+andirc3temperature sensitive cells at 37⁰C have reduced translation rates from majority of mRNAs. In contrast, when galactose was the carbon source, reduction in mitochondrial translation was observed predominantly from Cox1 mRNA inΔirc3ρ+but no defect was observed inirc3temperature sensitive cells, at 37⁰C. In support, of a model wherebyIRC3responds to metabolic cues, suppressors of Δirc3isolated for restoration of growth on glycerol media restore mitochondrial translation differentially in presence of glucose vs. glycerol.
MiR-137 and miR-122, two outer subventricular zone-enriched non-coding RNAs, regulate basal progenitor expansion and neuronal differentiation
Authors: Tomasello Ugo , Klingler Esther , Niquille Mathieu , Mule Nandkishor , de Vevey Laura , Prados Julien , Santinha Antonio J , Platt Randall , Borrell Victor , Jabaudon Denis , Dayer Alexandre
Published: April 2021

Cortical expansion in the primate brain relies on the presence and the spatial enlargement of multiple germinal zones during development and on a prolonged developmental period. In contrast to other mammals, which have two cortical germinal zones, the ventricular zone (VZ) and subventricular zone (SVZ), gyrencephalic species display an additional germinal zone, the outer subventricular zone (OSVZ), which role is to increase the number and types of neurons generated during corticogenesis. How the OSVZ emerged during evolution is poorly understood but recent studies suggest a role for non-coding RNAs, which allow tight regulations of transcriptional programs in time and space during development (Dehay et al. 2015; Arcila et al., 2014). Here, usingin vivofunctional genetics, single-cell RNA sequencing, live imaging and electrophysiology to assess progenitor and neuronal properties in mice, we identify two ferret and human OSVZ-enriched microRNAs (miR), miR-137 and miR-122, which regulate key cellular features associated with cortical expansion. MiR-137 promotes basal progenitor self-replication and superficial layer neuron fate, while miR-122 slows down neuronal differentiation pace. Together, these findings support a cell-type specific role for miR-mediated transcriptional regulation in cortical expansion.
A meta-analysis of areas of structural variation in grey matter in individuals with Autism Spectrum Disorder (ASD) in relation to gene expression of candidate ASD genes
Authors: Panzeri Elisa , Camasio Alessia , Mancuso Lorenzo , Liloia Donato , Manuello Jordi , Ferraro Mario , Cauda Franco , Costa Tommaso
Published: April 2021

Autism Spectrum Disorder (ASD) is a set of developmental pathologies with a strong genetic basis and high heritability. Although neuroimaging studies have indicated anatomical changes in grey matter (GM) morphometry, their associations with gene expression remain elusive. In the present study, we aim to understand how gene expression correlates with structural brain aberration in ASD and how it distributes in a functional network perspective. First, we performed an activation likelihood estimation (ALE) meta-analysis to determine GM alteration in the brain, then we selected genes from the SHANK, NRXN, NLGN family and MECP2, which have been implicated with ASD, particularly in regards to altered synaptic transmission. Gene expression maps were built. We then assessed the correlation between the gene expression maps and the GM alteration maps. We found that the default mode network regions were the most significantly correlated with gene expression of selected genes in both areas of GM decrease and increase. The dorsal attention and the cerebellar network regions are significantly correlated with ASD genes. Different networks, namely somatomotor, limbic and basal ganglia/thalamus network - were found in the increase; for each of these networks, however, only a few genes were significant. Our approach allowed to combine the well beaten path of genetic and brain imaging in a novel way, to specifically investigate the relation between gene expression and brain with structural damage, and individuate genes of interest for further investigation in specific functional networks.