bluuebunny/crossref_metadata_2025 huggingface dataset:
Netrin‐1 attenuates cerebral ischemia/reperfusion injury by limiting mitochondrial ROS and Ca2+ levels via activation of AKT phosphorylation and mitochondrial m‐AAA protease AFG3L2
Authors: Yang Xiaosheng , Liu Yang , Zhong Weijie , Li Yi , Zhang Wenchuan
Published: February 2023

Cerebral ischemia–reperfusion (I/R) injury as the consequence of revascularization after ischemic stroke is associated with mitochondrial dysfunction, oxidative stress, and neuron loss. In this study, we used a deprivation/reoxygenation (OGD/R) model to determine whether interactions between Netrin‐1, AKT, and the mitochondrial AAA protease AFG3L2 could influence mitochondrial function in neurons after I/R. We found that Netrin‐1 protects primary cortical neurons from OGD/R‐induced cell death and regulates mitochondrial reactive oxygen species (ROS) and Ca2+ levels. The accumulation of mitochondrial calcium uniporter (MCU) subunits was monitored in cells by immunoblot analysis. Although the regulatory subunits MICU1 and MICU2 were relatively unaffected, the accumulation of the essential MCU regulator (EMRE) subunit was impaired. In OGD/R‐induced cells, the 7 kDa form of EMRE was significantly reduced. Netrin‐1 inhibited the accumulation of EMRE and mitochondrial Ca2+ levels by upregulating AFG3L2 and AKT activation. Loss of AFG3L2 or inhibition of AKT increased levels of 7 kDa EMRE. Moreover, overexpression of AKT increased the expression of AFG3L2 in Netrin‐1‐knockdown neurons after OGD/R. Our results demonstrate that Netrin‐1 enhanced AFG3L2 protein expression via activation of AKT. We also observed that overexpression of Netrin‐1 significantly reduced infarction size in an I/R‐induced brain injury model in rats but not when AKT was inhibited. Our data suggest that AFG3L2 is a protein substrate of AKT and indicate that Netrin‐1 attenuates cerebral I/R injury by limiting mitochondrial ROS and Ca2+ levels through activating AKT phosphorylation and AFG3L2.
Test Analysis Through the Lens of Objective Compassion
Authors: Nelan Philip , Prepetit Jessica
Published: February 2023

Test construction and test reviews are responsibilities nursing faculty arduously undertake, with an obligation to give appropriate effort and time to prepare and review exams. During test review, item analysis and statistical analysis offer valuable empirical information about the exam. However, objective compassion is also needed and can be demonstrated through careful test question construction and item analysis. Furthermore, compassion is needed in preparing students for the Next Generation NCLEX-RN (NGN) and constructing exams that appropriately test students' clinical judgment.
A Case Report: False-Negative HIV Antibody Test in a Patient Presenting With an Unusual Case of Cytomegalovirus Oropharyngeal Ulcerations
Authors: Kandiwo Nyakulira , Hapunda Racheal , Chanda Chitalu , Shams Madeeha , Toeque Mona-Gekanju , Riedel David J. , Mumbi Willard , Mulenga Lloyd , Claassen Cassidy W. , Fwoloshi Sombo , Hachaambwa Lottie
Published: February 2023

Background

Cytomegalovirus (CMV) oropharyngeal ulcerations are rare diagnoses that usually only occur in immunocompromised individuals. False-negative third-generation HIV tests in a patient with AIDS are also exceedingly rare and, when they occur, underscore the complex host and viral relationships involved in HIV disease mediation.

Case Presentation

We present a case of CMV oropharyngeal ulcerations in a patient diagnosed with advanced AIDS with a persistently negative HIV antibody test. Confirmative testing and diagnosis of HIV were performed with a qualitative DNA polymerase chain reaction and confirmed with a quantitative RNA polymerase chain reaction. Cytomegalovirus oropharyngeal ulcerations were managed with ganciclovir 5 mg/kg with significant improvement in oral ulcers.

Conclusions

We present a rare case of an HIV-seronegative patient clinically diagnosed with advanced AIDS and CMV oropharyngeal ulcerations. False-negative HIV tests can delay diagnosis and treatment; hence, clinical suspicion is needed for accurate diagnosis and early treatment.
Emphysematous hepatitis with successful treatments: A rare case report
Authors: Pan Nannan , Wang Shuo , Miao Zhenwei
Published: February 2023

Rationale:

Emphysematous hepatitis (EH) is a rare and fulminant gas-forming liver infection. Only 3 patients were successfully treated. Diabetes mellitus and a history of digestive system cancer may predispose individuals to EH. Computed tomography (CT) findings support the diagnosis of EH and monitor progress.

Patient concerns:

A 48-year-old man with diabetes presented with nausea, vomiting (gastric contents) and diarrhea. Laboratory test results revealed elevated levels of inflammatory indicators and abnormal liver function. CT showed a large-scale air collection with some remaining parenchymal debris in the left lobe of the liver. Remarkably, no fluid was observed inside the lesion.

Diagnose:

The abdominal CT features and laboratory examination results rationalized the diagnosis of EH.

Interventions and outcomes:

The patient finally recovered from this severe disease through a series of effective treatments, including strict glucose control, sensitive antibiotic therapy, and subsequent percutaneous drainage.

Lessons:

EH generally deteriorates rapidly and eventually leads to death. This case will raise awareness of the rare and severe disease, strengthen diagnostic capacities, and provide advice to treat it.
Immunohistochemical characteristics of thyroid-like low-grade nasopharyngeal papillary adenocarcinoma: A case report and review
Authors: Guo Hongjie , Zhang Zixiong , Huang Chuying , Qiu Jiao , Qu Xiaochun
Published: February 2023

Background:

Thyroid-like low-grade nasopharyngeal papillary adenocarcinoma (TL-LGNPPA) is a rare nasopharyngeal malignant tumor that is easy to misdiagnose. Immunohistochemistry plays an indispensable role in distinguishing TL-LGNPPA from other malignancies. However, there is no article to summarize the immunohistochemical characteristics of TL-LGNPPA. Herein, we report a case of TL-LGNPPA and present the immunohistochemical results reported in the Chinese literature.

Methods:

An electronic search of the CNKI (China National Knowledge Infrastructure) database was performed. From our literature survey, 53 cases of TL-LGNPPA (including the case described in this report) have been identified in China. We summarize the Chinese literature's clinical characteristics, immunohistochemical results, treatments, and prognosis of 53 cases.

Results:

Based on our literature survey, 53 cases of TL-LGNPPA (including the case described in this report) have been reported in China. We found TL-LGNPPA and papillary thyroid carcinoma were positive for TTF-1 and CK19. TL-LGNPPA was negative for TG and PAX-8, whereas papillary thyroid carcinoma was positive for TG and PAX-8. However, negative expression of TTF-1 and positive expression of TG were also found in some TL-LGNPPA cases. Our literature survey found that all TL-LGNPPA cases were negative for PAX-8.

Therefore, we suggest that simultaneous immunohistochemical determination of TTF-1 and CK19, as well as TG and PAX-8, can increase the diagnostic accuracy of TL-LGNPPA.

Conclusion:

The 4th edition of the World Health Organization Classification of Head and Neck Tumors (WHO-HNT) indicates that NPPA with positive expression of cytokeratin 19 (CK19) and TTF-1 and negative expression of TG is called TL-LGNPPA.
Effect of cyclosporine A on focal segmental glomerulosclerosis caused by MYO1E mutation in a Chinese adult patient: A case report
Authors: Li Ruizhao , Dong Wei , Chen Yingwen , Tang Tianwei , Zhao Xingchen , Zhang Li , Liang Xinling
Published: February 2023

Rationale:

Focal segmental glomerulosclerosis (FSGS) describes a renal histologic lesion with diverse causes and pathogenicities. Monogenic abnormalities which are associated with impaired function of podocyte could result in FSGS. Most of genetic FSGS do not respond to immunosuppressive agents and often develop end-stage kidney disease. We reported a case of FSGS caused by myosin1e (MYO1E) mutation, alleviated by cyclosporine A (CsA) and low-dose glucocorticoid.

Patient concerns:

The patient was a 38-year-old male with nephrotic range proteinuria. He didn’t respond to prednisone 65mg/day. Kidney biopsy in our hospital showed FSGS with several hypoplasia and tiny loops. In addition, focal thickening and disorganization of the glomerular gasement membrane as well as diffuse foot process effacement were observed in electron microscope.

Diagnoses:

Genetic testing indicated homozygous deletion mutation of MYO1E. The patient was diagnosed with genetic FSGS caused by MYO1E homozygous mutation.

Interventions:

The patient was treated with CsA 50mg twice a day and low-dose methylprednisolone.

Outcomes:

CsA and low-dose glucocorticoid dramatically reduced proteinuria, and partial remission was attained in 3 years follow-up.

Lessons:

MYO1E autosomal recessive mutation was a rare FSGS causative mutation that might benefit from CsA treatment. However, the long-term effect of CsA on FSGS caused by this mutation should be investigated in the future.
Anesthetic management of a pediatric patient with Dravet syndrome: A case report
Authors: Hase Yuri , Takuma Shigeru , Hojo Takayuki , Nitta Yukie , Kamekura Nobuhito
Published: February 2023

Introduction:

Dravet syndrome (DS) is a rare and severe myoclonic epilepsy, with onset commonly occurring in infancy. Seizures are triggered by various causes, including fever, bathing, and light stimulus. DS is refractory to drug treatment. Moreover, status epilepticus (SE) can cause serious encephalopathy and epilepsy-related deaths. There are very few reports of general anesthesia in DS patients. Herein, we report our experience with the anesthetic management of a pediatric patient with DS.

Patient concerns and diagnoses:

A 5-year-old boy (height, 112 cm; weight, 19 kg) was diagnosed with DS through SCN1A genetic testing, which revealed a de novo novel missense mutation. His medical history included drug-resistant epilepsy, developmental delay, and hypotonia. His seizures tended to be triggered daily by a rise in body temperature (BT), bathing, and light stimulus. He could not receive adequate dental treatment due to DS, although he had previously undergone dental treatment under restraint at the pediatric dentistry department of our hospital.

Interventions and outcomes:

The patient was scheduled for intensive dental treatment under general anesthesia due to noncooperation, and DS-related limitations. By considering the risk posed by elevated BT, seizure-inducing drugs were avoided, and general anesthesia was completed as planned, uneventfully. Although fluctuation of BT occurred during the procedure, it was finally controlled at the end of anesthesia at about the same level as at anesthesia induction. However, small seizures and a single generalized convulsion were observed accompanied by fever on postoperative day 1. The patient was discharged from the hospital without major problems on postoperative day 3, because of detailed planning and close preoperative cooperation with the attending pediatrician.

Conclusion:

It is essential to pay attention to managing BT and to avoid drugs that induce seizures during anesthesia for patients with DS. Cautious preoperative planning for anesthesia based on evaluation of the patient and rapid postoperative response in collaboration with the attending pediatrician is necessary in case an epileptic seizure occurs.
Induction chemotherapy with sequential nimotuzumab plus concurrent chemoradiotherapy in advanced nasopharyngeal carcinoma: A retrospective real-world study
Authors: Jiang Danxian , Cao Jinxin , Guo Linying , Chen Yonghua , Yuan Ge , Huang Jing
Published: February 2023

Many locally advanced nasopharyngeal carcinoma patients develop local recurrence or distant metastasis. Our retrospective real-world study aims to evaluate the efficacy and safety of curative sequential approach with induction chemotherapy followed by concurrent chemoradiation + nimotuzumab as first-line therapy in advanced nasopharyngeal carcinoma. From 2015 to 2021, the clinic data of 117 patients with advanced nasopharyngeal carcinoma (stage III–IV a) who were treated in the Affiliated Hospital of Guangdong Medical University were retrospectively reviewed. Fifty-four patients in observation group received taxanes, cisplatin, and 5-fluorouracil/taxanes and cisplatin induction chemotherapy and nimotuzumab (200 mg, weekly) combined with concurrent chemo-radiotherapy (cisplatin: 40 mg/m2 weekly; intensity-modulated radiation therapy); 63 patients in control group received same therapy without nimotuzumab. There was no significant difference in patients’ characteristic baseline between 2 groups (P > .05). The complete response rate and objective response rate of the observational group was significantly higher than control group (46.30% vs 17.64%, P = .01; 96.30% vs 82.54%, P = .02). The median follow-up time was 24.77 (3.53–65.97) months. Both of the median progress free survival time and overall survival time were not reached. The 5-year progression-free survival rate of observation group was greater than control group (84.40% vs 63.70%, hazard ratios 0.365, 95% confidence intervals 0.147–0.909, P = .03). The 5-year overall survival rate of observation group and control group were 91.70% and 84.60%, respectively (P = .20). None of the patients withdrew from the study due to adverse events. Nimotuzumab combined with concurrent chemoradiotherapy as first-line therapy in advanced nasopharyngeal carcinoma can improve objective response rate and 5-year progress free survival rate with good safety profile.
Effect of methylene blue on hemodynamic response in the early phase of septic shock: A case series
Authors: Luis-Silva Fabio , Menegueti Mayra Gonçalves , Sato Lucas , Peres Leandro Moreira , dos Reis Sepeda Corina , Petroski-Moraes Bruno C. , Donadel Mariana Dermínio , Gallo Gabriela Bortoleto , Jordani Maria Cecília , Mestriner Fabiola , Becari Christiane , Basile-Filho Anibal , Evora Paulo R. B. , Martins-Filho Olindo Assis , Auxiliadora-Martins Maria
Published: February 2023

Rationale:

Methylene blue (MB) has been used to increase blood pressure in septic shock, acting on the activity of guanylate cyclase and nitric oxide synthase.

Patience concerns:

The aim of this study is to demonstrate the benefit of MB in early phase of septic shock.

Diagnoses: We report 6 cases of patients with septic shock with up to 72 hours of evolution.

Interventions:

We used MB after fluid replacement, use of norepinephrine and vasopressin. Patients received a loading dose of MB and maintenance for 48 hours.

Outcomes:

All patients presented a reduction in the dose of vasopressors and lactate levels soon after the administration of the loading dose of MB, an effect that was maintained with the maintenance dose for 48 hours. Interleukin 6 and interleukin 8 were elevated at the beginning of the septic condition, with a progressive and marked reduction after the beginning of MB infusion, demonstrating a role of MB in reducing the inflammatory activity.

Lessons:

This case series suggests that MB used early in the treatment of septic shock may be useful in reducing vasopressor dose and lactate levels. Further studies are still required to further validate these findings.
Large intramural hematoma of the esophagus after endoscopic injection sclerotherapy: A case report
Authors: Wu Bo , Xie Xincheng , Li Xiao , Zhu Qun , Zhou Chunhua
Published: February 2023

Rationale:

Endoscopic injection sclerotherapy (EIS) is a common treatment for patients with liver cirrhosis and esophageal varices. It can effectively treat variceal rupture and bleeding caused by liver cirrhosis. However, EIS has many complications, including postoperative bleeding, retrosternal pain, esophageal ulcers, esophageal stenosis, and ectopic embolism. Intramural hematoma of the esophagus (IHE) is a rare complication of EIS that can lead to chest tightness, chest pain, and dysphagia.

Patient’s concerns:

A 55-year-old man developed severe nausea and vomiting accompanied by chest pain after EIS.

Diagnosis:

Comprehensive imaging features, the patient was diagnosed as IHE.

Interventions:

A vascular clamp was used for hemostasia, and a feeding tube was placed in the patient’s jejunum.

Outcomes:

After the removal of the jejunal feeding tube and the intake of a semiliquid diet, the patient had no episodes of chest pain, chest tightness, or dysphagia and was discharged after 2 days of observation.

Lessons:

Although IHE rarely occurs after EIS, we should not overlook its risk. The occurrence of IHE is not directly related to the number of EISs received or the degree of liver cirrhosis but is more likely related to postoperative nausea and vomiting. Therefore, timely medication and observation are particularly important for patients with nausea and vomiting after endoscopic treatment.
Neoadjuvant chemotherapy in advanced epithelial ovarian cancer by histology: A SEER based survival analysis
Authors: Liu Yuexi , Ni Meng , Huang Fanfan , Gu Qiuying , Xiao Yao , Du Xinyue
Published: February 2023

To evaluate the prognostic effect of neoadjuvant chemotherapy (NACT) in advanced epithelial ovarian cancer (EOC) patients with different histological subtype. Stage III/IV EOC patients diagnosed between 2010 and 2018 were identified from the surveillance, epidemiology, and end results database (SEER) database and stratified by histological subtype. Kaplan–Meier analysis was used for the assessment of overall survival (OS) cause-specific survival (CSS) before and after matching for baseline characteristics between NACT and primary debulking surgery (PDS) groups. Cox proportional risk model was conducted to identify independent prognostic factors. A total of 13,582 patients were included in the analysis. Of them, 9505 (74.50%) received PDS and 3253 (25.50%) received NACT. Overall, an inferior OS and CSS was observed among patients with high-grade serous carcinoma (HGSC) receiving NACT, while NACT served as a protective factor in clear cell carcinoma and carcinosarcoma in both original cohorts and adjusted cohorts. For other histo-subtypes, PDS showed survival benefit over NACT in certain cohorts of models. Prognostic effect of NACT in advanced EOC differed from pathological subtypes. Although it served as a risk factor for HGSC, patients with less common subtypes may benefit from NACT.
Safety and effects of endovascular treatment of basilar tip aneurysms in patients with moyamoya diseases
Authors: Chen Chun-Guang , Gao Bu-Lang , Yang Cheng-Bao , Hao Xiao-Hong , Ren Chun-Feng , Yang Lei , Han Yong-Feng , Cao Qin-Ying
Published: February 2023

The effect and safety of endovascular treatment of basilar tip aneurysms associated with moyamoya disease are unknown. This study was to investigate the safety and effect of endovascular treatment of basilar tip aneurysms associated with moyamoya disease. Patients with moyamoya disease concurrent with basilar tip aneurysms were retrospectively enrolled and treated with endovascular embolization. The clinical and angiographic data were analyzed. Thirty patients with a basilar tip aneurysm were enrolled, including 8 (26.67%) male and 22 (73.33%) female patients aged 38 to 72 years (mean 54.4 ± 8.15). Endovascular treatment was successfully performed in 29 (96.67%) patients but failed in 1 (3.33%). Immediately after embolization, aneurysm occlusion degree was Raymond-Roy grade I in 26 (89.66%), grade II in 2 (6.90%), and grade III in 1 (3.45%). Intraprocedural complications occurred in 2 (10%) patients, including aneurysm rupture in 1 (3.33%), leading to death of the patient, and stent thrombosis in 2 (6.67%) which was successfully treated with thrombolysis. At discharge, good clinical outcome (modified Rankin Scale 0–2) was achieved in 29 (96.67%) and death in 1 (3.03%). Follow-up was performed 6 to 26 months (median 15) in 27 (93.1%) patients. Aneurysm occlusion degree was Raymond-Roy grade I in 21 (77.78%) patients, grade II in 4 (14.81%), and grade III in 2 (7.41%), not significantly (P = .67) different from those immediately after embolization. Aneurysm recurrence was found in 4 patients (14.81%). The clinical outcome was modified Rankin Scale 0 to 2 in all 27 patients, not significantly different from that at discharge. Endovascular embolization can be performed safely and effectively for basilar tip aneurysms associated with moyamoya disease even though more advanced embolization techniques are necessary.
Intra-abdominal hypertension among medical septic patients associated with worsening kidney outcomes (IAH-WK study)
Authors: Suphatheerawatr Nitcha , Jaturapisanukul Solos , Prommool Surazee , Kurathong Sathit , Pongsittisak Wanjak
Published: February 2023

High intra-abdominal pressure (IAP) is associated with acute kidney injury (AKI). However, the relationship between intra-abdominal hypertension (IAH) and AKI in medical septic patients is still inconclusive. This prospective cohort study enrolled patients admitted in the Medical Intensive Care Unit from April 2020 to February 2021. Demographic, therapeutic, and laboratory data were obtained upon admission. The evaluation of IAP was performed via the intra-vesical method during the first and second 24 hours of admission. Kidney function was evaluated on the first 3 days and at least on the 7th day of enrollment. Among 79 patients, 30 (38%) developed IAH, while 50 (63.3%) developed AKI within 7 days. On the first day, the mean IAP was 15.4 (interquartile range [IQR], 4) and 7.0 (IQR, 3.7) mm Hg in the IAH and non-IAH groups, respectively. A total of 52 patients (65.8%) developed the primary outcome (i.e., a composite outcome including AKI, treatment with kidney replacement therapy, or death). On Cox proportional-hazards model between IAH and outcomes, after adjustment for multiple covariates, IAH was associated with a composite outcome (hazard ratio [HR], 6.5; 95% confidence interval [CI], 2.3–18.6; P < .005) and the development of AKI (HR, 6.5; 95% CI, 2.3–18.8; P < .005). IAH was associated with a composite outcome of AKI, treatment with kidney replacement therapy, or death in medical septic patients. thaiclinicaltrial.org, Identifier: TCTR20200531001, Registered May 24, 2020.
Association of physical activity and the risk of COVID-19 hospitalization: A dose–response meta-analysis
Authors: Li Dan , Jin Shengzhen , He Ziying , Lu Songtao
Published: February 2023

Background:

Many people have experienced a high burden due to the spread of the coronavirus disease (COVID-19) and its serious consequences for health and everyday life. Prior studies have reported that physical activity (PA) may lower the risk of COVID-19 hospitalization. The present meta-analysis explored the dose–response relationship between PA and the risk of COVID-19 hospitalization.

Methods:

Epidemiological observational studies on the relationship between PA and the risk of COVID-19 hospitalization were included. Categorical dose–response relationships between PA and the risk of COVID-19 hospitalization were assessed using random effect models. Robust error meta-regression models assessed the continuous relationship between PA (metabolic equivalent [Met]-h/wk) and COVID-19 hospitalization risk across studies reporting quantitative PA estimates.

Results:

Seventeen observational studies (cohort\case–control\cross-section) met the criteria for inclusion in the meta-analysis. Categorical dose-relationship analysis showed a 40% (risk ratio [RR] 0.60, 95% confidence interval [CI]: 0.48–0.71) reduction in the risk of COVID-19 hospitalization compared to the lowest dose of PA. The results of the continuous dose–response relationship showed a non-linear inverse relationship (Pnon-linearity < .05) between PA and the risk of COVID-19 hospitalization. When total PA was < or >10 Met-h/wk, an increase of 4 Met-h/wk was associated with a 14% (RR = 0.83, 95% CI: 0.85–0.87) and 11% (RR = 0.89, 95% CI: 0.87–0.90) reduction in the risk of COVID-19 hospitalization, respectively.

Conclusions:

There was an inverse non-linear dose–response relationship between PA level and the risk of COVID-19 hospitalization. Doses of the guideline-recommended minimum PA levels by the World Health Organization may be required for more substantial reductions in the COVID-19 hospitalization risk.
Ethics of allocation of donor organs
Authors: Bunnik Eline M.
Published: February 2023

Purpose of review

There is no widely accepted single ethical principle for the fair allocation of scarce donor organs for transplantation. Although most allocation systems use combinations of allocation principles, there is a particular tension between ‘prioritizing the worst-off’ and ‘maximizing total benefits’. It is often suggested that empirical research on public preferences should help solve the dilemma between equity and efficiency in allocation policy-making.

Recent findings

This review shows that the evidence on public preferences for allocation principles is limited, and that the normative role of public preferences in donor organ allocation policy making is unclear. The review seeks to clarify the ethical dilemma to the transplant community, and draws attention to recent attempts at balancing and rank-ordering of allocation principles.

This review suggests that policy makers should make explicit the relative weights attributed to equity and efficiency considerations in allocation policies, and monitor the effects of policy changes on important ethics outcomes, including equitable access among patient groups. Also, it draws attention to wider justice issues associated not with the distribution of donor organs among patients on waiting lists, but with barriers in referral for transplant evaluation and disparities among patient groups in access to waiting lists.
GGEM: Gender, Geography, and EMployment differences based on mobility levels among lower limb prosthesis users living in the United States
Authors: England Dwiesha L. , Miller Taavy A. , Stevens Phillip M. , Campbell James H. , Wurdeman Shane R.
Published: February 2023

Background:

For individuals with a disability, an increase in functional mobility may improve their quality of life and well-being. Greater understanding is needed on how factors such as gender, geography, and employment may play a role in mobility levels among individuals with lower limb amputation.

Objectives:

To assess the relationship between gender, geography, and employment status on mobility among lower limb prosthesis users.

Methods:

A cross-sectional analysis of 7,524 patient mobility outcomes completed across the United States was performed. The regression model included the independent variables, such as age, gender, region, employment status, and amputation level. Mobility was entered as the dependent variable.

Results:

Individuals who were employed had 3.6 times the odds of reaching increased mobility (Prosthetic Limb Users’ Survey of Mobility ≥ 50) than those unemployed (odds ratio 3.56, 95% confidence interval 3.10–4.09). Gender and geography were significantly associated with mobility as well.

Conclusions:

Being employed is associated with greater odds of reaching increased mobility. Addressing factors such as returning to employment may aid in improving mobility levels among prosthesis users.
High-dimensional proteomics identifies organ injury patterns associated with outcomes in human trauma
Authors: Li Shimena R. , Moheimani Hamed , Herzig Brachman , Kail Michael , Krishnamoorthi Neha , Wu Junru , Abdelhamid Sultan , Scioscia Jacob , Sung Eunseo , Rosengart Anna , Bonaroti Jillian , Johansson Par I. , Stensballe Jakob , Neal Matthew D. , Das Jishnu , Kar Upendra , Sperry Jason , Billiar Timothy R.
Published: February 2023

INTRODUCTION

Severe traumatic injury with shock can lead to direct and indirect organ injury; however, tissue-specific biomarkers are limited in clinical panels. We used proteomic and metabolomic databases to identify organ injury patterns after severe injury in humans.

METHODS

Plasma samples (times 0, 24, and 72 hours after arrival to trauma center) from injured patients enrolled in two randomized prehospital trials were subjected to multiplexed proteomics (SomaLogic Inc., Boulder, CO). Patients were categorized by outcome: nonresolvers (died >72 hours or required ≥7 days of critical care), resolvers (survived to 30 days and required <7 days of critical care), and low Injury Severity Score (ISS) controls. Established tissue-specific biomarkers were identified through a literature review and cross-referenced with tissue specificity from the Human Protein Atlas. Untargeted plasma metabolomics (Metabolon Inc., Durham, NC), inflammatory mediators, and endothelial damage markers were correlated with injury biomarkers. Kruskal-Wallis/Mann-Whitney U tests with false discovery rate correction assessed differences in biomarker expression across outcome groups (significance; p < 0.1).

RESULTS

Of 142 patients, 78 were nonresolvers (median ISS, 30), 34 were resolvers (median ISS, 22), and 30 were low ISS controls (median ISS, 1). A broad release of tissue-specific damage markers was observed at admission; this was greater in nonresolvers. By 72 hours, nine cardiac, three liver, eight neurologic, and three pulmonary proteins remained significantly elevated in nonresolvers compared with resolvers. Cardiac damage biomarkers showed the greatest elevations at 72 hours in nonresolvers and had significant positive correlations with proinflammatory mediators and endothelial damage markers. Nonresolvers had lower concentrations of fatty acid metabolites compared with resolvers, particularly acyl carnitines and cholines.

CONCLUSION

We identified an immediate release of tissue-specific biomarkers with sustained elevation in the liver, pulmonary, neurologic, and especially cardiac injury biomarkers in patients with complex clinical courses after severe injury. The persistent myocardial injury in nonresolvers may be due to a combination of factors including metabolic stress, inflammation, and endotheliopathy.
The effects of hypocalcemia in severely injured pediatric trauma patients
Authors: Ciaraglia Angelo , Lumbard Derek , Deschner Benjamin , Barry Lauran , Braverman Maxwell , Eastridge Brian , Stewart Ronald , Liao Lillian , Jenkins Donald , Nicholson Susannah
Published: February 2023

INTRODUCTION

The role of calcium is ubiquitous in human physiology. Emerging evidence suggests that the lethal triad be revised to include hypocalcemia (hypoCa) and thus be known as the lethal diamond. There are data showing that traumatic injury may result in hypoCa independent from the mechanism of calcium chelation by citrate-based blood preservatives. Minimal literature exists analyzing the role of hypoCa in pediatric trauma patients. We hypothesize that there is an independent association of hypoCa with increased blood product requirements and mortality.

METHODS

A retrospective cohort study of severely injured pediatric trauma patients was conducted. Trauma registry data were collected from January 2016 to August 2021. Ionized calcium (iCa) levels were obtained from arrival blood draws. Subjects were categorized into two groups by a threshold iCa level of 1.00 mmol/L and compared. Shock Index Pediatric Adjusted scores were used to adjust for age-specific differences in vital signs.

RESULTS

A total of 142 patients were compared, of which 46.5% were hypocalcemic (iCa <1.00 mmol/L). Patients were well matched in terms of demographics and injury severity. The hypocalcemic group had lower systolic blood pressure and a higher percentage of Shock Index Pediatric Adjusted–positive patients. Weight-adjusted transfusion volumes were significantly higher in the hypocalcemic group at both the 4-hour and 24-hour time points without a difference in prehospital transfusion requirements. There was no observed difference in early or in-hospital mortality.

CONCLUSION

This study contributes to the body of literature regarding the association between hypoCa and traumatic injury in the pediatric population. Hypocalcemia was associated with increased blood product requirements without a difference in prehospital transfusion requirements, suggesting a possible independent association. Further prospective studies are needed to better understand this relationship.

LEVEL OF EVIDENCE

Therapeutic/Care Management; Level IV.
Elucidating the molecular mechanisms of fibrinolytic shutdown after severe injury: The role of thrombin-activatable fibrinolysis inhibitor
Authors: Coleman Julia R. , Moore Ernest E. , Kelher Marguerite R. , Jones Kenneth , Cohen Mitchell J. , Banerjee Anirban , Silliman Christopher C.
Published: February 2023

BACKGROUND

The mechanisms underlying trauma-induced coagulopathy remain elusive. Hyperfibrinolysis has been linked to increased plasminogen activation and antiprotease consumption; however, the mechanistic players in its counterpart, fibrinolysis shutdown, remain unclear. We hypothesize that thrombin-activatable fibrinolysis inhibitor (TAFI) plays a major role in fibrinolytic shutdown after injury.

METHODS

As part of this observational cohort study, whole blood was collected from trauma activation patients at a single, level 1 trauma center. Citrated rapid thrombelastography and the following enzyme-linked immunosorbent assays were conducted: thrombin, antithrombin, thrombin-antithrombin complex, TAFI, plasminogen, antiplasmin, plasmin-antiplasmin (PAP), tissue plasminogen activator, plasminogen activator inhibitor 1, and tissue plasminogen activator–plasminogen activator inhibitor 1 complex. Univariate and cluster analysis were performed.

RESULTS

Overall, 56 patients (median age, 33.5 years; 70% male) were included. The majority (57%) presented after blunt mechanism and with severe injury (median New Injury Severity Score, 27). Two clusters of patients were identified: Group 1 (normal fibrinolysis, n = 21) and Group 2 (fibrinolysis shutdown, n = 35). Group 2 had significantly lower fibrinolysis with a median LY30 of 1.1% (interquartile range [IQR], 0.1–1.9%) versus 2.1% (IQR, 0.5–2.8%) in Group 1; while the median LY30 was within physiologic range, 45% of patients in Group 2 were in shutdown (vs. 24% in Group 1, p = 0.09). Compared with Group 1, Group 2 had significantly higher PAP (median, 4.7 [IQR, 1.7–9.3] vs. 1.4 [1.0–2.1] μg/mL in Group 1; p = 0.002) and higher TAFI (median, 152.5% [IQR, 110.3–190.7%] vs. 121.9% [IQR, 93.2–155.6%]; p = 0.04). There was a strong correlation between PAP and TAFI (R
2 = 0.5, p = 0.0002).

CONCLUSION

The presented data characterize fibrinolytic shutdown, indicating an initial plasmin burst followed by diminished fibrinolysis, which is distinct from hypofibrinolysis (inadequate plasmin burst and fibrinolysis). After an initial thrombin and plasmin burst (increased PAP), fibrinolysis is inhibited, mediated in part by increased TAFI.
Human Tracheal Transplantation
Authors: Genden Eric M. , Laitman Benjamin M.
Published: February 2023

Long-segment tracheal airway defects may be congenital or result from burns, trauma, iatrogenic intubation damage, or tumor invasion. Although airway defects <6 cm in length may be reconstructed using existing end-to-end reconstructive techniques, defects >6 cm continue to challenge surgeons worldwide. The reconstruction of long-segment tracheal defects has long been a reconstructive dilemma, and these defects are associated with significant morbidity and mortality. Many of these defects are not compatible with life or require a permanent extended-length tracheostomy that is fraught with complications including mucus plugging and tracheoesophageal fistula. Extensive circumferential tracheal defects require a reconstructive technique that provides a rigid structure able to withstand the inspiratory pressures, a structure that will biologically integrate, and contain functional ciliated epithelium to allow for normal mucociliary clearance. Tracheal transplantation has been considered the reconstructive “Holy Grail;” however, there has been a long-held scientific dogma that revascularization of the trachea was not possible. This dogma stifled research to achieve single-staged vascularized tracheal transplantation and prompted the introduction of many creative and inventive alternatives. Throughout history, alloplastic material, nonvascularized allografts, and homografts have been used to address this dilemma. However, these techniques have largely been unsuccessful. The recent introduction of a technique for single-staged vascularized tracheal transplantation may offer a solution to this dilemma and potentially a solution to management of the fatal tracheoesophageal fistula.
Pediatric DUCT Score: A Highly Specific Predictive Model for Choledocholithiasis in Children
Authors: Ignacio Romeo C , Kelley-Quon Lorraine I , Ourshalimian Shadassa , Padilla Benjamin E , Jensen Aaron R , Shew Stephen B , Lofberg Katrine M , Smith Caitlin A , Roach Jonathan P , Pandya Samir R , Russell Katie W , Wang Kasper ,   for the Western Pediatric Surgery Research Consortium Choledocholithiasis Investigative Group
Published: February 2023

Background:

Current adult guidelines in the management of choledocholithiasis (CDL) may not be appropriate for children. We hypothesized adult preoperative predictive factors are not reliable for predicting CDL in children.

Study Design:

A multicenter retrospective cohort study was performed evaluating children (≤18 years of age) who underwent cholecystectomy for gallstone disease at 10 children’s hospitals. Univariate and multivariable analyses were used to identify factors independently associated with CDL. Patients were stratified into risk groups demonstrating based on the presence of predictive factors for CDL. Statistical analyses were performed, and chi-square analyses were used with a significance of p<0.05

Results:

A total of 979 cholecystectomy patients were analyzed. The diagnosis of CDL was confirmed in 222 patients (22.7%) by MRCP, ERCP, or IOC. Three predictive factors were identified 1)
D
ilated common bile duct (CBD) ≥6mm, 2)
U
ltrasound (US) with
C
holedocholithiasis, and 3)
T
otal bilirubin ≥1.8 mg/dL (Pediatric DUCT criteria). Risk groups were based on the number of predictive factors: Very High (3), High (2), Intermediate (1) and Low (0). The Pediatric DUCT criteria demonstrated accuracies of >76%, specificity of >78%, and negative predictive values of >79%. Adult factors (elevated AST/ALT, pancreatitis, BMI, and age) did not independently predict CDL. Based on risk stratification, the high and very-high risk groups demonstrated higher predictive capacity for CDL.

Conclusions:

Our study demonstrated that the Pediatric DUCT criteria, incorporating CBD dilation, choledocholithiasis seen on US, and total bilirubin ≥1.8 mg/dL, highly predicts the presence of choledocholithiasis in children. Other adult preoperative factors are not predictive of CBD stones in children.
Materialism,
Lebenskraft
and the limits of science: metaphysical vitalism in post-Kantian scenarios
Authors: Pecere Paolo
Published: February 2023

Kant's legacy in the history of life sciences has notoriously included a critique of the use of soul and ‘vital force’ (
Lebenskraft
). In this paper I focus on a less-known side of this legacy, i.e. Kant's late critique of vital materialism and its impact on nineteenth-century German science and philosophy. I show that Kant considered materialism as a kind of metaphysical hypothesis since the 1760s and pointed out that it was empirically impossible to distinguish it from different kinds of hypotheses (such as monadology). I focus on Kant's late essay on Samuel Sömmering (1796), arguing that the critical rejection of materialism and the notion of
Lebenskraft
belonged to an anti-reductive program for life sciences. I maintain that Kant's views influenced Alexander von Humboldt's turn concerning vitalism in the late 1790s and the anti-metaphysical and physicalist epistemology of Hermann von Helmholtz. I follow this Kantian legacy in the works of Friedrich Lange, Emil du Bois-Reymond and Erich Adickes. Finally, I argue that this tradition provides a vantage point to reconsider contemporary debates over materialism and panpsychism.
Efficiency of an allosteric protein: Multiple affinity-efficacy correlations link agonist binding to nicotinic receptor activation
Authors: Indurthi Dinesh , Auerbach Anthony
Published: February 2023

Receptors signal by switching between resting and active shapes under the influence of agonists. The maximum response produced by an agonist (‘efficacy’) depends on its relative binding strength (‘affinity’) to active versus resting conformations. Efficiency, the logcorrelation between these two agonist properties, is the fraction of binding energy converted into energy for the receptor’s conformational change. In adult muscle nicotinic receptors, efficiencies estimated from 76 concentration-response curves (23 agonists, 53 mutations) segregate into 5 discrete classes (%): 0.56 (17), 0.51(32), 0.45(13), 0.41(26) and 0.31(12). There is a strong linear correlation between affinity and efficacy within each class, but the multiplicity of classes precludes the appearance of any overall relationship. The efficiency class distribution indicates that there are at least 5 resting versus active binding site structural pairs. We discuss efficiency as a quantitative measure of energy coupling between agonist binding and protein conformational change that is fundamental to receptor operation.
Chromatin remodeling enzyme Snf2h is essential for retinal cell proliferation and photoreceptor maintenance
Authors: Kuzelova Andrea , Dupacova Naoko , Antosova Barbora , Sunny Sweetu Susan , Kozmik Zbynek , Paces Jan , Skoultchi Arthur I. , Stopka Tomas , Kozmik Zbynek
Published: February 2023

Chromatin remodeling complexes are required for many distinct nuclear processes such as transcription, DNA replication and DNA repair. However, how these complexes contribute to the development of complex tissues within an organism is poorly characterized. Imitation switch (ISWI) proteins are among the most evolutionarily conserved ATP-dependent chromatin remodeling factors and are represented by yeast Isw1/Isw2, and their vertebrate counterparts Snf2h (Smarca5) and Snf2l (Smarca1). In this study, we focused on the role of theSnf2hgene during development of the mammalian retina. We show thatSnf2his expressed in both retinal progenitors and post-mitotic retinal cells. UsingSnf2hconditional knockout mice (Snf2hcKO), we found that whenSnf2his deleted the laminar structure of the adult retina is not retained, the overall thickness of the retina is significantly reduced compared with controls, and the outer nuclear layer (ONL) is completely missing. Depletion of Snf2h did not influence the ability of retinal progenitors to generate all of the differentiated retinal cell types. Instead, Snf2h function is critical for proliferation of retinal progenitor cells. Cells lacking Snf2h have a defective S-phase, leading to the entire cell division process impairments. Although, all retinal cell types appear to be specified in the absence of Snf2h function, cell cycle defects and concomitantly increased apoptosis inSnf2hcKO result in abnormal retina lamination, complete destruction of the photoreceptor layer and, consequently, in a physiologically non-functional retina.
Functional convergence of genomic and transcriptomic genetic architecture underlying sociability in a live-bearing fish
Authors: Corral-Lopez Alberto , Bloch Natasha I. , van der Bijl Wouter , Cortazar-Chinarro Maria , Szorkovszky Alexander , Kotrschal Alexander , Darolti Iulia , Buechel Severine D. , Romenskyy Maksym , Kolm Niclas , Mank Judith E.
Published: February 2023

The organization and coordination of fish schools provide a valuable model to investigate the genetic architecture of affiliative behaviors and dissect the mechanisms underlying social behaviors and personalities. We used quantitative genetic methods in replicate guppy selection lines that vary in schooling propensity to investigate the genetic basis of sociability phenotypes. Alignment and attraction, the two major traits forming the sociability personality axis in this species, showed heritability estimates at the upper end of the range previously described for social behaviors, with important variation across sexes. Consistent with findings in collective motion patterns, experimental evolution of schooling propensity increases the sociability of female, but not male, guppies when swimming with unfamiliar conspecifics, a highly relevant trait in a species with fission-fusion social systems in natural populations. Our results from PoolSeq and RNASeq convergently identify genes involved in neuron migration and synaptic function, highlighting a crucial role of glutamatergic synaptic function and calcium-dependent signaling processes in the evolution of schooling.
Lymphocyte activation gene 3 (Lag3) supports Foxp3+Treg cell function by restraining c-Myc-dependent aerobic glycolysis
Authors: Kim Dongkyun , Kim Giha , Yu Rongzhen , Lee Juyeun , Kim Sohee , Qiu Kevin , Montauti Elena , Fang Deyu , Chandel Navdeep S. , Choi Jaehyuk , Min Booki
Published: February 2023

Lymphocyte activation gene 3 (Lag3) has emerged as the next-generation immune checkpoint molecule due to its ability to inhibit effector T cell activity. Foxp3+regulatory T (Treg) cells, a master regulator of immunity and tolerance, also highly express Lag3. While Lag3 is thought to be necessary for Treg cell-mediated regulation of immunity, the precise roles and underlying mechanisms remain largely elusive. In this study, we report that Lag3 is indispensable for Treg cells to control autoimmune inflammation. Utilizing a newly generated Treg cell specific Lag3 mutant mouse model, we found that these animals are highly susceptible to autoimmune diseases, suggesting defective Treg cell function. Genome wide transcriptome analysis further uncovered that Lag3 mutant Treg cells upregulated genes involved in metabolic processes. Mechanistically, we found that Lag3 limits Treg cell expression of Myc, a key regulator of aerobic glycolysis. We further found that Lag3-dependent Myc expression determines Treg cells’ metabolic programming as well as the in vivo function to suppress autoimmune inflammation. Taken together, our results uncovered a novel function of Lag3 in supporting Treg cell suppressive function by regulating Myc-dependent metabolic programming.
Motives, propensities and consistencies among Swedish consumers in relation to the food choice concept of clean eating
Authors: Edenbrandt Anna Kristina , Lagerkvist Carl-Johan
Published: February 2023

Purpose

The purpose of this study is to explore how consumers apply clean-eating criteria to a range of food characteristics, and the extent to which individuals are consistent in how they apply clean-eating criteria across products. Further, this study investigates how the clean-eating approach relates to underlying food choice motives.

Design/methodology/approach

Data were collected in a consumer survey (n = 666) in Sweden, where participants were prompted about the importance of a set of intrinsic food attributes of the “free-from” and “added” types, for three different food product types (bread, processed meat, ready meals). Data were analyzed using latent class cluster analysis, to explore segments of consumers that place similar importance to the food characteristics and hold similar food choice motives.

Findings

Clean eating can be described by two distinctly different attainment strategies: avoiding undesirable characteristics or by simultaneously approaching desirable characteristics. Notably, individuals who apply clean-eating criteria in their food choices strive for healthy, natural and environmentally friendly food, but the clean-by-approach strategy implies a stronger focus on personal health in the form of weight control.

Originality/value

While claims and labels on food packages concerning clean eating are implemented by food manufacturers, it remains unregulated. This study provides information for future regulations on how consumers apply clean-eating criteria, and their motives thereof. Further, the results provide insights food manufacturers regarding motives for clean eating in different consumer segments.