bluuebunny/crossref_metadata_2025 huggingface dataset:
Characterization of the dual role of Plasmodium falciparum DNA methyltransferase in regulating transcription and translation
Authors: Lucky Amuza B , Wang Chengqi , Li Xiaolian , Chim-Ong Anongruk , Adapa Swamy R , Quinlivan Eoin P , Jiang Rays , Cui Liwang , Miao Jun
Published: April 2023

DNA modifications are critical in fine-tuning the biological processes in model organisms. However, the presence of cytosine methylation (5mC) and the function of the putative DNA methyltransferase, PfDNMT2, in the human malaria pathogen, Plasmodium falciparum, remain controversial. Here, we revisited the 5mC in the parasite genome and the function of PfDNMT2. Low levels of genomic 5mC (0.1–0.2%) during asexual development were identified using a sensitive mass spectrometry procedure. Native PfDNMT2 displayed substantial DNA methylation activities, and disruption or overexpression of PfDNMT2 resulted in reduced or elevated genomic 5mC levels, respectively. PfDNMT2 disruption led to an increased proliferation phenotype, with the parasites having an extended schizont stage and producing a higher number of progenies. Consistent with PfDNMT2’s interaction with an AP2 domain-containing transcription factor, transcriptomic analyses revealed that PfDNMT2 disruption led to a drastic alteration in the expression of many genes, some of which provided the molecular basis of enhanced proliferation after PfDNMT2 disruption. Furthermore, levels of tRNAAsp and its methylation rate at position C38, and the translation of a reporter containing an aspartate repeat were significantly reduced after PfDNMT2 disruption, while the levels of tRNAAsp and its C38 methylation were restored after complementation of PfDNMT2. Our study sheds new light on the dual function of PfDNMT2 during P. falciparum asexual development.
Requirement of transcription-coupled nucleotide excision repair for the removal of a specific type of oxidatively induced DNA damage
Authors: Sarmini Leen , Meabed Mohammed , Emmanouil Eirini , Atsaves George , Robeska Elena , Karwowski Bolesław T , Campalans Anna , Gimisis Thanasis , Khobta Andriy
Published: April 2023

Accumulation of DNA damage resulting from reactive oxygen species was proposed to cause neurological and degenerative disease in patients, deficient in nucleotide excision repair (NER) or its transcription-coupled subpathway (TC-NER). Here, we assessed the requirement of TC-NER for the repair of specific types of oxidatively generated DNA modifications. We incorporated synthetic 5′,8-cyclo-2′-deoxypurine nucleotides (cyclo-dA, cyclo-dG) and thymine glycol (Tg) into an EGFP reporter gene to measure transcription-blocking potentials of these modifications in human cells. Using null mutants, we further identified the relevant DNA repair components by a host cell reactivation approach. The results indicated that NTHL1-initiated base excision repair is by far the most efficient pathway for Tg. Moreover, Tg was efficiently bypassed during transcription, which effectively rules out TC-NER as an alternative repair mechanism. In a sharp contrast, both cyclopurine lesions robustly blocked transcription and were repaired by NER, wherein the specific TC-NER components CSB/ERCC6 and CSA/ERCC8 were as essential as XPA. Instead, repair of classical NER substrates, cyclobutane pyrimidine dimer and N-(deoxyguanosin-8-yl)-2-acetylaminofluorene, occurred even when TC-NER was disrupted. The strict requirement of TC-NER highlights cyclo-dA and cyclo-dG as candidate damage types, accountable for cytotoxic and degenerative responses in individuals affected by genetic defects in this pathway.
Truth and Reconciliation in Medical Schools: Forging a Critical Reflective Framework to Advance Indigenous Health Equity
Authors: Henderson Rita , Sehgal Anika , Barnabe Cheryl , Roach Pamela , Crowshoe Lindsay (Lynden)
Published: April 2023

In 2015, the Truth and Reconciliation Commission (TRC) of Canada outlined 94 Calls to Action, which formalized a responsibility for all people and institutions in Canada to confront and craft paths to remedy the legacy of the country’s colonial past. Among other things, these Calls to Action challenge medical schools to examine and improve existing strategies and capacities for improving Indigenous health outcomes within the areas of education, research, and clinical service. This article outlines efforts by stakeholders at one medical school to mobilize their institution to address the TRC’s Calls to Action via the Indigenous Health Dialogue (IHD). The IHD used a critical collaborative consensus-building process, which employed decolonizing, antiracist, and Indigenous methodologies, offering insights for academic and nonacademic entities alike on how they might begin to address the TRC’s Calls to Action. Through this process, a critical reflective framework of domains, reconciliatory themes, truths, and action themes was developed, which highlights key areas in which to develop Indigenous health within the medical school to address health inequities faced by Indigenous peoples in Canada. Education, research, and health service innovation were identified as domains of responsibility, while recognizing Indigenous health as a distinct discipline and promoting and supporting Indigenous inclusion were identified as domains within leadership in transformation. Insights are provided for the medical school, including that dispossession from land lays at the heart of Indigenous health inequities, requiring decolonizing approaches to population health, and that Indigenous health is a discipline of its own, requiring a specific knowledge base, skills, and resources for overcoming inequities.
Lumbar Arthroplasty Is Associated With a Lower Incidence of Adjacent Segment Disease Compared With ALIF
Authors: Shukla Geet G. , Wu Andrew , Matur Abhijith V. , McGrath Kyle , Khalid Syed , Garner Rebecca , Owen Bryce , Ivey Natalie , Vorster Phillip , Onyewadume Louisa , Tao Xu , Motley Benjamin , Cheng Joseph , Adogwa Owoicho
Published: April 2023

Study Design.

Retrospective Cohort Study

Objective.

The objective of this study was to compare the rate of adjacent segment disease (ASD) between lumbar disk arthroplasty (LDA) and anterior lumbar interbody fusion (ALIF).

Summary of Background Data.

LDA and ALIF are alternative surgical approaches used to treat lumbar degenerative disk disease. However, there is a paucity of studies comparing the risk of ASD after these procedures.

Methods.

Patients who underwent 1- to 2-level LDA or ALIF between 2010 and 2022 were identified in the PearlDiver Mariner insurance all-claims database. Exclusion criteria included the history of prior lumbar spine surgery or surgery for tumors, trauma, or infection. 1:1 propensity matching was performed using demographic factors, medical comorbidities, and surgical factors, which were significantly associated with ASD.

Results.

1:1 propensity matching created two equal groups of 1625 patients without baseline differences who underwent LDA or ALIF. LDA was significantly associated with a lower risk of ASD (relative risk: 0.932, 95% CI, 0.899–0.967, P<0.001) and need for revision within 30 days (relative risk: 0.235, 95% CI, 0.079–0.698, P=0.007). There were no differences in all-cause surgical and medical complications between both groups.

Conclusions.

After risk adjustment for demographic and clinical characteristics, the results suggest that LDA is associated with a lower risk of ASD compared with ALIF. LDA was also associated with lower hospital cost and shorter length of stay.
10-year Longitudinal MRI Study of Intervertebral Disk Degeneration in Patients With Lumbar Spinal Canal Stenosis After Posterior Lumbar Decompression Surgery
Authors: Fujii Takeshi , Daimon Kenshi , Ozaki Masahiro , Suzuki Satoshi , Takahashi Yohei , Tsuji Osahiko , Nagoshi Narihito , Yagi Mitsuru , Michikawa Takehiro , Matsumoto Morio , Nakamura Masaya , Watanabe Kota
Published: April 2023

Study Design.

A prospective longitudinal magnetic resonance imaging (MRI) study.

Objective.

The objective of this study was to describe the progression of intervertebral disk (IVD) degeneration in patients who underwent posterior decompression surgery for lumbar spinal canal stenosis (LSS).

Summary of Background Data.

IVD degeneration contributes to the pathogenesis of LSS; however, the long-term consequences of degenerative changes after decompression surgery remain unknown.

Materials and Methods.

Of 258 consecutive patients who underwent posterior lumbar decompression surgery for LSS, 62 who underwent MRI at their 10-year follow-up were included; 17 age-matched asymptomatic volunteers were analyzed as controls. Three MRI findings representing IVD degeneration were graded on their severity: decrease in signal intensity, posterior disk protrusion (PDP), and disk space narrowing (DSN). Clinical outcome was assessed using the low back pain (LBP) score from the Japanese Orthopaedic Association scoring system. We examined the association between the progression of degenerative changes on MRI and LBP/associated factors using logistic regression adjusting for age at baseline and sex.

Results.

The severity of IVD degeneration tended to be higher in patients with LSS than asymptomatic volunteers at both baseline and follow-up. IVD degeneration progressed in all patients during the 10-year follow-up period. Progression of decrease in signal intensity and PDP was observed at L1/2 in 73% and at L2/3 in 34%, respectively (the highest frequencies in the lumbar spine). Progression of DSN was highest at L4/5 in 42%. The rates of PDP and DSN progression during the 10-year follow-up period tended to be greater in patients with LSS than in asymptomatic volunteers. No significant difference in the proportion of LBP deterioration was evident for individuals with and without MRI findings of progression.

Conclusions.

Our study reveals a natural history of the long-term postoperative course of IVD degeneration after posterior decompression surgery for LSS. Compared with healthy controls, patients with LSS seemed to be predisposed to IVD degeneration. Lumbar decompression surgery may promote the progression of DSN; however, progression of IVD degeneration after lumbar decompression surgery was not associated with worsening LBP scores.
The Role of Antibiotics in Nasal Fractures after Closed Reduction
Authors: Vishwanath Neel , Rhee Ben , Sobti Nikhil , Beqiri Dardan , Xi Kevin , Lerner Julia , Woo Albert S
Published: April 2023

Background:

Nasal fractures represent the most common fracture in facial trauma. The role of prophylactic antibiotics in these injuries is debated, given low infection rates and demonstrated risks of antibiotics. We studied the isolated effect of prophylactic antibiotics on infection rate in patients with nasal fracture after closed reduction.

Methods:

Retrospective cohort study of a prospectively maintained facial trauma database was conducted. Demographics, comorbidities, fracture classifications, and management of patients who received antibiotics at the time of closed nasal reduction were compared against those who did not receive antibiotics. Infection rates between groups were analyzed. Multivariate analysis was conducted to control for confounding variables. Qualitative analysis was performed for patients who experienced infection following nasal fracture.

Results:

A total of 282 patients met inclusion criteria (n = 144, antibiotic; n = 138, nonantibiotic). Six patients experienced infection. There was no difference in infection rate between antibiotic and nonantibiotic groups (2.0% versus 2.2%; P = 0.90). On multivariate regression, antibiotics did not significantly decrease odds of infection (OR 1.7 [0.17–13.6]; P = 0.64). Moreover, patients with open nasal fractures did not have significantly higher odds of infection (OR 1.9 [0.08–20.8]; P = 0.64). Similarly, increasing severity of injury based on Rohrich classification did not significantly impact odds of infection (OR 0.68 [0.23–1.9]; P = 0.46). All six infections were managed at the bedside, with zero infections following operating room management (P = 0.32).

Conclusions:

Prophylactic antibiotics do not decrease infection rates following nasal fractures managed by closed reduction. Bedside management may be a risk factor for the development of infection; however, this finding requires further evaluation.
Association of preoperative IL-6 levels with overt HE in patients with cirrhosis after TIPS
Authors: Li JinYu , Liu Yang , Li ManBiao , Rong XueTong , Yuan Zhen , Ren Chao , Liu Shuai , Li Lei , Zhao Chao , Gao Long , Feng DuiPing
Published: April 2023

Background:

HE is a common and dangerous complication after TIPS. The relationship between IL-6 levels and overt HE (OHE) after TIPS is rarely reported.We aimed to explore the relationship between the preoperative serum IL-6 levels and OHE risk after TIPS, and to evaluate its value in predicting the OHE risk.

Methods:

This prospective cohort study included 125 participants with cirrhosis who received TIPS. Logistics regression analyses were performed to explore the relationship between IL-6 and OHE risk, and the receiver operating characteristic analysis was used to compare the predictive power of IL-6 and other indexes.

Results:

Among 125 participants, 44 (35.2%) participants developed OHE after TIPS. Logistics regression showed preoperative IL-6 was associated with a higher OHE risk after TIPS in different models (all p < 0.05). Participants with IL-6 > 10.5 pg/mL had a higher cumulative incidence of OHE after TIPS than those with IL-6 ≤ 10.5 pg/mL (log-rank = 0.0124). The predictive power of IL-6 (AUC = 0.83) for the OHE risk after TIPS was higher than that of other indexes. Age (RR = 1.069, p = 0.002) and IL-6 (RR = 1.154, p < 0.001) were independent risk factors for OHE after TIPS. IL-6 was also a risk factor for the occurrence of coma in patients with OHE (RR = 1.051, p = 0.019).

Conclusion:

Preoperative serum IL-6 levels are closely related to the occurrence of OHE in patients with cirrhosis after TIPS. Patients with cirrhosis with high serum IL-6 levels following TIPS were at a higher risk of developing severe HE.
Efficacy and Safety of Intranasal Betahistine in the Treatment of Surgery-Induced Acute Vestibular Syndrome: A Double-Blind, Randomized, Placebo-Controlled Phase 2 Study
Authors: Van de Heyning Paul , Betka Jan , Chovanec Martin , Devèze Arnaud , Giannuzzi Anna Lisa , Krempaská Silvia , Przewoźny Tomasz , Scheich Matthias , Strupp Michael , Van Rompaey Vincent , Meyer Thomas
Published: April 2023

Objective

To evaluate the safety and efficacy of AM-125 nasal spray (intranasal betahistine) in the treatment of surgery-induced acute vestibular syndrome (AVS).

Study Design

Prospective, double-blind, randomized, placebo-controlled exploratory phase 2 study with dose escalation (part A) followed by parallel dose testing (part B); open-label oral treatment for reference.

Setting

Twelve European study sites (tertiary referral centers).

Patients

One hundred and twenty-four patients 18 to 70 years old undergoing surgery for vestibular schwannoma resection, labyrinthectomy or vestibular neurectomy with confirmed bilateral vestibular function presurgery and acute peripheral vertigo postsurgery.

Interventions

AM-125 (1, 10, or 20 mg) or placebo or betahistine 16 mg p.o. t.i.d. for 4 weeks, starting 3 days postsurgery; standardized vestibular rehabilitation.

Main Outcome Measures

Tandem Romberg test (TRT) for primary efficacy, standing on foam, tandem gait, subjective visual vertical and spontaneous nystagmus for secondary efficacy, Vestibular Rehabilitation Benefit Questionnaire (VRBQ) for exploratory efficacy; nasal symptoms and adverse events for safety.

RESULTS

At treatment period end, mean TRT improvement was 10.9 seconds for the 20-mg group versus 7.4 seconds for the placebo group (mixed model repeated measures, 90% confidence interval = 0.2 to 6.7 s; p = 0.08). This was corroborated by nominally higher frequency of complete spontaneous nystagmus resolution (34.5% vs. 20.0% of patients) and improvement in the VRBQ; the other secondary endpoints showed no treatment effect. The study drug was well tolerated and safe.

CONCLUSIONS

Intranasal betahistine may help accelerate vestibular compensation and alleviate signs and symptoms of vestibular dysfunction in surgery-induced AVS. Further evaluation in a confirmatory manner appears warranted.
Ergonomic Analysis of Otologic Surgery: Comparison of Endoscope and Microscope
Authors: Arrighi-Allisan Annie E. , Fan Caleb J. , Wong Kevin , Wong Anni , Garvey Katherine L. , Schwam Zachary G. , Filip Peter , Jategaonkar Ameya A. , Perez Enrique , Wanna George B. , Govindaraj Satish , Iloreta Alfred-Marc , Cosetti Maura K.
Published: April 2023

Objective

The comparative postural health of surgeons performing endoscopic and microscopic otologic surgeries has been a topic of active debate, with many nascent or anecdotal reports suggesting the latter encourages suboptimal ergonomics. Using inertial body sensors to measure joint angles, this study sought to objectively evaluate and compare the ergonomics of surgeons during endoscopic and microscopic otologic surgeries.

Study Design

Prospective pilot trial.

Setting

Large, multicenter, academic hospital system. Performed 21 otologic operations (10 endoscopic and 11 microscopic) in November 2020 and January 2021. All attendings were fellowship trained in otology/neurotology.

Subjects

Eight otolaryngologists (four attendings and four residents) performing 21 otologic surgeries (11 microscopic and 10 endoscopic).

Intervention

Approach to otologic surgery: endoscope or microscope.

Main Outcome Measures

Surgeons’ neck and back angles while wearing ergonomic sensors affixed to either side of each major joint, mental and physical burdens and pain after each surgery (via modified NASA Task Load Index).

Results

Residents’ necks (9.54° microscopic vs. −4.79° endoscopic, p = 0.04) and backs (16.48° microscopic vs. 3.66° endoscopic, p = 0.01) were significantly more flexed when performing microscopic surgery than when performing endoscopic surgery, although attending neck and back flexion were comparable during microscopic and endoscopic surgeries. Attendings reported significantly higher pain levels after operating microscopically than after operating endoscopically (0.13 vs. 2.76, p = 0.01).

Conclusions

Residents were found to operate with significantly higher risk back and neck postures (as defined by the validated ergonomic tool, Rapid Entire Body Assessment) when operating microscopically. Attendings reported significantly higher levels of pain after operating microscopically versus endoscopically, suggesting that the suboptimal microscopic postures adopted earlier in training may pose an indelible risk later in a surgeon’s career.
Transcanal Endoscopic Stapedial and Tensor Tympani Tenotomy for Middle Ear Myoclonus: A Retrospective Case Series of Surgical Outcomes
Authors: Moon Seoungjun , Yeon Eun-Kyeong , Son Hyo One , Choi Jin Woong
Published: April 2023

Objective

To describe and analyze the surgical outcomes of transcanal endoscopic resection of the stapedial tendon (ST) and tensor tympani tendon (TT) in the management of middle ear myoclonus (MEM).

Study Design

A retrospective case series.

Setting

Tertiary academic center.

Patients

Seven consecutive patients (seven ears) with tinnitus were diagnosed with MEM.

Intervention

Transcanal endoscopic resection of both the ST and TT using either microinstruments or a laser.

Main Outcome Measures

The symptom of tinnitus, based on visual analog scale and Tinnitus Handicap Inventory scores, was analyzed preoperatively and postoperatively for each patient. The intraoperative findings and postoperative complications were also evaluated.

Results

Amelioration of objective tinnitus with significant improvement in visual analog scale and Tinnitus Handicap Inventory scores was noted in all seven patients. The ST and TT were easily identified in the same endoscopic field, with minimal or no removal of the scutum. There was no need to perform an anterior tympanotomy to expose the TT. Resection of both the ST and TT and creating a gap between the cut edges were achieved by using either microinstruments or a laser under an endoscopic field. Conversion to or conjunction with the microscopic approach was unnecessary for any of the seven patients. No hearing loss or hyperacusis occurred postoperatively.

Conclusions

Transcanal endoscopic resection of the ST and TT successfully ameliorated the symptom of tinnitus in patients with MEM. A transcanal endoscopic approach provides an alternative method to manage MEM, providing excellent visualization and minimal invasiveness.
Effectiveness of prophylactic antimicrobial levofloxacin against postureteroscopic lithotripsy infection: A multicenter prospective open-label randomized controlled trial
Authors: Du Zhen , Sun Hui , Zhang Yong , Cui Liang , Hou Jianping , Chen Jun , Chen Shan , Qiao Ludong
Published: April 2023

Background:

To verify the appropriate prophylactic agent to prevent ureteroscopic lithotripsy infection, which is safe, effective, convenient, reasonable, and with best pharmacoeconomic benefit ratio, to provide evidence for clinical practice.

Methods:

This study is a multicenter, open-label, randomized, positive drug-controlled trial design. From January 2019 to December 2021, patients with ureteral calculi who were going to undergo retrograde flexible ureteroscopic lithotripsy were selected from urology departments in 5 research centers. The patients enrolled were randomly divided into the experimental group and the control group according to the random number table by blocking randomization. In the experimental group (Group A), 0.5 g levofloxacin was given 2 to 4 hours before surgery. In the control group (Group B), cephalosporin was injected 30 minutes before surgery. The infectious complications, the incidence of adverse drug reactions and the economic benefit ratio were compared between the 2 groups.

Results:

A total of 234 cases were enrolled. There was no statistically significant difference between the 2 groups at baseline. Postoperative infection complications were 1.8% in the experimental group, which was significantly lower than 11.2% in control group. The type of infection complication in both groups was asymptomatic bacteriuria. The cost of drugs in the experimental group was 19.89 ± 13.11 yuan, which was significantly lower than cost of drugs in the control group of 41.75 ± 30.12 yuan. The levofloxacin application had favorable cost-effectiveness ratio. The difference in safety between 2 groups was not significant.

Conclusion:

The application of levofloxacin is safe, effective, and low-cost regimen for postureteroscopic lithotripsy infection prevention.
Prognostic value of O6-methylguanine-DNA methyltransferase hypermethylation and expression in head and neck cancer: A systematic review and meta-analysis
Authors: Yang Huiwen , Zhou Liuqing , Yang Fan , Chen Jingcai , Wang Yanjun
Published: April 2023

Background:

O6-methylguanine-DNA methyltransferase (MGMT) is a DNA repair enzyme that maintains the stability of genetic information. MGMT is a strong prognostic biomarker in patients with glioblastoma. However, the effect of its gene hypermethylation and expression on the survival rate of head and neck cancer (HNC) patients is still disputed. Therefore, we conducted a meta-analysis to evaluate the prognostic value of MGMT hypermethylation and expression in HNC patients.

Methods:

This meta-analysis was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2020 guidelines and was registered at the International Prospective Register of Systematic Reviews (CRD42021274728). Literature related to the survival rate of HNC patients and MGMT was systematically searched in PubMed, Embase, The Cochrane Library and Web of Science electronic databases (published from inception to February 1, 2023). The association was evaluated by the combined hazard ratio (HR) and related 95% confidence interval (CI). Two authors independently screened all records and extracted the data. The certainty of evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation system. All of the statistical tests used in this meta-analysis were conducted with Stata 12.0 software.

Results:

We included 5 studies with 564 HNC patients for the meta-analysis. All of the included patients were primary tumors and underwent surgical resection without prior radiotherapy or chemotherapy therapy. No significant heterogeneity was noted between MGMT and overall survival, MGMT and disease-free survival, and a fixed-effects model was used. HNC patients with MGMT hypermethylation and low expression had a poor prognosis, with pooled HR for overall survival (HR = 1.23, 95% CI: 1.10–1.38, P < .001) and disease-free survival (HR = 2.28, 95% CI: 1.45–3.58, P < .001). Subgroup analysis stratified by molecular abnormalities, such as hypermethylation or low expression, showed similar results. The insufficient number of trials included in our study encountered high risk of bias and may increase the deviation of the final meta-analysis results.

Conclusion:

HNC patients with MGMT hypermethylation and low expression were more likely to exhibit poorer survival. MGMT hypermethylation and low expression can predict survival in patients with HNC.
Important Factors to Expect the Outcome After Intracerebral Hemorrhage
Authors: Albakr Aishah , Almatar Ahmad , AlFajri Abdullah , Zafar Azra , Nazish Saima , Shahid Rizwana , AlJaafari Danah , Soltan Nehad , Alarfaj Zainab , Al Ghamdi Omar , Alfilw Suad , Abdelhady Ahmed , Albaker Waleed
Published: April 2023

Background:

Intracerebral hemorrhage (ICH) has worse clinical outcomes than other stroke types. The risk factors contributing to ICH outcomes are not entirely understood, and published literature from Saudi Arabia on ICH outcomes is limited. Our goal was to study the specific clinical and imaging determinants of ICH outcomes.

Methods:

We retrospectively retrieved all patients with spontaneous ICH (SICH) from a prospective King Fahd Hospital University registry between 2017 and 2019. The clinical characteristics of ICH events and data on clinical outcomes (6 to 12 mo) were recorded. Groups of patients with a favorable modified Rankin Scale of 0 to 2 and nonfavorable outcomes of a modified Rankin Scale of 3 to 6 were investigated. The relationship between the clinical characteristics of the SICH event and its outcomes was assessed using linear and logistic regression analyses.

Results:

A total of 148 patients with a mean age of 60.3 years (±15.2) and a median follow-up of 9 months were included. Unfavorable outcomes were reported in 98 patients (66.2%). The ICH event variables associated with unfavorable outcomes were impaired renal function, Glasgow Coma Score <8, hematoma volume, hematoma expansion, and intraventricular extension (IVE).

Conclusions:

Our study demonstrated important clinical and radiologic features in patients with ICH that may affect their clinical long-term functional outcomes. A larger multicenter study is required to validate our results and evaluate the methods to improve health care in patients with SICH.
Acute Mania and Psychosis in the Context of Primary Adrenal Insufficiency: A Systematic Review of the Literature
Authors: Ovakimyan Andrew , Patel Neal A. , Brown Nolan J. , Reardon Taylor , Fote Gianna , Gendreau Julian
Published: April 2023

Background:

Given the sparse nature of acute mania or psychosis in primary adrenal insufficiency (PAI), physicians may not be aware of the association of these two entities.

Objective:

To conduct a systematic review of the literature for the purpose of identifying all studies reporting mania and/or psychosis in individuals with PAI.

Method:

We conducted a systematic review according to PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines using the PubMed, Embase, and Web of Science databases from June 22, 1970 to June 22, 2021, for the purpose of identifying all studies reporting instances of mania or psychosis associated with PAI.

Results:

We identified nine case reports featuring nine patients (Mage = 43.3 years, male = 44.4%) over eight countries that fit our inclusion/exclusion criteria. Eight (89%) of the patients had experienced psychosis. Manic and/or psychotic symptom resolution was achieved in 100% of the cases, of which steroid replacement therapy was efficacious in seven (78%) cases and was sufficient in six (67%).

Conclusion:

Acute mania and psychosis in the context of PAI is a very rare presentation of an already uncommon disease. Resolution of acute psychiatric change is reliably achieved with the correction of underlying adrenal insufficiency.
Impact of a High Observation Trauma Protocol on Patients with Isolated Traumatic Brain Injury
Authors: Hamlin Sean , Alexander Rosalyn , Hayes Kathryn , Szoke AnnMarie , Benton Adam , Wilde-Onia Rebecca , Castillo Roberto , Thomas Peter , Cipolla James , Braverman Maxwell A
Published: April 2023

Background:

Nationally, the volume of geriatric falls with intracranial hemorrhage (ICH) is increasing. Our institution began observing patients with ICH, a GCS ≥ 14, and no midline shift or intraventricular hemorrhage with hourly neurologic examination outside the ICU in a high observation trauma (HOT) protocol. We first excluded patients on anticoagulants/antiplatelets (HOT I), then included antiplatelets and warfarin (HOT II) and finally included direct oral anticoagulants (HOT III). Our hypothesis is that HOT protocol safely reduces ICU utilization and creates cost savings in this patient population.

Study Design:

Our institutional trauma registry was retrospectively queried for all patients on HOT protocol. Patients were stratified based on date of admission: HOT I (2008-2014), HOT II (2015-2018) and HOT III (2019-2021). Demographics, anticoagulant use, injury characteristics, lengths of stay (LOS), incidence of neuro-intervention, and mortality.

Results:

Over the study period, 2343 patients were admitted, including HOT I (n=939), HOT II (n=794), and HOT III (n=610). Of these patients, 331 (35%), 554 (70%), and 495 (81%) were admitted to the floor under HOT protocol. HOT patients required neurointervention in 3.0%, 0.5% and 0.4% of cases over HOT I, II, and III, respectively. Mortality among HOT protocol patients was found to be 0.6% in HOT I, 0.9% in HOT II and 0.2% in the HOT III cohort (p=0.33).

Conclusion:

Across the study period, ICU utilization decreased without an increase in neurosurgical intervention or mortality indicating the efficacy of the HOT selection criteria in identifying appropriate candidates for stepdown admission and high observation trauma protocol.
Investigation and analysis of the clinical application of Perampanel in the Southeast of China
Authors: Li Lingqi , Huang Yan , Ma Lei , Shao Zhiyu
Published: April 2023

ABSTRACT Objective: The aim of this study was to investigate the clinical trials of Perampanel(PER)at the First affiliated Hospital of Xiamen University (FAHXU). Recommendations have been developed for the use of Perampanel in clinical practice. Design: A retrospective single-center validation study. Setting A tertiary general hospital in Xiamen, a city located on the southeastern coast of China. Participants A total of 831 prescriptions were included for 188 patients who were treated with Perampanel. Outcome measures Record the patient's medication, including the diagnosis of the patient's disease, the dose, course of medication, and the combination of medication, analyze the characteristics of the drug population and the medication unreasonableness by comparing the drug instructions and referring to relevant literature and guidelines. Results PER was mainly used in Neurology. Epilepsy is the most common condition prescribed. There were 119 cases of inconsistent drug indications, 56 inappropriate dosing frequency, 3 inconsistent dose, and 6 inconsistent dose adjustment intervals. Conclusion There is an improper use of PER within the FAHXU. Greater attention should be paid to changes in patients'condition and observation of discomfort following medication administration. Monitoring of PER use should be further enhanced. A rational drug evaluation system should be established to promote the rational use of PER.
Emergence of belief-like representations through reinforcement learning
Authors: Hennig Jay A. , Romero Pinto Sandra A. , Yamaguchi Takahiro , Linderman Scott W. , Uchida Naoshige , Gershman Samuel J.
Published: April 2023

To behave adaptively, animals must learn to predict future reward, or value. To do this, animals are thought to learn reward predictions using reinforcement learning. However, in contrast to classical models, animals must learn to estimate value using only incomplete state information. Previous work suggests that animals estimate value in partially observable tasks by first forming “beliefs”—optimal Bayesian estimates of the hidden states in the task. Although this is one way to solve the problem of partial observability, it is not the only way, nor is it the most computationally scalable solution in complex, real-world environments. Here we show that a recurrent neural network (RNN) can learn to estimate value directly from observations, generating reward prediction errors that resemble those observed experimentally, without any explicit objective of estimating beliefs. We integrate statistical, functional, and dynamical systems perspectives on beliefs to show that the RNN’s learned representation encodes belief information, but only when the RNN’s capacity is sufficiently large. These results illustrate how animals can estimate value in tasks without explicitly estimating beliefs, yielding a representation useful for systems with limited capacity.

Author Summary

Natural environments are full of uncertainty. For example, just because my fridge had food in it yesterday does not mean it will have food today. Despite such uncertainty, animals can estimate which states and actions are the most valuable. Previous work suggests that animals estimate value using a brain area called the basal ganglia, using a process resembling a reinforcement learning algorithm called TD learning. However, traditional reinforcement learning algorithms cannot accurately estimate value in environments with state uncertainty (e.g., when my fridge’s contents are unknown). One way around this problem is if agents form “beliefs,” a probabilistic estimate of how likely each state is, given any observations so far. However, estimating beliefs is a demanding process that may not be possible for animals in more complex environments. Here we show that an artificial recurrent neural network (RNN) trained with TD learning can estimate value from observations, without explicitly estimating beliefs. The trained RNN’s error signals resembled the neural activity of dopamine neurons measured during the same task. Importantly, the RNN’s activity resembled beliefs, but only when the RNN had enough capacity. This work illustrates how animals could estimate value in uncertain environments without needing to first form beliefs, which may be useful in environments where computing the true beliefs is too costly.
Improved predictive diagnosis of diabetic macular edema based on hybrid models: an observational study
Authors: Hughes-Cano JA , Quiroz-Mercado H , Hernández-Zimbrón LF , García-Franco R , Mijangos JF Rubio , López-Star E , García-Roa M , Lansingh VC , Olivares-Pinto U , Thébault SC
Published: April 2023

Diabetic Macular Edema (DME) is the most common sight-threatening complication of type 2 diabetes. Our goal was to develop an alternative method to optical coherence tomography (OCT) for DME diagnosis by introducing spectral information derived from spontaneous electroretinogram (ERG) signals as a single input or combined with eye fundus. To this end, an observational study was completed (n = 233 participants). Basal ERGs were used to generate scalograms and spectrograms via Wavelet and Fourier transforms, respectively. Using transfer learning, distinct Convolutional Neural Networks (CNN) were trained as classifiers for DME using OCT, scalogram, spectrogram, and fundus images. Input data were randomly split into training and test sets with a proportion of 80 % to 20 %, respectively. The top performers for each input type were selected, OpticNet-71 for OCT and DenseNet-201 for fundus and non-evoked ERG-derived scalograms, to generate a combined model by assigning different weights for each of the selected models. Model validation was performed using a dataset alien to the training phase of the models. None of the models powered by non-evoked ERG-derived input performed well. Metrics of the best hybrid models were all above 0.81 for fundus combined with non-evoked ERG-derived information; and above 0.85 for OCT combined with non-evoked ERG-derived scalogram images. These data show that the spontaneous ERG-based model improves all the performance metrics of the fundus and OCT-based models, with the exception of sensitivity for the OCT model, to predict DME. Combining non-evoked ERG with OCT represents an improvement to the existing OCT-based models, and combining non-evoked ERG with fundus is a reliable and economical alternative for the diagnosis of DME in underserved areas where OCT is unavailable.

Author summary

Providing an alternative diagnostic method to those that already exist for diabetic macular edema (DME) that is reliable and physically and economically accessible is needed in places where optical coherence tomography (OCT) is unavailable. In this work, we combined artificial intelligence (AI) classifying techniques with information from a newly introduced signal that can be captured in a non-invasive manner, the spontaneous oscillations of the electroretinogram (ERG). We found that if these signals alone are ineffective in diagnosing DME cases, they improve the performance of AI models based on either eye fundus or OCT in the prediction of DME. We therefore conclude that combining spontaneous ERG with fundus, which is a basic optometric test even in underserved areas, represents a reliable alternative to OCT for the diagnosis of DME. Also, combining OCT with spontaneous ERG signals will help ameliorate the diagnosis of DME.
Comparative Effectiveness of mRNA-1273 and BNT162b2 COVID-19 Vaccines in Immunocompromised Individuals: A Systematic Review and Meta-Analysis Using the GRADE Framework
Authors: Wang Xuan , Haeussler Katrin , Spellman Anne , Phillips Leslie E. , Ramiller Allison , Bausch-Jurken Mary T. , Sharma Pawana , Krivelyova Anna , Vats Sonam , Van de Velde Nicolas
Published: April 2023

Introduction

Despite representing only 3% of the US population, immunocompromised (IC) individuals account for nearly half of the COVID-19 breakthrough hospitalizations. IC individuals generate a lower immune response following vaccination in general, and the US CDC recommended a third dose of either mRNA-1273 or BNT162b2 COVID-19 vaccines as part of their primary series. Influenza vaccine trials have shown that increasing dosage could improve effectiveness in IC populations. The objective of this systematic literature review and pairwise meta-analysis was to evaluate the clinical effectiveness of mRNA-1273 (50 or 100 mcg/dose) versus BNT162b2 (30 mcg/dose) in IC populations using the GRADE framework.

Methods

The systematic literature search was conducted in the World Health Organization COVID-19 Research Database. Studies were included in the pairwise meta-analysis if they reported comparisons of mRNA-1273 and BNT162b2 in IC individuals ≥18 years of age; outcomes of interest were SARS-CoV-2 infection, hospitalization due to COVID-19, and mortality due to COVID-19. Risk ratios (RR) were pooled across studies using random-effects meta-analysis models. Outcomes were also analyzed in subgroups of patients with cancer, autoimmune disease, and solid organ transplant. Risk of bias was assessed for randomized and observational studies using the Risk of Bias 2 tool and the Newcastle-Ottawa Scale, respectively. Evidence was evaluated using the GRADE framework.

Results

Overall, 22 studies were included in the pairwise meta-analysis. Compared with BNT162b2, mRNA-1273 was associated with significantly reduced risk of SARS-CoV-2 infection (RR 0.87, 95% CI 0.79–0.96;P=0.0054;I2=61.9%), COVID-19–associated hospitalization (RR 0.83, 95% CI 0.76–0.90;P<0.0001;I2=0%), and COVID-19–associated mortality (RR 0.62, 95% CI 0.43–0.89;P=0.011;I2=0%) in IC populations. Results were consistent across subgroups. Because of sample size limitations, relative effectiveness of COVID-19 mRNA vaccines in IC populations cannot be studied in randomized trials and evidence certainty among comparisons was type 3 (low) and 4 (very low), reflecting potential biases in observational studies.

Conclusion

This GRADE meta-analysis based on a large number of consistent observational studies showed that the mRNA-1273 COVID-19 vaccine is associated with improved clinical effectiveness in IC populations compared with BNT162b2.
Association Between the Degree of Vertebrobasilar Stenosis, Location, Infarction Pattern and QMRA Flow State
Authors: Ballout Ahmad A. , Huang Brendan , Oh Seok Yoon , Black Karen , Sideras Panagiotis , Arora Rohan , Yaghi Shadi , Katz Jeffrey M. , Libman Richard B.
Published: April 2023

Background and Purpose

The relationship between the degree and location of vertebrobasilar stenosis and QMRA distal-flow status is uncertain. Our aim was to investigate the relationship between QMRA distal-flow status with degree and location of vertebrobasilar stenosis.

Methods

We retrospectively reviewed patients who presented with acute ischemic stroke, had neurovascular imaging demonstrating ≥50% stenosis of extracranial or intracranial vertebral or basilar arteries, and QMRA performed within one year of stroke, between 2009 and 2021. Standardized methods were used to measure the degree of stenosis and to dichotomize vertebrobasilar distal-flow status. Patients were grouped based on the involved artery and the location and severity of disease. P-values were calculated using chi-squared analysis and Fisher exact test with statistical significance defined as p <0.05.

Results

Sixty-nine patients met study inclusion, consisting of 31 with low distal-flow and 38 with normal distal-flow states. Low distal-flow states were found exclusively in patients with severe stenosis or occlusion; however, severe stenosis or occlusion was poorly predictive of distal-flow status as nearly half of these patients had normal flow states (47%). Bilateral vertebral disease was significantly associated with low distal-flow states compared to patients with unilateral vertebral (70.8% versus 14.3%; p = 0.01), isolated basilar (70.8% versus 28.6%; p = 0.01), or mixed (71.4% versus 47.1%; p = 0.01) disease.

Conclusions

Severe stenosis of ≥70% may mark the minimal threshold required to cause hemodynamic insufficiency in the posterior circulation, but nearly half of these patients may remain hemodynamically sufficient. The presence of bilateral vertebral stenosis resulted in a five-fold increase in the probability of QMRA low distal-flow status compared to unilateral vertebral disease. Our findings may have implications for the design of future treatment trials of endovascular versus medical management that may use hemodynamic markers as inclusion criteria.
Planning optimal sequence for arteriovenous fistula creation in hemodialysis patients, using quality-of-life adjusted access patency
Authors: Kumar Manoj , Usulumarty Deepa , Brahmbhatt Ravi , Rangaraj Narayan , Noronha Santosh , Billa Viswanath
Published: April 2023

Objective

The study proposes a decision strategy for the choice of arm for placement of an arteriovenous fistula (AVF) in patients with kidney failure who undergo hemodialysis (HD). The possible surgical sites for placement of the AVF are located in the arm and at two locations in each arm, the wrist (distal AVF) and the elbow (proximal AVF). Recommendations are made for the location of the first AVF and subsequent ones, as needed.

Method

A retrospective analysis of AVFs created between 2015 and 2022 in patients at five HD centers was performed. The study uses qualityadjusted survival, parametric, and nonparametric survival methods. We conducted two surveys to assess the HD patient’s quality of life. In addition, the Cox proportional hazard model is used to suggest a patient-specific strategy. The survival functions are compared using the log-rank and Tarone-Ware tests.

Results

The results of the multivariate analysis showed that placing AVFs on the non-dominant arm leads to superior patient quality of life compared to the dominant arm. The quality-adjusted survival was also found to be better when AVFs were located on the non-dominant arm. Considering both these aspects and also clinical constraints on the sequence, the optimal sequence is found to be non-dominant distal followed by non-dominant proximal locations, followed by a similar sequence on the dominant hand if required.

Conclusion

The study identifies criteria for data-driven decision-making as to good locations for AVFs for Hemodialysis and supports clinical experience and practice in this matter.
Linezolid population pharmacokinetic model in plasma and cerebrospinal fluid among patients with tuberculosis meningitis
Authors: Abdelgawad Noha , Wasserman Sean , Abdelwahab Mahmoud Tareq , Davis Angharad , Stek Cari , Wiesner Lubbe , Black John , Meintjes Graeme , Wilkinson Robert J. , Denti Paolo
Published: April 2023

Background

Linezolid is being evaluated in novel treatment regimens for tuberculous meningitis (TBM). The pharmacokinetics of linezolid have not been characterized in this population, particularly in cerebrospinal fluid (CSF) where exposures may be affected by changes in protein concentration and rifampicin co-administration.

Methods

This was a sub-study of a phase 2 clinical trial of intensified antibiotic therapy for adults with HIV-associated TBM. Participants in the intervention groups received high-dose rifampicin (35 mg/kg) plus linezolid 1200 mg daily for 28 days followed by 600 mg daily until day 56. Plasma was intensively sampled, and lumbar CSF was collected at a single timepoint in a randomly allocated sampling window, within 3 days after enrolment. Sparse plasma and CSF samples were also obtained on day 28. Linezolid concentrations were analyzed using non-linear mixed effects modelling.

Results

30 participants contributed 247 plasma and 28 CSF linezolid observations. Plasma PK was best described by a one-compartment model with first-order absorption and saturable elimination. The typical value of maximal clearance was 7.25 L/h. Duration of rifampicin co-treatment (compared on day 3 versus day 28) did not affect linezolid pharmacokinetics. Partitioning between plasma and CSF correlated with CSF total protein concentration up to 1.2 g/L where the partition coefficient reached a maximal value of 37%. The equilibration half-life between plasma and CSF was estimated at ∼3.5 hours.

Conclusion

Linezolid was readily detected in CSF despite co-administration of the potent inducer rifampicin at high doses. These findings support continued clinical evaluation of linezolid plus high-dose rifampicin for the treatment of TBM in adults.