bluuebunny/crossref_metadata_2025 huggingface dataset:
Isolated Abducens Nerve Palsy in a Patient With COVID-19
Authors: Manolopoulos Apostolos , Katsoulas Georgios , Kintos Vasileios , Koutsokera Maria , Lykou Christina , Lapaki Konstantina-Maria , Acquaviva Pascua T.
Published: December 2021

Introduction:

The pandemic of coronavirus disease 2019 (COVID-19) stands as a major global health and social burden. As cases are growing, several other symptoms, besides the typical respiratory ones, are emerging. The involvement of the nervous system is increasingly recognized with manifestations ranging from hyposmia to meningoencephalitis and cranial neuropathies.

Case Report:

We report the case of a 41-year-old female patient who presented to the emergency department complaining of diplopia and headache over the last 2 days. She denied any medical history, as well as any other neurological or respiratory symptom. A detailed neurological and ophthalmological examination revealed a limitation to the abduction of the right eye due to palsy of the right lateral rectus muscle causing painless, horizontal diplopia in the right gaze. The computed tomography of the brain was normal. Based on the detected lymphopenia, she was tested for COVID-19 and was positive. The cerebrospinal fluid analysis showed no abnormalities, while also a repeated head computed tomography was similarly normal. The patient received no specialized medical treatment, and after 6 days, she was discharged home having a minimal degree of persistent diplopia. Two weeks later, brain magnetic resonance imaging was performed that was similarly unrevealing.

Conclusions:

Isolated abducens nerve palsy can be the only presenting symptom in COVID-19. Although several pathophysiological mechanisms have been proposed, the exact nature of this manifestation has not been clarified yet. Vigilance is required by neurologists to detect and manage patients with such subtle clinical presentations.
Reversible Cerebral Vasoconstriction Syndrome in the Setting of COVID-19 and Pleomorphic Sarcoma
Authors: Harahsheh Ehab , Gritsch David , Mbonde Amir , Apolinario Michael , Hoxworth Joseph M. , Demaerschalk Bart M.
Published: December 2021

Introduction:

Reversible cerebral vasonstriction syndrome (RCVS) is an increasingly recognized clinical and radiologic syndrome. However, it has been rarely reported in the setting of the novel coronavirus disease-2019 (COVID-19) infection or sarcomatous tumors. RCVS might be the initial manifestations of COVID-19 infection or noncatecholamine producing masses including sarcoma.

Case Report:

A 44-year-old male who developed COVID-19–related symptoms followed by rapid onset of severe headaches in the setting of persistently elevated blood pressure (BP). Brain imaging showed multifocal arterial narrowing in the anterior and posterior circulation consistent with RCVS. Serial imaging demonstrated resolution of the arterial narrowing after BP control was achieved with improvement in the patient’s headaches. Further investigation for secondary causes of the patient’s elevated BP revealed a right renal mass, and the patient underwent right nephrectomy, and the biopsy results confirmed the diagnosis of pleomorphic sarcoma.

Conclusion:

Our case suggests a possible association between severe acute respiratory syndrome coronavirus 2 with development of RCVS, but further studies are needed to validate this observation, establish a causal relationship and define a pathophysiological mechanism. Considering tumors other than catecholamine-producing masses as a potential risk factor for developing RCVS might lead to earlier detection and treatment of any underlying malignancy in patients whom the main and sole presentation could be RCVS.
Platelet-to-Neutrophil Ratio is Related to Hemorrhagic Transformation in Patients With Acute Cerebral Infarction
Authors: Liu Fan , Jin Ming , Zhang Zhuo , Gao Jia , Wang Xiaopeng
Published: December 2021

Background:

As a common complication of cerebral infarction, hemorrhagic transformation (HT) often indicates a worse clinical outcome. The aim of this study was to explore the relationship between the platelet-to-neutrophil ratio (PNR) and HT in patients with acute cerebral infarction.

Methods:

Patients with HT after acute cerebral infarction were enrolled in the HT group. Matched patients with acute cerebral infarction without HT were enrolled at the same time. All patients included in this study did not receive reperfusion therapy. The PNR was obtained on the second day of admission. Multivariate logistic analysis was used to evaluate the relationship between the PNR and HT.

Results:

We collected data from a total of 137 patients: 61 patients with HT and 76 patients without HT. After adjusting for confounders, the PNR was independently associated with HT (odds ratio=0.922, 95% confidence interval: 0.891-0.955, P<0.05). The receiver operating characteristic curve demonstrated that the PNR could better predict HT (area under the curve=0.808, 95% confidence interval: 0.735-0.882, P<0.05). When the cut-off value of the PNR was 50.4765, the sensitivity was 70.5%, and the specificity was 82.9%. After stratifying the PNR to 50.4765, logistic analysis was performed again. The risk of HT in patients with a low PNR was 12.995 times that of patients with a high PNR. In patients without atrial fibrillation, the PNR was still independently related to HT.

Conclusions:

The PNR is a predictor of HT, and patients with a low PNR have a higher risk of HT.
Progressive Multifocal Leukoencephalopathy Misdiagnosed as Neuropsychiatric Systemic Lupus Erythematosus With a Catastrophic Outcome
Authors: Algahtani Hussein , Shirah Bader , Othman Leen , Almarri Abdullah Khaled , Alwafi Emad , Alassiri Ali H.
Published: December 2021

Introduction:

Progressive multifocal leukoencephalopathy (PML) is a rare infection of the central nervous system due to the reactivation of the John Cunningham polyomavirus. It is commonly a progressive fatal disease with worldwide distribution.

Case Report:

We describe a rare case of PML, which was misdiagnosed as neuropsychiatric systemic lupus erythematosus (SLE) with a catastrophic outcome due to delay in diagnosis with superadded cyclophosphamide therapy.

Conclusion:

There are several lessons taught from our case. Firstly, in patients with autoimmune disorders who are strongly immunosuppressed, the new onset of cognitive impairment and seizures should alert the treating physician to look carefully for PML. Secondly, in cases of SLE where the diagnosis of the cause of cognitive impairment and seizures is not clear, we suggest that immunosuppression should not be intensified until PML has clearly been ruled out. Lastly, multidisciplinary care in patients with suspected neuropsychiatric SLE including a neurologist, an infectious diseases consultant, a neuroradiologist, and a rheumatologist is needed.
Use of Diterpene Ginkgolides Meglumine Injection to Regulate Plasma Levels of PAI-1 and t-PA in Patients With Acute Atherosclerotic Cerebral Infarction
Authors: Chen Rui , Yan Luxia , Xie Peng , Tian Jisha , Zhao Ying , Liu Yue , Xu Jie , Wang Yuqian , Zhao Liandong
Published: December 2021

Background:

To: (i) explore the effect of diterpene ginkgolides meglumine injection (DGMI) on neurological deficit symptoms in acute atherosclerotic cerebral infarction (AACI) patients; (ii) measure the level of plasma plasminogen activator inhibitor (PAI)-1 and tissue plasminogen activator (t-PA).

Methods:

Eighty AACI patients were divided equally and randomly into the DGMI group and control group. In addition to basic treatment, the DGMI group was treated with DGMI (25 mg/d) for 14 days. The control group had basic treatment without DGMI. Before and after treatment, the degree of neurological deficit was assessed, thromboelastography undertaken, and plasma levels of PAI-1 and t-PA measured.

Results:

The National Institutes of Health Stroke Scale score of patients in the DGMI group after treatment was lower than that in the control group, and the Barthel Index was higher than that in the control group (P<0.05). Thromboelastography revealed that, in the DGMI group, the R value and K value after treatment were higher than before treatment, the angle and maximum amplitude value were lower than before treatment, and both were significant (P<0.05). Compared with the control group, the plasma PAI-1 level of patients in the DGMI group was lower than that in the control group, and the t-PA level was higher than that in the control group (P<0.05) after 14 days of treatment.

Conclusions:

DGMI may affect the activity of the blood coagulation and fibrinolysis system by regulating the plasma level of PAI-1 and t-PA, and improving neurological deficit symptoms. DGMI is important for improving the prognosis of patients with AACI.
Association of Changed Serum Brain Biomarkers With Perihematomal Edema and Early Clinical Outcome in Primary ICH Patients
Authors: Simani Leila , Ramezani Mahtab , Mohammadi Ehsan , Abbaszadeh Fatemeh , Karimialavijeh Ehsan , Pakdaman Hossein
Published: December 2021

Background:

Perihematomal edema (PHE) following primary intracranial hemorrhages (ICHs) affects the patient outcome. Also, serum biomarkers such as S100 calcium-binding protein B (S100B) and glial fibrillary acidic protein (GFAP) have been associated with ICHs outcome. We aimed to investigate the association between these biomarkers and PHE in ICH patients.

Methods:

In this cross-sectional study, patients with primary ICH between January 2020 and August 2020 were evaluated. All participants underwent spiral brain computed tomography scans upon admission, and 48 to 72 hours later and quantification of initial hematoma volume was performed. Serum level of matrix metalloproteinase-9 (MMP-9), vascular endothelial growth factor (VEGF), GFAP, and S100B on admission were measured by enzyme-linked immunosorbent assays. Acute clinical outcome was assessed by the modified-Rankin scale, National Institute of Health Stroke Scale (NIHSS), and ICH score.

Results:

Thirty-seven ICH patients (21 patients with a favorable outcome and 16 unfavorable) were studied. Compared with survival patients, nonsurvivor patients showed a higher serum level of MMP-9, VEGF, GFAP, and S100B (P<0.05). Scores of absolute PHE, edema expansion distance, and PHE growth rate in the nonsurvivor group were higher than the survivors (P<0.001). The regression model revealed that MMP-9, VEGF, ICH score, and hematoma volume were associated with the PHE growth rate. S100B and ICH score were associated with edema expansion distance.

Conclusions:

Our data showed that the serum level of molecular biomarkers was associated with higher PHE volume and PHE scores were higher in nonsurvival patients, suggesting it may have a pathogenic role in developing PHE after ICH.
Concurrent Cerebral, Splenic, and Renal Infarction in a Patient With COVID-19 Infection
Authors: Rigual Ricardo , Ruiz-Ares Gerardo , Rodriguez-Pardo Jorge , Fernández-Prieto Andrés , Navia Pedro , Novo Joan R. , Alonso de Leciñana María , Alonso-Singer Pablo , Fuentes Blanca , Díez-Tejedor Exuperio
Published: December 2021

Introduction:

Thrombotic events are potentially devastating complications of coronavirus disease 2019 (COVID-19) infection. Although less common than venous thromboembolism, arterial thrombosis has been reported in COVID-19 cohorts in almost 3% of patients. We describe a patient with COVID-19 infection and concurrent cerebral and noncerebral infarction.

Case Report:

A 53-year-old man with history of COVID-19 pneumonia was admitted to a primary stroke center for speech disturbances and left hemiplegia. Urgent laboratory tests showed a great increase of inflammatory and coagulation parameters as D-dimer, ferritin, interleukin-6 and C-reactive protein. Neuroimaging found occlusion of the M1 segment of the right middle cerebral artery with early signs of ischemic stroke. He received intravenous thrombolysis and mechanical thrombectomy. Abdominal computed tomography discovered a splenic infarction with hemorrhagic transformation and bilateral renal infarction. Urgent angiography showed an associated splenic pseudoaneurysm, which was embolized without complications. He was treated with intermediate-dose anticoagulation (1 mg subcutaneous enoxaparin/kg/24 h), acetylsalicylic acid 100 mg and 5 days of intravenous corticosteroids. In the following days, inflammatory markers decreased so anticoagulant treatment was stopped and acetylsalicylic acid 300 mg was prescribed. His condition improved and he was discharged to a rehabilitation facility on hospital day 30.

Conclusion:

In this case, a patient with multiple thrombotic events in the acute phase of COVID-19 infection, the delimitation of the inflammatory state through analytical markers as D-dimer helped to individualize the antithrombotic treatment (full anticoagulation or anticoagulation at intermediate doses plus antiplatelet treatment as used in our patient) and its duration. However, more data are needed to better understand the mechanisms and treatment of stroke in patients with COVID-19 infection.
Pharmacokinetics and Safety of the Abacavir/Lamivudine/Lopinavir/Ritonavir Fixed-Dose Granule Formulation (4-in-1) in Neonates: PETITE Study
Authors: Bekker Adrie , Rabie Helena , Salvadori Nicolas , du Toit Samantha , Than-in-at Kanchana , Groenewald Marisa , Andrieux-Meyer Isabelle , Kumar Mukesh , Cressey Ratchada , Nielsen James , Capparelli Edmund , Lallemant Marc , Cotton Mark F. , Cressey Tim R. ,   for the PETITE Study Team
Published: December 2021

Background:

Antiretroviral options for neonates (younger than 28 days) should be expanded. We evaluated the pharmacokinetics, safety, and acceptability of the "4-in-1" fixed-dose pediatric granule formulation of abacavir/lamivudine/lopinavir/ritonavir (30/15/40/10 mg) in neonates.

Methods:

The PETITE study is an ongoing phase I/II, open-label, single-arm, 2-stage trial conducted in South Africa. In stage 1, term neonates exposed to HIV on standard antiretroviral prophylaxis (nevirapine ± zidovudine) received single dose(s) of the 4-in-1 formulation, followed by intensive pharmacokinetic sampling and safety assessments. At each PK visit, blood was drawn after an observed dose at 1, 2, 4, 8, and 12 hours postdose. In this study, we have reported the planned interim pharmacokinetic and safety analysis after completion of the single-dose administration.

Results:

Sixteen neonates, with a median (range) birth weight of 3130 g (2790–3590 g), completed 24 pharmacokinetic visits. The 4-in-1 formulation imposed relatively high doses of abacavir [8.6 mg/kg (6.6–11.4)] and lamivudine [4.3 mg/kg (3.3–5.7)] but lower doses of lopinavir [11.5 mg/kg (8.8–15.2)]. The geometric means (GM, 90% CI) AUC0–12 of abacavir, lamivudine, and lopinavir were 29.87 (26.29–33.93), 12.61 (10.72–14.83), and 3.49 (2.13–5.72) µg.h/mL, respectively. Lopinavir GM AUC0–12 was below the predefined target (20–100 µg.h/mL), and ritonavir concentrations were only detectable in 4 of the 120 (3%) samples. No adverse events were related to study drugs. No neonate had difficulty swallowing the 4-in-1 formulation.

Conclusions:

The high doses of abacavir and lamivudine (in mg/kg) and AUCs were safe, and the formulation was well tolerated; however, lopinavir/ritonavir exposures were extremely low, preventing its use in neonates use in neonates. Alternative pediatric solid antiretroviral formulations must be studied in neonates.
HIV and Herpes Simplex Virus Type 2 Incidence Among Adolescent Mothers in South Africa: A Longitudinal Analysis of HIV Prevention Trials Network 068 Data
Authors: Groves Allison K. , Bhushan Nivedita L. , Stoner Marie C. D. , Gómez-Olivé Francesc X. , Kahn Kathleen , Pettifor Audrey E.
Published: December 2021

Background:

Adolescent motherhood is common in South Africa and occurs against a backdrop of high HIV risk. While childbearing during adolescence may result in social and economic strain that may negatively impact health, there has been limited study of whether adolescent motherhood increases the risk of HIV or herpes simplex virus type 2 (HSV-2) acquisition or engagement in high-risk sexual partnerships.

Setting:

Data are from HIV Prevention Trials Network 068, a longitudinal conditional cash transfer study of adolescent girls and young women (age, 13–23) in rural South Africa.

Methods:

We used survival analysis to estimate hazard ratios to determine if adolescent motherhood (live birth before 20 years) predicted incident HIV and incident HSV-2 and generalized estimating equations for behavioral risk ratios to determine if adolescent motherhood was associated with transactional sex and age-disparate partnerships.

Results:

Of 2452 adolescent girls and young women who were HIV negative at baseline, 5% were adolescent mothers; 16% were adolescent mothers by the end of the study period. After controlling for covariates, adolescent motherhood predicted incident HSV-2 acquisition [ adjusted hazard ratios, 1.30; 95% confidence interval (CI): 1.01 to 1.95] but not HIV acquisition ( adjusted hazard ratios, 1.19; 95% CI, 0.76 to 1.86). Adolescent motherhood was also associated with being in an age-disparate partnership (adjusted risk ratio, 1.30; 95% CI: 1.07 to 1.58) but not transactional sex.

Conclusion:

Adolescent motherhood increased the risk of HSV-2 and engagement in age-disparate partnerships, both known risk factors for HIV infection. Sexually transmitted infection screening and/or tailored combination HIV prevention interventions that account for the context of adolescent motherhood are critical to maximize adolescent mothers' long-term health and to meet UNAIDS 95-95-95 targets by 2030.
Simultaneous Zygomatic Osteotomies With Reduction Mandibuloplasty – An Approach to Mid- and Lower-Facial Feminization in the Transfeminine Patient
Authors: Kotha Vikas S. , Kanuri Arjun , Mandelbaum Max , Lakhiani Chrisovalantis , Hung Rex W. , Wang Jing , Rashid Waleed , Chao Jerry W.
Published: December 2021

Background:

Facial feminization surgery (FFS) is effective at treating gender dysphoria associated with anthropometrically masculine facial features. For many transgender women, FFS is a crucial component of the gender transition process. The purpose of this study is to report our experience with a pragmatic technique for simultaneous mid- and lower-face feminization by zygomatic osteotomy malarplasty and reduction mandibuloplasty.

Methods:

The technique to perform zygomatic osteotomy malarplasty and reduction mandibuloplasty is described, utilizing harvested bone from the mandible for bone grafting the zygomatic osteotomy gap. A retrospective chart review was performed for patients who underwent simultaneous middle and lower FFS using the described technique. Independent reviewers evaluated cropped preoperative and postoperative photographs of the mid and lower face and assigned each photograph a “femininity score.”

Results:

Seventeen transgender women underwent simultaneous zygomatic osteotomy malarplasty and reduction mandibuloplasty over the study period with adequate follow-up (average 11.1 months). Transient nerve weaknesses were the primary complications noted. A statistically significant improvement in femininity score was reported in postoperative photographs, compared to preoperative photographs (P < 0.01).

Conclusions:

The technique described in this study is an effective application of craniofacial approaches and techniques for feminizing the facial skeleton in transgender women by utilizing harvested mandibular bone for simultaneous malarplasty.
Social withdrawal as a trans-diagnostic predictor of short-term remission: a meta-analysis of five clinical cohorts
Authors: Oliva Vincenzo , Fanelli Giuseppe , Kasper Siegfried , Zohar Joseph , Souery Daniel , Montgomery Stuart , Albani Diego , Forloni Gianluigi , Ferentinos Panagiotis , Rujescu Dan , Mendlewicz Julien , Kas Martien J. , De Ronchi Diana , Fabbri Chiara , Serretti Alessandro
Published: December 2021

Social withdrawal is an early manifestation of several neuropsychiatric disorders, and it is characterised by a gradual disengagement from social interactions, potentially leading to complete isolation. This study investigated the association between social withdrawal at baseline and short-term symptom remission in five independent cohorts, including patients with major depressive disorder (MDD), bipolar spectrum disorders, and schizophrenia. Measures of social withdrawal were derived in each study, and clinical remission was estimated based on the psychopathological severity assessed after short-term psychopharmacological treatment (12 weeks). Logistic regression was performed in each sample, adjusting for age and baseline psychopathological severity residualised for social withdrawal. Results were then meta-analysed across samples within a random-effect framework. A total of 4461 patients were included in the analyses (3195 patients with MDD, 655 with bipolar spectrum disorders and 611 with schizophrenia). The meta-analysis showed that higher baseline levels of social withdrawal were associated with a decreased likelihood of short-term remission (ORadj = 0.67, 95% CI, 0.58–0.79, P = 5.28 × 10−7), with the strongest effect in patients with schizophrenia. Overall, our study highlighted the need to address social withdrawal in the early phases of the disease to promote symptom remission in patients with major psychiatric disorders. Understanding the neurobiology underlying social withdrawal may aid the development of medications that can specifically reverse social impairment, thereby fostering clinical remission.
SARS-CoV-2 infection dynamics revealed by wastewater sequencing analysis and deconvolution
Authors: Schumann Vic-Fabienne , de Castro Cuadrat Rafael Ricardo , Wyler Emanuel , Wurmus Ricardo , Deter Aylina , Quedenau Claudia , Dohmen Jan , Faxel Miriam , Borodina Tatiana , Blume Alexander , Meixner Martin , Grau José Horacio , Liere Karsten , Hackenbeck Thomas , Zietzschmann Frederik , Gnirss Regina , Böckelmann Uta , Uyar Bora , Franke Vedran , Barke Niclas , Altmüller Janine , Rajewsky Nikolaus , Landthaler Markus , Akalin Altuna
Published: December 2021

The use of RNA sequencing from wastewater samples is a valuable way for estimating infection dynamics and circulating lineages of SARS-CoV-2. This approach is independent from testing individuals and can therefore become the key tool to monitor this and potentially other viruses. However, it is equally important to develop easily accessible and scalable tools which can highlight critical changes in infection rates and dynamics over time across different locations given sequencing data from wastewater. Here, we provide an analysis of lineage dynamics in Berlin and New York City using wastewater sequencing and present PiGx SARS-CoV-2, a highly reproducible computational analysis pipeline with comprehensive reports. This end-to-end pipeline includes all steps from raw data to shareable reports, additional taxonomic analysis, deconvolution and geospatial time series analyses. Using simulated datasets (in silico generated and spiked-in samples) we could demonstrate the accuracy of our pipeline calculating proportions of Variants of Concern (VOC) from environmental as well as pre-mixed samples (spiked-in). By applying our pipeline on a dataset of wastewater samples from Berlin between February 2021 and January 2022, we could reconstruct the emergence of B.1.1.7(alpha) in February/March 2021 and the replacement dynamics from B.1.617.2 (delta) to BA.1 and BA.2 (omicron) during the winter of 2021/2022. Using data from very-short-reads generated in an industrial scale setting, we could see even higher accuracy in our deconvolution. Lastly, using a targeted sequencing dataset from New York City (receptor-binding-domain (RBD) only), we could reproduce the results recovering the proportions of the so-called cryptic lineages shown in the original study. Overall our study provides an in-depth analysis reconstructing virus lineage dynamics from wastewater, and that our tool can be used to identify new mutations and to detect any emerging new lineages with different amplification and sequencing methods. Our approach can support efforts to establish continuous monitoring and early-warning projects for detecting SARS-CoV-2 or any other pathogen.
Estimating the increase in reproduction number associated with the Delta variant using local area dynamics in England
Authors: Abbott Sam ,   CMMID COVID-19 Working Group, Kucharski Adam J. , Funk Sebastian
Published: December 2021

Background

Local estimates of the time-varying effective reproduction number (Rt) of COVID-19 in England became increasingly heterogeneous during April and May 2021. This may have been attributable to the spread of the Delta SARS-CoV-2 variant. This paper documents real-time analysis that aimed to investigate the association between changes in the proportion of positive cases that were S-gene positive, an indicator of the Delta variant against a background of the previously predominant Alpha variant, and the estimated time-varying Rt at the level of upper-tier local authorities (UTLA).

Method

We explored the relationship between the proportion of samples that were S-gene positive and the Rt of test-positive cases over time from the 23 February 2021 to the 25 May 2021. Effective reproduction numbers were estimated using the EpiNow2 R package independently for each local authority using two different estimates of the generation time. We then fit a range of regression models to estimate a multiplicative relationship between S-gene positivity and weekly mean Rt estimate.

Results

We found evidence of an association between increased mean Rt estimates and the proportion of S-gene positives across all models evaluated with the magnitude of the effect increasing as model flexibility was decreased. Models that adjusted for either national level or NHS region level time-varying residuals were found to fit the data better, suggesting potential unexplained confounding.

Conclusions

Our results indicated that even after adjusting for time-varying residuals between NHS regions, S-gene positivity was associated with an increase in the effective reproduction number of COVID-19. These findings were robust across a range of models and generation time assumptions, though the specific effect size was variable depending on the assumptions used. The lower bound of the estimated effect indicated that the reproduction number of Delta was above 1 in almost all local authorities throughout the period of investigation.
Antimicrobial stewardship among Nigerian children: A pilot study of the knowledge, attitude, and practices of prescribers at two tertiary healthcare facilities in Bayelsa State
Authors: Orubu Ebiowei S.F , Robert Faith O. , Emuren Leonard , Ifie-Ombeh Boboye
Published: December 2021

Antimicrobial stewardship (AMS), the evidence-based use of antimicrobials, is an effective strategy in controlling antimicrobial resistance (AMR) in humans by reducing the irrational use of antimicrobials. Stewardship in children is less studied. This study assessed the knowledge, attitude, and practice of physicians prescribing antibiotics to children in Bayelsa State, Nigeria to identify gaps in AMS and possible solutions. Following ethical approval, a semi-structured questionnaire was distributed among 40 paediatricians and gynaecologists at the two public tertiary healthcare facilities in Bayelsa State – the Niger Delta University Teaching Hospital and the Federal Medical Centre – for self-completion. Responses were expressed as percentages and analyzed using Bloom’s cutoffs. The Capability, Opportunity, Motivation, and Behaviour (COM-B) model was employed to identify gaps for intervention in prescribing behavior with gaps in each component identified by aggregate scores <80%. Perceived approaches to improve prescribing among 14 selected options were assessed using 5-point Likert scales and options with scores >90% rated the most acceptable. Questionnaires were administered from August to September 2021. The response rate was 68% (27/40). Participants were paediatricians (81%, 22/27) and gynaecologists (19%, 5/27). Antimicrobial Susceptibility Testing (AST) was not performed before antibiotic selection nine times out of 10 (89%, 24/27). In a third (37%, 10/27) of cases, 2-3 antibiotics were prescribed. The top three antibiotics, in rank order, were: cefuroxime or amoxicillin 41% (11/27); ciprofloxacin or amoxicillin 30% (8/27), and azithromycin (33%, 9/27). Aggregate COM-B scores were: capability, 74%; opportunity, 78%; and motivation, 87%. The most acceptable (100%, 27/27) options to improving antibiotic prescribing were: availability of resistance data, availability of guidelines, readily accessible microbiological data, and easy access to infectious disease physicians. There are gaps in knowledge of AMR and opportunity for rational prescribing. There is need for antimicrobial resistance data to promote pediatric AMS at the surveyed healthcare facilities.
Clinical Risk Factors for COVID-19 related Severe Outcome
Authors: Huang Chaorui C.
Published: December 2021

Background

We aimed to evaluate the risk factors for Coronavirus disease 2019 (COVID-19) related severe outcome in New York State (NYS) and proposed a method that could be used to inform future work to develop clinical algorithms and predict resource needs for COVID-19 patients.

Methods

We analyzed COVID-19 related hospital encounter and hospitalization in NYS from April 1st to November 17th, 2020, using Statewide Planning and Research Cooperative System (SPARCS) hospital discharge dataset. Logistic regression was performed to evaluate the risk factors for COVID-19 related in-hospital death using demographic variables, symptom, rapid clinical examination, and medical history of chronic co-morbid conditions. Receiver operating characteristic (ROC) curve was calculated, and cut-off points for predictors were selected to stage the risk of COVID-19 related fatal outcome.

Findings

Logistic regression analysis showed age was the greatest risk factor for COVID-19 related fatal outcome, which by itself achieved the diagnostic accuracy of 0.78 represented by the area under the ROC curve. By adding other demographic variables, dyspnea or hypoxemia and multiple chronic co-morbid conditions, the diagnostic accuracy was improved to 0.85. We selected cut-off points for predictors and provided a general recommendation to categorize the levels of risk for COVID-19 related fatal outcome.

Interpretation

We assessed risk factors associated with in-hospital COVID-19 mortality and identified cut-off points that might be used to categorize the level of risk. Further studies are warranted to evaluate laboratory tests and develop laboratory biomarkers to improve the diagnostic accuracy for early intervention.
Sexual risk among pregnant women at risk of HIV infection in Cape Town, South Africa: What does alcohol have to do with it?
Authors: Miller Amanda P. , Shoptaw Steven , Mvududu Rufaro , Mashele Nyiko , Coates Thomas J. , Bekker Linda-Gail , Essack Zaynab , Groenewald Candice , Peterson Zaino , Gorbach Pamina M. , Myer Landon , Joseph Davey Dvora L.
Published: December 2021

This study examines associations between alcohol use and HIV sexual risk among a cohort of HIV-uninfected pregnant women (n=1201) residing in a high HIV burden community in South Africa. Alcohol use was measured using a modified version of the Alcohol Use Disorder Identification Test (AUDIT). HIV sexual risk was measured through a composite variable of four risk factors: diagnosis with a STI, self-report of >1 recent sex partners, partner HIV serostatus (unknown or HIV+) and condomless sex at last sex. Any past year alcohol use prior to pregnancy was reported by half of participants (50%); 6.0% reported alcohol use during pregnancy. Alcohol use prior to pregnancy was associated with increased odds of being at high risk of HIV (aOR=1.33 for 2 risks and aOR=1.47 for 3 risks). In addition to reducing alcohol use, several other strategies to address HIV sexual risk in this population were identified.
Harbingers of Aggressive Prostate Cancer: Precision Oncology Case Studies
Authors: Cyrta Joanna , Prandi Davide , Arora Arshi , Hovelson Daniel H. , Sboner Andrea , Rodriguez Antonio , Fedrizzi Tarcisio , Beltran Himisha , Robinson Dan R. , Gopalan Anurandha , True Lawrence , Nelson Peter S. , Robinson Brian D. , Mosquera Juan Miguel , Tomlins Scott A. , Shen Ronglai , Demichelis Francesca , Rubin Mark A.
Published: December 2021

Primary prostate cancer (PCa) can show marked molecular heterogeneity. However, systematic analyses comparing primary PCa and matched metastases in individual patients are lacking. We aimed to address the molecular aspects of metastatic progression while accounting for heterogeneity of primary PCa.

In this pilot study, we collected 12 radical prostatectomy (RP) specimens from men who subsequently developed metastatic castration-resistant prostate cancer (mCRPC). We used histomorphology (Gleason grade, focus size, stage) and immunohistochemistry (IHC) (ERG and p53) to identify independent tumors and/or distinct subclones of primary PCa. We then compared molecular profiles of these primary PCa areas to matched metastatic samples using whole exome sequencing (WES) and amplicon-based DNA and RNA sequencing. Based on combined pathology and molecular analysis, seven (58%) RP specimens harbored monoclonal and topographically continuous disease, albeit with some degree of intra-tumor heterogeneity; four (33%) specimens showed true multifocal disease; and one displayed monoclonal disease with discontinuous topography. Early (truncal) events in primary PCa included SPOP p.F133V (one patient), BRAF p.K601E (one patient), and TMPRSS2:ETS rearrangements (nine patients). Activating AR alterations were seen in eight (67%) mCRPC patients, but not in matched primary PCa. Hotspot TP53 mutations, found in metastases from three patients, were readily present in matched primary disease. Alterations in genes encoding epigenetic modifiers were observed in several patients (either shared between primary foci and metastases or in metastatic samples only).

WES-based phylogenetic reconstruction and/or clonality scores were consistent with the index focus designated by pathology review in six out of nine (67%) cases. The three instances of discordance pertained to monoclonal, topographically continuous tumors, which would have been considered as unique disease in routine practice.

Overall, our results emphasize pathologic and molecular heterogeneity of primary PCa, and suggest that comprehensive IHC-assisted pathology review and genomic analysis are highly concordant in nominating the “index” primary PCa area.
Emergence of planar cell polarity from the interplay of local interactions and global gradients
Authors: Singh Divyoj , Ramaswamy Sriram , Jolly Mohit Kumar , Rizvi Mohd. Suhail
Published: December 2021

Planar cell polarity (PCP) – tissue-scale alignment of the direction of asymmetric localization of proteins at cell-cell interface – is essential for embryonic development and physiological functions. Abnormalities in PCP can lead to neural tube closure defects and misaligned hair follicles. Decoding the mechanism responsible for PCP establishment and maintenance remains a fundamental open question. While the roles of various molecules – broadly classified into “global” and “local” modules – have been well-studied, their necessity and sufficiency in explaining PCP and connecting their perturbations to experimentally observed patterns has not been examined. Here, we develop a minimal model that captures the proposed features of these modules – a global tissue-level gradient and local asymmetric distribution of protein complexes. Our model suggests that while polarity can emerge without a gradient, the gradient can provide the direction of polarity and maintain PCP robustly in presence of stochastic perturbations. We also recapitulated swirling patterns seen experimentally and features of domineering non-autonomy, using only three free model parameters - protein binding rate, concentration of proteins forming heterodimer across cell boundaries and gradient steepness. We explain how self-stabilizing asymmetric localizations in presence of tissue-level gradient can lead to robust PCP patterns and reveal minimal design principles for a polarized system.
Identifying potential key genes and existing drugs for Multiple sclerosis, Schizophrenia, and Autism- an in silico approach
Authors: Dey Sajal Kumar , Bhowmick Sushmita , Chakraborty Souvik
Published: December 2021

Nowadays, neurological conditions are a major concern as it not only preys on a patient’s health but also is a huge economic burden that is placed on the patient’s family. The diagnosis and treatment of disease sometimes cause methodological limitations. This is mainly common for individuals who have the signs of MS and schizophrenia (SZ). Patients suffering from multiple sclerosis are more likely to develop schizophrenia. Besides, a significant portion of patients who have been diagnosed with Autism Spectrum Disorder (ASD) later acquire the symptoms of Schizophrenia. In this study, we used bioinformatics tools to determine differentially expressed genes (DEGs) in all these diseases, and then we created a protein-protein interaction network using the online software STRING and identified 15 significant genes with the help of Cytohubba a plug-in tool in Cytoscape, the offline software (version3.8.2). We then used a drug-gene interaction database to conduct a drug-gene interaction study of the 15 hub genes and from there we identified 37 FDA-approved drugs. These findings may provide a new and common therapeutic approach for MS, SZ, and ASD therapy.
Mutated neuronal voltage-gated CaV2.1 channels causing familial hemiplegic migraine 1 increase the susceptibility for cortical spreading depolarization and seizures and worsen outcome after experimental traumatic brain injury
Authors: Terpolilli Nicole A. , Dolp R. , Waehner K. , Schwarzmaier S. M. , Török E. , Todorov Boyan , Ferrari Michel D. , van den Maagdenberg Arn M.J.M. , Plesnila Nikolaus
Published: December 2021

Patients suffering from familial hemiplegic migraine type 1 (FHM1) may have a disproportionally severe outcome after head trauma, but the underlying mechanisms are unclear. Hence, we subjected knock-in mice carrying the severer S218L or milder R192Q FHM1 gain-of-function missense mutation in the CACNA1A gene that encodes the α1A subunit of neuronal voltage-gated CaV2.1 (P/Q-type) calcium channels and their wild-type (WT) littermates to experimental traumatic brain injury (TBI) by controlled cortical impact (CCI) and investigated cortical spreading depolarizations (CSDs), lesion volume, brain edema formation, and functional outcome. After TBI, all mutant mice displayed considerably more CSDs and seizures than WT mice, while S218L mutant mice had a substantially higher mortality. Brain edema formation and the resulting increase in intracranial pressure was more pronounced in mutant mice, while only S218L mutant mice had larger lesion volumes and worse functional outcome. Here we show that gain of CaV2.1 channel function worsens histopathological and functional outcome after TBI in mice. This phenotype was associated with a higher number of CSDs, increased seizure activity, and more pronounced brain edema formation. Hence, our results suggest increased susceptibility for CSDs and seizures as potential mechanisms for bad outcome after TBI in FHM1 mutation carriers.
Neural basis for anxiety and anxiety-related physiological responses during a driving situation: An fMRI study
Authors: Sasaoka Takafumi , Harada Tokiko , Sato Daichi , Michida Nanae , Yonezawa Hironobu , Takayama Masatoshi , Nouzawa Takahide , Yamawaki Shigeto
Published: December 2021

While the exteroceptive and interoceptive prediction of a negative event increases a person’s anxiety in daily life situations, the relationship between the brain mechanism of anxiety and the anxiety-related autonomic response has not been fully understood. In this fMRI study, we examined the neural basis of anxiety and anxiety-related autonomic responses in a daily driving situation. Participants viewed a driving video clip in the first-person perspective. During the video clip, participants were presented with a cue to indicate whether a subsequent crash could occur (attention condition) or not (safe condition). Enhanced activities in the anterior insula, bed nucleus of the stria terminalis, thalamus, and periaqueductal gray, and higher sympathetic nerve responses (pupil dilation and peripheral arterial stiffness) were triggered by the attention condition but not with the safe condition. Autonomic response-related functional connectivity was detected in the visual cortex, cerebellum, brainstem, and MCC/PCC with the right anterior insula and its adjacent regions as seed regions. Thus, the right anterior insula and adjacent regions, in collaboration with other regions play a role in eliciting anxiety based on the prediction of negative events, by mediating anxiety-related autonomic responses according to interoceptive information.
Human ventromedial prefrontal cortex lesions enhance expectation-related pain modulation
Authors: Motzkin JC , Hiser J , Carroll I , Wolf R , Baskaya MK , Koenigs M , Atlas LY
Published: December 2021

Pain is strongly modulated by expectations and beliefs. Research across species indicates that subregions of the ventromedial prefrontal cortex (VMPFC) play a fundamental role in learning and generating predictions about valued outcomes. Consistent with this overarching framework, neuroimaging studies of experimental pain indicate that VMPFC activation tracks expectations of pain relief and statistically mediates expectation-related reductions in responses to painful stimuli across a distributed pain processing network. However, lesion studies in preclinical models and in humans with refractory chronic pain suggest that VMPFC may play a more general role in representing the affective and motivational qualities of pain that contribute to its strong aversive drive. To test whether VMPFC is necessary for pain processing in general, or instead plays a more specific role in the modulation of pain by expectations, we studied responses to experimental heat pain in five adults with bilateral surgical lesions of VMPFC and twenty healthy adults without brain damage.

All participants underwent quantitative sensory testing (QST) to characterize pain sensitivity, followed by a pain expectancy task. Participants were instructed that auditory cues would be followed by heat calibrated to elicit low or high pain. Following a conditioning phase, each cue was intermittently paired with a single temperature calibrated to elicit moderate pain. We compared ratings of moderate heat stimuli and subjective expectancy ratings as a function of cue to evaluate whether VMPFC lesions impact cue-based expectancy and expectancy effects on pain intensity and unpleasantness. We also analyzed QST measures to evaluate whether VMPFC lesions were associated with overall shifts in pain sensitivity.

Compared to adults without brain damage, individuals with VMPFC lesions reported larger differences in expectations as a function of pain-predictive cues, and stronger cue-based modulation of pain ratings, particularly for ratings of pain unpleasantness. There were no group differences in pain sensitivity, nor in the relationship between pain and autonomic arousal, indicating that the impact of VMPFC lesions is specific to expectancy-based modulation of pain unpleasantness.

Our findings suggest that the VMPFC is not essential for basic subjective and physiological responses to painful stimuli. Rather, our findings of significantly enhanced cue- related expectancy effects may suggest that VMPFC plays an important role in updating expectations or integrating sensory information with expectations to guide subjective judgements about pain. Taken together, these results expand our understanding VMPFC’s contribution to pain and highlight the role of VMPFC in integrating cognitive representations with sensory information to yield affective responses.
Repeated genetic adaptation to high altitude in two tropical butterflies
Authors: Montejo-Kovacevich Gabriela , Meier Joana I. , Bacquet Caroline N. , Warren Ian A. , Chan Yingguang Frank , Kucka Marek , Salazar Camilo , Rueda Nicol , Montgomery Stephen H. , McMillan W. Owen , Kozak Krzysztof M. , Nadeau Nicola J. , Martin Simon , Jiggins Chris D.
Published: December 2021

Repeated evolution can provide insight into the mechanisms that facilitate adaptation to novel or changing environments. Here we study adaptation to high altitude in two divergent tropical butterflies, H. erato and H. melpomene, which have repeatedly and independently adapted to high elevations on either side of the Andean mountains. We sequenced 518 whole genomes from elevational transects and found many regions under selection at high altitude, with repeated genetic differentiation across multiple replicates, including allopatric comparisons. In contrast, there is little ‘molecular parallelism’ between H. erato and H. melpomene. With a further 85 whole genomes of five close relatives, we find that a large proportion divergent regions have arisen from standing variation and putative adaptive introgression from high-altitude specialist species. Taken together our study supports a key role of standing genetic variation and gene flow from pre-adapted species in promoting parallel genetic local adaptation to the environment.
Evolutionary history of sexual differentiation mechanism in insects
Authors: Chikami Yasuhiko , Okuno Miki , Toyoda Atsushi , Itoh Takehiko , Niimi Teruyuki
Published: December 2021

Gain of alternative splicing gives rise to functional diversity in proteins and underlies the complexity and diversity of biological aspects. However, it is still not fully understood how alternatively spliced genes develop the functional novelty. To this end, we infer the evolutionary history of the doublesex gene, the key transcriptional factor in the sexual differentiation of arthropods. doublesex is controlled by sex-specific splicing and promotes both male and female differentiation in some holometabolan insects. In contrast, doublesex promotes only male differentiation in some hemimetabolan insects. Here, we investigate ancestral states of doublesex using Thermobia domestica belonging to Zygentoma, the sister group of winged insects. We find that doublesex of T. domestica expresses sex-specific isoforms but is only necessary for male differentiation of sexual morphology. This result ensures the hypothesis that doublesex was initially only used to promote male differentiation during insect evolution. However, T. domestica doublesex has a short female-specific region and upregulates the expression of vitellogenin homologs in females, suggesting that doublesex may have already controlled some aspects of feminization in the common ancestor of winged insects. Reconstruction of the ancestral sequence and prediction of the protein structure show that the female-specific isoform of doublesex has a long C-terminal disordered region in holometabolan insects, but not in non-holometabolan species. We propose that doublesex acquired a female-specific isoform and then underwent a change in the protein motif structure, which became essential for female differentiation in sexual dimorphisms.