bluuebunny/crossref_metadata_2025 huggingface dataset:
Hemophagocytosis in a Severe COVID-19 Patient
Authors: Zheng Kenneth I. , Jin Xianghong , Lin Xuanru , Lu Hong , Liu Wenyue , Zheng Minghua
Published: December 2021

The novel coronavirus (SARS-CoV-2) infection has become a heavy burden on global health. Although the coronavirus disease 2019 (COVID-19) may adversely affect multiple organs and systems of infected patients, to the best of our knowledge, there is little investigation of the SARS-CoV-2's impact on bone marrow. Our clinical and cytological findings in this case of severe COVID-19 infection provide novel insights into the pathogenesis of SARS-CoV-2 infection in the hematopoietic system. We recommend that physicians consider SARS-CoV-2 infection's effect on bone marrow in patients who are slow to recover and suggest that a better understanding of the bone marrow morphology in COVID-19-infected patients is needed.
Clinical Efficacy of Inhaled Nitric Oxide in Preventing the Progression of Moderate to Severe COVID-19 and Its Correlation to Viral Clearance: Results of a Pilot Study
Authors: Moni Merlin , Madathil Thushara , Sathyapalan Dipu T. , Menon Veena , Gutjahr Georg , Edathadathil Fabia , Sureshkumar Deepthi , Prasanna Preetha , Jose Soumya , Jerome Roshni , Krishnan Ajai , Pillai Indulekha C.L. , Kumar Geetha , Nair Bipin , Nizet Victor , Jayant Aveek
Published: December 2021

Hypoxic patients with coronavirus disease 2019 (COVID-19) are at high risk of adverse outcomes. Inhaled nitric oxide (iNO) has shown anti-viral and immunomodulatory effects in vitro. However, in vivo evidence of efficacy in hypoxic COVID-19 is sparse. This open label feasibility study was conducted at a single referral center in South India and evaluated the effectiveness of repurposed iNO in improving clinical outcomes in COVID-19 and its correlation with viral clearance. We recruited hypoxemic COVID-19 patients and allocated them into treatment (iNO) and control groups (1:1). Viral clearance on day 5 favored the treatment group (100% vs 72%, P < 0.01). The speed of viral clearance as adjudged by normalized longitudinal cycle threshold (Ct) values was positively impacted in the treatment group. The proportion of patients who attained clinical improvement, defined as a ≥2-point change on the World Health Organization ordinal scale, was higher in the iNO cohort (n = 11, 79%) as compared to the control group (n = 4, 36%) (odds ratio 6.42, 95% confidence interval 1.09-37.73, P = 0.032). The proportion of patients progressing to mechanical ventilation in the control group (4/11) was significantly higher than in the treatment group (0/14). The all-cause 28-day mortality was significantly different among the study arms, with 36% (4/11) of the patients dying in the control group while none died in the treatment group. The numbers needed to treat to prevent an additional poor outcome of death was estimated to be 2.8. Our study demonstrates the putative role of repurposed iNO in hypoxemic COVID-19 patients and calls for extended validation.
Individual Meropenem Clearance in Infants on ECMO and CVVHDF is Difficult to Predict
Authors: Jabareen Ali , Nassar Laila , Karasik Marina , Efrati Edna , Hadash Amir , Kassis Imad , Kurnik Daniel
Published: December 2021

Objectives:

Meropenem is a broad-spectrum carbapenem antibiotic with mostly renal excretion. Conflicting data are available regarding meropenem pharmacokinetics in critically ill neonates on concomitant continuous renal replacement therapy (CRRT) and/or extracorporeal membrane oxygenation (ECMO). Our objectives were to assess meropenem clearance in a neonate on CRRT and ECMO, compare it to previously published data and assess whether dose recommendations can be generalized in this population.

Case description:

A 2.5 kg male infant with a large diaphragmatic hernia was delivered by cesarean section at week 35 and immediately mechanically ventilated due to shock and respiratory insufficiency. He underwent surgical correction of the hernia, but developed recurrent sepsis, multiorgan failure and pulmonary hypertension. He remained mechanically ventilated and required ECMO and continuous venovenous hemodiafiltration. He was started on meropenem 40 mg/kg/dose, every 8 hs for Enterobacter cloacae bacteremia and sepsis, but due to lack of clinical and microbiologic response despite in vitro susceptibility, he was started on a continuous meropenem infusion of 240 mg/kg/d, based on dose recommendations in a similar case. We measured steady state meropenem plasma concentrations on 2 occasions, during ECMO and continuous venovenous hemodiafiltration (CVVHDF) and then on CVVHDF only.

Results:

Meropenem serum concentrations were 90 and 64 mg/L on the first and second occasion (therapeutic target concentration, 10 mg/L) corresponding to a clearance of 1.9 and 2.6 mL/kg/min. This clearance estimate was substantially lower than that reported in toddlers on CRRT and ECMO in some studies.

Conclusion:

In neonates and infants, meropenem clearance is difficult to predict because of dynamic ontogenetic changes in renal function. This problem is further aggravated in acutely ill infants with decreased renal function, renal replacement therapy and/or ECMO. Therefore, Target Concentration Intervention based on meropenem plasma concentrations is indispensable to ensure therapeutic exposure in this population.
Oral Azithromycin Versus Doxycycline in the Treatment of Children With Uncomplicated Scrub Typhus
Authors: Kabir Karthika I. , John Joseph , Satapathy Amit Kumar , Sahu Suchanda , Behera Bijayini , Padhy Biswa Mohan
Published: December 2021

Objectives:

To compare the efficacy of azithromycin versus doxycycline in treatment of children with uncomplicated scrub typhus in terms of percentage of children who attained remission of fever after 72 hours of administration of first dose of the study drug, mean time taken to attain fever defervescence, normalization of laboratory parameters, resolution of hepatosplenomegaly and lymphadenopathy.

Design:

Interventional, open-labeled randomized controlled trial.

Study methods:

Patients admitted with undifferentiated fever in the In-Patient Department (IPD), Department of Paediatrics, All India Institute of Medical Sciences, Bhubaneswar, India, as per the inclusion criteria were randomized and was treated with azithromycin at 10 mg/kg/d in one group and doxycycline at 4.4 mg/kg/d for 5 days in the other group and was assessed based on the primary and secondary objectives.

Results:

There was no statistically significant difference between the percentage of children who attained remission of fever after 72 hours of administration of azithromycin (98.2%) and doxycycline (96.5%) (P value 0.47) and the average time taken for fever defervescence (azithromycin: 24.53 hours; doxycycline: 25.82 hours; P value 0.36). The odds of attaining fever remission in the doxycycline group as compared with the azithromycin group was 1.01 (95% confidence interval −0.60 to −1.71), which was also statistically not significant. There was less incidence of adverse drug events in the azithromycin group (1.78%) as compared with the doxycycline group (8.6%), which was statistically significant (P value 0.02).

Conclusion:

Azithromycin is equally efficacious in terms of fever defervescence, resolution of clinical signs and laboratory parameters as doxycycline, is safer and better tolerated in children.
Perceptions of Occupational Cancer Risk and Prevention Among Dominican Republic Firefighters
Authors: Louzado-Feliciano Paola , Santiago Katerina M. , Paule Laura , Rivera Geovanny , Schaefer Solle Natasha , Miric Marija , Perez-Then Eddy , Caban-Martinez Alberto J.
Published: December 2021

Objectives:

Characterize occupational cancer risk perceptions and attitudes toward cancer prevention practices among firefighters in the Dominican Republic.

Methods:

Focus group discussions and key informant interviews were conducted in June 2019 among firefighters from three fire departments. Themes were inductively created using a qualitative descriptive approach.

Results:

Thirty-seven firefighters were interviewed with a group mean age of 36.2 ± 10.3 years, of which 97.3% were male, and 37.1% worked at least 10 years. Six themes emerged: 1) availability of personal protective equipment (PPE); 2) toxic exposure during fire suppression; 3) work-related stress; 4) lack of workplace health promotion activities; 5) Dominican culture impacts medical checkups; and 6) expensive medical copays limits healthcare access.

Conclusion:

Dominican firefighters are willing to adopt cancer prevention practices, however organizational barriers (ie, PPE availability, cultural barriers, and health promotion practices) limit engagement.
The Mental Well-Being of Health Care Professionals During the COVID-19 Pandemic
Authors: Ariza-Montes Antonio , Mahmood Faisal , Han Heesup , Saleem Maria
Published: December 2021

Objectives:

Adopting the protection motivation theory and self-determination theory as frameworks, the present study examined whether the mental well-being of health care workers is determined by a combination of COVID-19-related factors (exposure and resources), organizational factors, and individual and attitudinal factors.

Methods:

The present study is based on Eurofound's Living, Working, and COVID-19 survey, and the fieldwork for this survey was performed via uncontrolled convenience sampling throughout June and July 2020 in the 27 European Union countries. This research utilized a subsample of 1824 health sector employees and 11,750 workers in the other service industries. Further, to meet the objectives of this study, different linear regression models are estimated.

Results:

Despite the close contact of health care workers with COVID-19, we found that the risk of contracting the coronavirus does not explain their poor or high well-being. However, the availability of personal protection equipment and mistrust in the national health system contribute to well-being, along with other organizational (eg, job insecurity) and individual-attitudinal factors (eg, health and life satisfaction).

Conclusions:

The present study offers various valuable insights for health institutes, organizations, practitioners, and employers to combat COVID-19 and identify the determinants of the mental well-being of health care professionals.
Psychological symptoms of illness and emotional distress in advanced cancer cachexia
Authors: Amano Koji , Hopkinson Jane , Baracos Vickie
Published: December 2021

Purpose of review

Cachexia induces both physical and psychological symptoms of illness in patients with advanced cancer and may generate emotional distress in patients and families. However, physical symptoms of cachexia received the most emphasis. The aims of this review are to elucidate a link between systemic inflammation underlying cachexia and psychological symptoms and emotional distress, and to advance care strategy for management of psychological symptoms and emotional distress in patients and families.

Recent findings

The main themes in the literature covered by this review are psychological symptoms in patients and emotional distress in patients and families. Studies of the underlying biology of cachexia identify the role of the central nervous system to amplify tumor-induced systemic inflammation. The brain mediates a cluster of symptoms, such as sleep disruption, anxiety, cognitive impairment, and reduction in motivated behavior (notably anorexia). These are distressing to patients as well as to families.

There is growing recognition that holistic multimodal interventions are needed to alleviate psychological symptoms and emotional distress and to improve quality of life in patients with cancer cachexia and families. This is an approach that addresses not only physical health but also psychological, emotional, and social well being issues.
Sternocleidomastoid size and upper trapezius muscle thickness in congenital torticollis patients
Authors: Kwon Dong Rak , Kim Yoontae
Published: December 2021

The purpose of this study was to investigate the upper trapezius muscle thickness (UTMT) in congenital muscular torticollis (CMT) patients and determine the correlation among sternocleidomastoid muscle thickness (SCMT), accessory nerve (AN) cross-sectional area (CSA), and UTMT in CMT.

This retrospective study consisted of 2 participant groups: Group 1 (SCM mass CMT, n = 20) and Group 2 (Postural CMT, n = 22). For both groups, B-mode ultrasound was performed by a physiatrist to measure the SCMT and UTMT and calculate the CSA of the AN. The correlation among SCMT, CSA of the AN, and UTMT in both groups was evaluated.

The between-group comparison revealed that Group 1 had significantly greater SCMT, UTMT, and CSA of the AN on the affected side than Group 2 (P < .05). The intragroup comparison between the affected and unaffected sides also revealed that, in Group 1, the SCMT, UTMT, and CSA of the AN were significantly higher on the affected side than on the unaffected side (P < .05), whereas no significant differences were observed in Group 2. In Group 1, a positive correlation (r = 0.55) was observed between the UTMT and CSA of the AN on the affected side, but not observed between the SCMT and CSA of the AN.

The findings of the study indicate that sternocleidomastoid muscle size may impact the thickness of the upper trapezius muscle via the accessory nerve in patients with congenital torticollis.
Red cell distribution width as a predictor of outcome in hospitalized cirrhotic patients
Authors: Abdel-Samiee Mohamed , Ahmed Samy Kohla Mohamed , Fathy Ragab Mohammed , Ghanem Heba Samy , Kamel AbouGabal Ashraf , Abdelsameea Eman
Published: December 2021

Background

A systemic inflammatory response syndrome (SIRS) is linked to red cell distribution width (RCDW), which produces pro-inflammatory signals that act directly on hematopoietic stem cells in the bone marrow. This stimulation may cause alterations in the membrane of red blood cells (RBCs), as assessed by RCDW, which have been linked to increased morbidity and death in a number of systemic disorders.

Aim

This study aims to evaluate RCDW as a predictor of outcome in hospitalized cirrhotic patients.

Methods

This prospective cross-sectional study was conducted on 1000 patients. The outcome was assessed by days of hospitalization; mortality in hospitalized patients or during short-term follow-up (3 months) and rehospitalization during follow-up of 6 months.

Results

Male represented 69.6%. Mean age was 57.67 ± 13.07 years old. Baseline co-morbidities were recorded as the presence of diabetes mellitus (200 patients) and hypertension (400 patients). Hepatitis C virus was the commonest etiology of the diseased liver (90%). Child-Pugh classes A, B and C of studied patients represented (21.2%, 38.8% and 40%). The survived patients during follow-up represented 63.3%. Area under the curve for RCDW was 0.923 (95% CI, 0.904–0.943), 0.910 for C-reactive protein (95% CI, 0.890–0.930), 0.904 for Hb (95% CI, 0.883–0.925) and 0.903 for platelets (95% CI, 0.882–0.924). RCDW cutoff point at 21.35 for predicting survival had sensitivity 93%, specificity 91%, accuracy 92%, positive predictive value 85 and negative predictive value 96. Regression analysis revealed a significant positive association between both RCDW and white blood cells with mortality.

Conclusion

RCDW could provide useful information for predicting the length of hospitalization and survival in hospitalized cirrhotic patients.
Ketamine as an Adjunct for Treatment of Methotrexate-induced Neurotoxicity
Authors: Ilahi Zara , Janardhan Shruthi , Dave Manasi , Khariton Megan , Feuer Pamela , Venkataraman Akila , Romanos-Sirakis Eleny
Published: December 2021

Methotrexate (MTX) is used in the treatment of several childhood cancers and is a main component of the treatment regimen for osteosarcoma. MTX has been linked with side effects of varying severity; headaches, nausea, emesis, lethargy, blurred vision, aphasia, hemiparesis, paresis, convulsions, leukoencephalopathy, and arachnoiditis are symptoms of MTX toxicity. MTX-induced neurotoxicity can occur in up to 15% of patients receiving high-dose MTX. The effects may be transient but can have life-threatening implications, sometimes requiring intubation for respiratory support and airway protection. Elevated homocysteine levels in the cerebrospinal fluid are documented in cases of MTX-induced neurotoxicity; dextromethorphan is used as an initial treatment for MTX-induced neurotoxicity as it works as a noncompetitive antagonist for the N-methyl D-aspartate receptors and suppresses homocysteine activity. In severe cases requiring intubation, medications for sedation are utilized. Ketamine is also an N-methyl D-aspartate receptor antagonist, and as such, may be considered as an optimal treatment choice when sedation is required. We describe the use of ketamine in a pediatric patient with MTX-induced neurotoxicity. The use of ketamine in the treatment of MTX-induced neurotoxicity has not been described in the literature.
Considerations in Methods and Timing for Delivery of Genetic Counseling Information to Pediatric Oncology Patients and Families
Authors: Li Kathleen A. , Sloat Lauren M. , Kung Julia , Jung Jessica , Li Ashley , Smith Christy H. , Schratz Kristen E. , Cooper Stacy L. , Pratilas Christine A. , Frankenfield Pamela , Bodurtha Joann
Published: December 2021

Many pediatric oncology patients and their families may benefit from genetic counseling and testing; however, identifying the best timing and delivery method for these referrals is sometimes a challenge. The goal of this study was to understand how and when caregivers prefer to receive information about genetic counseling and testing. A total of 56 surveys completed by caregivers at The Johns Hopkins Hospital Pediatric Oncology unit in Baltimore, Maryland were analyzed. A sizeable subset of respondents was interested in receiving information about the availability of genetic counseling from an oncology doctor or nurse, but not a genetic counselor (n=13/55, 24%). Most respondents preferred to be informed about genetic services at diagnosis (n=28/54, 52%) or within 1 to 2 months of diagnosis (n=14/54, 26%). In conclusion, patients and their families may benefit from prompt and early recognition of the risk of cancer predisposition syndromes, preferably within the first 2 months following diagnosis. Oncology professionals are an important source of information, and can introduce the availability of genetic counseling services and motivate families to undergo genetic testing, though alternative communication methods such as brochures may also be useful.
Theory of Planned Behavior
Authors: Khatib Anwar , Abo-Rass Fareeda , Gelkopf Marc
Published: December 2021

Based on the theory of planned behavior (TPB), this study aimed to examine factors influencing therapist uptake of digital mental health interventions in Israel. Two hundred twenty-nine mental health professionals recruited through a convenience sample completed a background and demographic questionnaire, as well as the TPB-based electronic-therapy attitudes and process questionnaire. Regressions were used to examine the contribution of attitudes, perceived behavioral control, subjective norms, and behavioral intentions. Intention to use and use of digital interventions were significantly predicted by attitudes, subjective norms, and perceived behavioral control, as suggested by the TPB. The use of cognitive behavioral therapy (CBT) and higher perceived behavioral control increased the likelihood of using digital interventions. Having a positive attitude, having expectations/social pressure from one’s professional environment, and having a sense of control over the process were found to predict the intent to use, as well as the actual use of, digital interventions.
Childhood Trauma Associations With the Interpersonal Psychological Theory of Suicide and Social Cognitive Biases in Psychotic Disorders
Authors: Chalker Samantha A. , Parrish Emma M. , Cano Mayra , Kelsven Skylar , Moore Raeanne C. , Granholm Eric , Pinkham Amy , Harvey Philip D. , Depp Colin A.
Published: December 2021

Childhood trauma (CT) is associated with suicidal ideation and behaviors (SI/SB) in people with psychosis. The interpersonal psychological theory of suicide (IPTS) suggests that there are four factors that increase suicide risk: thwarted belongingness, perceived burdensomeness, acquired capacity for suicide, and hopelessness. The IPTS constructs and social cognitive biases are associated with SI/SB in psychotic disorders. However, the role of CT in IPTS constructs and social cognitive biases has not been examined in psychosis. In an outpatient community sample of persons with psychotic disorders (N = 96) assessed with the Childhood Trauma Questionnaire, the aims of this study were to a) evaluate rates of CT in this sample, b) determine the relationship between CT types and lifetime SI/SB, and c) explore the relationship between CT types, IPTS constructs, and social cognitive biases. All participants reported experiencing CT. Emotional abuse was associated with greater SI severity and higher rates of lifetime suicide attempts, as well as with greater perceived burdensomeness and more severe negative social cognitive biases. Other CT types were minimally associated with SI/SB or IPST constructs; hopelessness was not associated. Overall, negative interpersonal beliefs and social cognitive biases may explain how CT increases suicide risk in psychosis.
Lower Incidence of HIV-1 Blips Observed During Integrase Inhibitor–Based Combination Antiretroviral Therapy
Authors: Dijkstra Suzan , Hofstra L. Marije , Mudrikova Tania , Wensing Annemarie M. J. , Oomen Patrick G. A. , Hoepelman Andy I. M. , van Welzen Berend J.
Published: December 2021

Background:

As the nature of viral blips remains unclear, their occurrence often leads to uncertainty. This study compares blip incidence rates during treatment with different combination antiretroviral therapy anchors.

Setting:

Retrospective cohort study in a tertiary hospital.

Methods:

All antiretroviral regimens between 2010 and 2020 containing 2 nucleos(-t)ide reverse transcriptase inhibitors and 1 anchor in virologically suppressed people living with HIV (PLWH) from our center were evaluated for the occurrence of blips [isolated viral loads (VLs) 50–499 copies/mL between measurements <50 copies/mL]. Factors associated with blips were identified using multivariable generalized estimating equation–based negative binomial models. The relationship between blips and either persistent low-level viremia (consecutive VLs ≥ 50 copies/mL not classified as failure) or virologic failure (consecutive VLs ≥ 200 or 1 VL ≥ 500 copies/mL) was also evaluated.

Results:

In total, 308 blips occurred during 3405 treatment courses in 1661 PLWH. Compared with a non-nucleoside reverse transcriptase inhibitor anchor, blip incidence was higher for protease inhibitors (incidence rate ratio 1.37; 95% confidence interval 1.05 to 1.78) and lower for integrase inhibitors (INSTIs) (incidence rate ratio 0.64; 95% confidence interval: 0.43 to 0.96). In addition, blips were associated with higher zenith VL, higher VL test frequency, and shorter time since antiretroviral therapy initiation. PLWH experiencing blips were more likely to demonstrate persistent low-level viremia but not virologic failure. Blips led to extra consultations and measurements.

Conclusions:

INSTI-based regimens display a low number of blips. Although we found no correlation with virologic failure, the occurrence of blips led to an increased clinical burden. Further research is needed to elucidate the implications and underlying mechanisms of these findings.
Impact of Platelet Transfusion Thresholds on Outcomes of Patients With Sepsis: Analysis of the MIMIC-IV Database
Authors: Zhou Wei , Fan Chenyu , He Shuangjun , Chen Yi , Xie Cuiying
Published: December 2021

Background:

The benefits of platelet thresholds for transfusion remain unclear. This study assessed the effect of two transfusion thresholds on the survival outcomes of patients with sepsis and thrombocytopenia.

Methods:

In this retrospective cohort study, data of patients with sepsis admitted to an intensive care unit (ICU) and who had received platelet transfusion were extracted from the Medical Information Mart for Intensive Care IV database. Patients were classified into the lower-threshold group (below 20,000/μL) and higher-threshold group (20,000–50,000/μL), based on thresholds calculated from their pretransfusion platelet count. The endpoints included 28- and 90-day mortality, red blood cell (RBC) transfusion, ICU-free days, and hospital-free days.

Results:

There were 76 and 217 patients in the lower-threshold and higher-threshold groups, respectively. The higher-threshold group had a higher rate of surgical ICU admission (35.0% vs. 9.2%) and lower quick Sequential Organ Failure Assessment (qSOFA) score than the lower-threshold group. In the higher-threshold group, 94 (43.3%) and 132 (60.8%) patients died within 28 and 90 days, compared to 51 (67.1%) and 63 (82.9%) patients in the lower-threshold group (adjusted odds ratio, 1.96; 95% confidence interval, 1.16 to 3.03; P = 0.012; adjusted odds ratio, 2.04; 95% confidence interval, 1.16 to 3.57; P = 0.012, respectively). After stratification by mortality risk, the subgroup analysis showed a consistent trend favoring higher-threshold transfusion but reached statistical significance only in the low-risk group. There were no differences in red blood cell transfusion, ICU-free days, and hospital-free days between the groups. The E-value analysis suggested robustness to unmeasured confounding.

Conclusions:

In patients with sepsis and thrombocytopenia, platelet transfusion at a higher threshold was associated with a greater reduction in the 28- and 90-day mortalities than that at a lower threshold.
Luminal Administration of a Water-soluble Carbon Monoxide–releasing Molecule (CORM-3) Mitigates Ischemia/Reperfusion Injury in Rats Following Intestinal Transplantation
Authors: Obara Takafumi , Yamamoto Hirotsugu , Aokage Toshiyuki , Igawa Takuro , Nojima Tsuyoshi , Hirayama Takahiro , Seya Mizuki , Ishikawa-Aoyama Michiko , Nakao Atsunori , Motterlini Roberto , Naito Hiromichi
Published: December 2021

Background.

The protective effects of carbon monoxide (CO) against ischemia/reperfusion (IR) injury during organ transplantation have been extensively investigated. Likewise, CO-releasing molecules (CORMs) are known to exert a variety of pharmacological activities via liberation of controlled amounts of CO in organs. Therefore, we hypothesized that intraluminal administration of water-soluble CORM-3 during cold storage of intestinal grafts would provide protective effects against IR injury.

Methods.

Orthotopic syngeneic intestinal transplantation was performed in Lewis rats following 6 h of cold preservation in Ringer solution or University of Wisconsin solution. Saline containing CORM-3 (100 µmol/L) or its inactive counterpart (iCORM-3) was intraluminally introduced in the intestinal graft before cold preservation.

Results.

Histopathological analysis of untreated and iCORM-3–treated grafts revealed a similar erosion and blunting of the intestinal villi. These changes in the mucosa structure were significantly attenuated by intraluminal administration of CORM-3. Intestinal mucosa damage caused by IR injury led to considerable deterioration of gut barrier function 3 h postreperfusion. CORM-3 significantly inhibited upregulation of proinflammatory mRNA levels, ameliorated intestinal morphological changes, and improved graft blood flow and mucosal barrier function. Additionally, CORM-3–treated grafts increased recipient survival rates. Pharmacological blockade of soluble guanylyl cyclase activity significantly reversed the protective effects conferred by CORM-3, indicating that CO partially mediates its therapeutic actions via soluble guanylyl cyclase activation.

Conclusions.

Our study demonstrates that luminally delivered CORM-3 provides beneficial effects in cold-stored rat small intestinal grafts and could be an attractive therapeutic application of CO in the clinical setting of organ preservation and transplantation.
Decreased Expression of Cerebral Dopamine Neurotrophic Factor in Platelets of Probable Alzheimer Patients
Authors: Joshi Hetshree , Shah Jill , Abu-Hijleh Fahed A. , Patel Vidhi , Rathbone Michel , Gabriele Simona , Gabriele Joseph , Baranowski David , Molloy David , Frey Benicio N. , Mishra Ram K.
Published: December 2021

Background:

Alzheimer disease (AD) patients experience progressive neurological and cognitive decline attributed to neurodegeneration. Cerebral dopamine neurotrophic factor (CDNF) has been identified to protect and rescue neurons in various preclinical neurodegeneration models. The expression of this protein occurs in both the central nervous system and peripheral blood. Blood platelets exhibit several biochemical impairments similar to the brain tissues of patients with neurological disorders. This study examines CDNF mRNA expression in human blood platelets in healthy subjects and Alzheimer-probable patients.

Methods:

Platelets were extracted from whole blood from patients. mRNA was extracted to synthesize cDNA and quantify CDNF gene expression from 21 Alzheimer-probable patients and 73 healthy age-matched control subjects using real-time qPCR. Grouping analysis of the data with regard to sex was conducted.

Results:

CDNF mRNA expression was significantly decreased in Alzheimer-probable patients relative to the control subjects (P<0.05). Further analysis demonstrated reduced CDNF expression in male Alzheimer-probable patients compared with their age and sex-matched controls (P<0.05). However, no change in female subjects was observed. Interestingly, there is a lower level of CDNF expression in the female control group relative to the control male group (P<0.05).

Conclusion:

Alzheimer-probable male patients demonstrated significant reductions in CDNF expression, suggesting that CDNF plays a significant role in the pathogenesis of AD. In addition, it may assist in diagnosing male Alzheimer patients.
The distinct roles of various neurotransmitters in modulating methamphetamine-induced conditioned place preference in relevant brain regions in mice
Authors: Su Hongliang , Bai Junmei , Fan Yao , Sun Tingting , Du Yan , Li Yanhua , Wei Zhiwen , Chen Teng , Guo Xiangjie , Yun Keming
Published: December 2021

Objectives

Previous studies have shown that methamphetamine (METH) can induce complex adaptive changes in the reward system in the brain, including the changes in the content of neurotransmitters in the signal transduction pathway. However, how the changes of various neurotransmitters in relevant brain reward circuits contribute to METH-induced conditioned place preference (CPP) remains unclear.

Methods

In this study, first, we designed an animal model of METH-induced CPP. Then we used liquid chromatography-mass spectrometry (LC-MS) to simultaneously determine the contents of various neurotransmitters – dopamine (DA), norepinephrine (NE), 5-hydroxytryptamine (5-HT), 5-hydroxyindole acetic acid (5-HIAA), glutamic acid (Glu) and glutamine (Gln) – in different brain regions of the prefrontal cortex (PFc), nucleus accumbens (NAc), caudate-putamen (CPu) and hippocampus (Hip), which are believed to be relevant to the drug’s reward effect.

Results

The results of the behavioral experiment suggested that 1.0 mg/kg METH could induce obvious CPP in mice. The results about various neurotransmitters showed that: DA significantly increased in NAc in the METH group; Glu increased significantly in the METH group in PFc and NAc and Gln increased significantly in the METH group in PFc.

Conclusions

These results suggested that the neurotransmitters of DA, Glu and Gln may work together and play important roles in METH-induced CPP in relevant brain reward circuits, especially in PFc and NAc. These findings therefore could help to advance the comprehensive understanding of the neurochemic and psychopharmacologic properties of METH in reward effect, which is important for future improvements in the treatment of drug addiction.
Mechanism of bisphosphonate-related osteonecrosis of the jaw (BRONJ) revealed by targeted removal of legacy bisphosphonate from jawbone using equilibrium competing inert hydroxymethylene diphosphonate
Authors: Okawa Hiroko , Kondo Takeru , Hokugo Akishige , Cherian Philip , Campagna Jesus J. , Lentini Nicholas , Sun Shuting , Sung Eric C. , Chiang Samantha , Lin Yi-Ling , Ebetino Frank H. , John Varghese , McKenna Charles E. , Nishimura Ichiro
Published: December 2021

Bisphosphonate-related osteonecrosis of the jaw (BRONJ) presents as a morbid jawbone lesion in patients exposed to a nitrogen-containing bisphosphonate (N-BP). Although it is rare, BRONJ has caused apprehension among patients and healthcare providers and decreased acceptance of this anti-resorptive drug class to treat osteoporosis and metastatic osteolysis. We report here a novel method to elucidate the pathological mechanism of BRONJ by the selective removal of legacy N-BP from the jawbone using an intra-oral application of hydroxymethylene diphosphonate (HMDP) formulated in deformable nanoscale vesicles (DNV). After maxillary tooth extraction, zoledronate-treated mice developed delayed gingival wound closure, delayed tooth extraction socket healing and increased jawbone osteonecrosis consistent with human BRONJ lesion. Single cell RNA sequencing of mouse gingival cells revealed oral barrier immune dysregulation and unresolved pro-inflammatory reaction. HMDP-DNV topical applications to nascent mouse BRONJ lesions resulted in accelerated gingival wound closure and bone socket healing as well as attenuation of osteonecrosis development. The gingival single cell RNA sequencing demonstrated resolution of chronic inflammation by increased anti-inflammatory signature gene expression of lymphocytes and myeloid-derived suppressor cells. This study suggests that BRONJ pathology was predominantly induced by the oral N-BP and demonstrates the potential of HMDP-DNV as an effective BRONJ therapy.

Brief Summary

The targeted removal of legacy bisphosphonate from the jawbone by competitive equilibrium therapy elucidated the pathological mechanism of aberrant oral barrier immunity and bisphosphonate-related osteonecrosis of the jaw (BRONJ)
Emergence in Southern France of a new SARS-CoV-2 variant of probably Cameroonian origin harbouring both substitutions N501Y and E484K in the spike protein
Authors: Colson Philippe , Delerce Jérémy , Burel Emilie , Dahan Jordan , Jouffret Agnès , Fenollar Florence , Yahi Nouara , Fantini Jacques , La Scola Bernard , Raoult Didier
Published: December 2021

SARS-CoV-2 variants have become a major virological, epidemiological and clinical concern, particularly with regard to the risk of escape from vaccine-induced immunity. Here we describe the emergence of a new variant. For twelve SARS-CoV-positive patients living in the same geographical area of southeastern France, qPCR testing that screen for variant-associated mutations showed an atypical combination. The index case returned from a travel in Cameroon. The genomes were obtained by next-generation sequencing with Oxford Nanopore Technologies on GridION instruments within ≈8 h. Their analysis revealed 46 mutations and 37 deletions resulting in 30 amino acid substitutions and 12 deletions. Fourteen amino acid substitutions, including N501Y and E484K, and 9 deletions are located in the spike protein. This genotype pattern led to create a new Pangolin lineage named B.1.640.2, which is a phylogenetic sister group to the old B.1.640 lineage renamed B.1.640.1. Both lineages differ by 25 nucleotide substitutions and 33 deletions. The mutation set and phylogenetic position of the genomes obtained here indicate based on our previous definition a new variant we named “IHU”. These data are another example of the unpredictability of the emergence of SARS-CoV-2 variants, and of their introduction in a given geographical area from abroad.
Prediction of SARS-CoV-2 Omicron Variant Immunogenicity, Immune Escape and Pathogenicity, through Analysis of Spike Protein-specific Core Unique Peptides
Authors: Pierros Vasileios , Kontopodis Evangelos , Stravopodis Dimitrios J. , Tsangaris George Th.
Published: December 2021

The recently discovered Omicron variant of the SARS-CoV-2 corona virus has raised a new, global, awareness, since it is considered as a new variant of concern from all major health organizations, including WHO and ECDC. Omicron variant is characterized by 30 amino acid changes, three small deletions and one small insertion in the Spike protein. In this study, we have identified the Core Unique Peptides (CrUPs) that reside exclusively in the Omicron variant of Spike protein and are absent from the human proteome, thus creating a new dataset of peptides named as C/H-CrUPs. Furthermore, we have analyzed their protein locations and compared them with the respective ones of Alpha and Delta SARS-CoV-2 variants. In Omicron, 115 C/H-CrUPs were generated and 119 C/H-CrUPs were lost, almost four times as many compared to the other two variants. From position 440 to position 508, at the Receptor Binding Motif (RBM), 8 mutations were detected, resulting in the construction of 28 novel C/H-CrUPs. Most importantly, in Omicron variant, new C/H-CrUPs carrying two or three mutant amino acids were produced, as a consequence of the accumulation of multiple mutations in the RBM. Remarkably, these Omicron-derived C/H-CrUPs that bear several mutated amino acids could not be recognized in any other viral Spike variant. We suggest that virus binding to the ACE2 receptor is facilitated by the herein identified C/H-CrUPs in contact point mutations and Spike-cleavage sites, while the immunoregulatory NF9 peptide is not detectably affected. Taken together, our findings indicate that Omicron variant contains intrinsic abilities to escape immune-system attack, while its mutations can mediate strong viral binding to the ACE2 receptor, leading to highly efficient fusion of the virus to the target cell. However, the intact NF9 peptide suggests that Omicron exhibits reduced pathogenicity compared to Delta variant.
Predicting the course of Covid-19 and other epidemic and endemic disease
Authors: Cascon Ana , Shadwick William F.
Published: December 2021

The Gompertz Function is an accurate model for epidemics from Cholera in 1853 to Spanish Flu in 1918 and Ebola in 2014. It also describes the acute phase of annual outbreaks of endemic influenza and in all of these instances it has significant predictive power.

For Covid-19, we show that the Gompertz Function provides accurate forecasts not just for cases and deaths but, independently, for hospitalisations, intensive care admissions and other medical requirements. In particular Gompertz Function projections of healthcare requirements have been reliable enough to allow planning for: hospital admissions,intensive care admissions,ventilator usage, peak loads and duration.

Analysis of data from the ‘Spanish Flu’ pandemic and the endemic influenza cycle reveals alternating periods of Gompertz Function growth and linear growth in cumulative cases or deaths. Linear growth means the Reproduction Number is equal to 1 which in turn indicates endemicity.

The same pattern has been observed with Covid-19. All the initial outbreaks ended in linear growth. Each new outbreak has been preceded by a period of linear growth and has ended with a transition from Gompertz Function growth to linear growth. This suggests that each of these outbreak cycles ended with a transition to endemicity for the current dominant strain and that the normal seasonal respiratory virus periods will continue to see new outbreaks. It remains to be seen if widespread vaccination will disrupt this cyclicality.

Because both Gompertz Function Growth and linear growth are accurately predictable, the forecasting problem is reduced to identifying the transition between these modes and to improving the performance in the early Gompertz Function growth phase where its predictive power is lowest.

The dynamics of the Gompertz Function are determined by the Gumbel probability distribution. This is an exceptional distribution with respect to the geometry determined by the affine group on the line which is the key to the role of the Gumbel distribution as an Extreme Value Theory attractor. We show that this, together with the empirically observed asymmetry in epidemic data, makes the Gompertz Function growth essentially inevitable in epidemic models which agree with observations.
Functional implications of aging-related lncRNAs for predicting prognosis and immune status in glioma patients
Authors: Zhang Guangying , Li Yanyan , Li Na , Shen Liangfang , Li Zhanzhan
Published: December 2021

Glioma, is the most prevalent intracranial tumor with high recurrence and mortality rate. Long noncoding RNAs (lncRNAs) play a critical role in the occurrence and progression of tumors as well as in aging regulation. Our study aimed to establish a new glioma prognosis model by integrating aging-related lncRNAs expression profiles and clinical parameters in glioma patients from the Chinese Glioma Genome Atlas (CGGA) and the Cancer Genome Atlas (TCGA) datasets. The Pearson correlation analysis (|R|> 0.6, P<0.001) was performed to explore the aging-related lncRNAs, and univariate cox tregresion and least absolute shrinkage and selection operator (LASSO) regression were used to screening prognostic signature in glioma patients. Based on the fifteen lncRNAs, we can divide glioma patients into three subtypes, and developed a prognostic model. Kaplan-Meier survival curve analysis showed that low-risk patients had longer survival time than high-risk group. Principal component analysis indicated that aging-related lncRNAs signature had a clear distinction between high- and low-risk groups. We also found that fifteen target lncRNAs were closely correlated with 119 genes by establishing a co-expression network. In addition, Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis displayed different function and pathways enrichment in high-and low-risk groups. The different missense mutations were observed in two groups, and the most frequent variant types were single nucleotide polymorphism (SNP). This study demonstrated that the novel aging-related lncRNAs signature had an important prognosis prediction and may contribute to individual treatment for glioma.
Replacement of the Gamma by the Delta variant in Brazil: impact of lineage displacement on the ongoing pandemic
Authors: Giovanetti Marta , Fonseca Vagner , Wilkinson Eduan , Tegally Houriiyah , San Emmanuel James , Althaus Christian L. , Xavier Joilson , Slavov Svetoslav Nanev , Viala Vincent Louis , Ranieri Jerônimo Lima Alex , Ribeiro Gabriela , Souza-Neto Jayme A. , Fukumasu Heidge , Coutinho Luiz Lehmann , Venancio da Cunha Rivaldo , Freitas Carla , Campelo de A e Melo Carlos F , Navegantes Wildo , do Carmo Said Rodrigo Fabiano , Almiron Maria , de Oliveira Tulio , Sampaio Sandra Coccuzzo , Elias Maria Carolina , Covas Dimas Tadeu , Holmes Edward C. , Lourenço Jose , Kashima Simone , de Alcantara Luiz Carlos Junior
Published: December 2021

The COVID-19 epidemic in Brazil was driven mainly by the spread of Gamma (P.1), a locally emerged Variant of Concern (VOC) that was first detected in early January 2021. This variant was estimated to be responsible for more than 96% of cases reported between January and June 2021, being associated with increased transmissibility and disease severity, a reduction in neutralization antibodies and effectiveness of treatments or vaccines, as well as diagnostic detection failure. Here we show that, following several importations predominantly from the USA, the Delta variant rapidly replaced Gamma after July 2021. However, in contrast to what was seen in other countries, the rapid spread of Delta did not lead to a large increase in the number of cases and deaths reported in Brazil. We suggest that this was likely due to the relatively successful early vaccination campaign coupled with natural immunity acquired following prior infection with Gamma. Our data reinforces reports of the increased transmissibility of the Delta variant and, considering the increasing concern due to the recently identified Omicron variant, argues for the necessity to strengthen genomic monitoring on a national level to quickly detect and curb the emergence and spread of other VOCs that might threaten global health.
Mechanically ventilated patients shed high titre live SARS-CoV2 for extended periods from both the upper and lower respiratory tract
Authors: Saud Zack , Ponsford Mark , Bentley Kirsten , Cole Jade M , Pandey Manish , Jolles Stephen , Fegan Chris , Humphreys Ian , Wise Matt P , Stanton Richard
Published: December 2021

Background

SARS-CoV-2 infection can lead to severe acute respiratory distress syndrome needing intensive care admission and may lead to death. As a virus that transmits by respiratory droplets and aerosols, determining the duration of viable virus shedding from the respiratory tract is critical for patient prognosis, and informs infection control measures both within healthcare settings and the public domain.

Methods

We examined upper and lower airway respiratory secretions for both viral RNA and infectious virions in mechanically ventilated patients admitted to the intensive care unit of the University Hospital of Wales. Samples were taken from the oral cavity (saliva), oropharynx (sub-glottic aspirate), or lower respiratory tract (non-directed bronchoalveolar lavage (NBL) or bronchoalveolar lavage (BAL)) and analyzed by both qPCR and plaque assay.

Results

117 samples were obtained from 25 patients. qPCR showed extremely high rates of positivity across all sample types, however live virus was far more common in saliva (68%) than in BAL/NBAL (32%). Average titres of live virus were higher in subglottic aspirates (4.5×107) than in saliva (2.2×106) or BAL/NBAL (8.5×106), and reached >108PFU/ml in some samples. The longest duration of shedding was 98 days, while the majority of patients (14/25) shed live virus for 20 days or longer.

Conclusions

Intensive care unit patients infected with SARS-CoV-2 can shed high titres of virus both in the upper and lower respiratory tract, and tend to be prolonged shedders. This information is important for decision making around cohorting patients, de-escalation of PPE, and undertaking potential aerosol generating procedures.

Patients on intensive therapy infected with SARS-CoV-2 tend to be prolonged shedders, excreting virus for far beyond the time periods specified in current guidelines, and live virus titres can be extremely high in both the upper and lower respiratory tracts.