The Nairovirus causing the Crimean Congo Hemorrhagic Fever (CCHF) is transferred mainly via ticks and farm animals. Its incidence is spread over several countries broadly categorized into continents, including Europe, Asia, and Africa. This editorial is shedding light on this concerning pathogen and suggesting several strategies to tackle it.

We present a case report of a 46-year-old immunocompetent male, in whom the first clinical symptom of syphilis was binocular visual deterioration. Due to prompt diagnosis and casual treatment reconstitution of vision occurred within four weeks.

Trigeminal trophic syndrome is a rare cause of persistent secondary facial ulceration due to trigeminal nerve damage. Lesions often mimic squamous cell carcinoma but can be differentiated histologically. We present an unusual case of trigeminal trophic syndrome with both clinical and histologic features of squamous cell carcinoma.

Environmental pollution can result in poor sperm quality either directly or indirectly. However, adaptive and compensatory sperm morphology change and motility improvement rapidly evolved in tree sparrow (Passer montanus) inhabited the polluted area within the past 65 years. To identify the genetic underpinnings of the rapidly evolved sperm phenotype, both the population genomic and transcriptomic methods were used in our study. We identified a gene encoding serine/threonine protein kinase PIM1 which may drive the rapid phenotypic evolution of sperm. An unprecedent and remarkably expansion of PIM gene family caused by tandem and segmental duplication of PIM1 was subsequently noticed in tree sparrow genome. Most of the PIM1 duplicates showed a testis-specific expression pattern, suggesting their functions related to male reproduction. Furthermore, the elevated expression level of PIM1 was consistent with our earlier findings of longer and faster swimming sperm in polluted site, indicating an important role of duplicated PIM1 in facilitating rapid evolution of sperm. Our results suggested that the duplicated PIM1 provide sources of genetic variation that enable rapid evolution of sperm under environmental heavy metal pollution. The findings in this study verified the duplicated genes can be targets of selection and predominant sources for rapid adaptation to environmental change and shed lights on the sperm evolution under environmental stress.

Epilepsy is a common neurological disorder in which excessive and abnormal neuronal discharges can be observed and is characterized by recurrent seizures. The epileptogenesis is usually involved in neuropathological processes such as ion channel dysfunction, neuronal injury, inflammatory response, synaptic plasticity, glial cell proliferation and mossin fibrosis, currently the pathogenesis of epilepsy is not yet completely understood. A growing body of studies have shown that epigenetic regulation, such as histone modifications, DNA methylation, noncoding RNAs (ncRNAs), and restrictive element-1 silencing transcription factor/neuron-restrictive silencing factor (REST/NRSF) are also involved in epilepsy. However, the functional roles of epigenetics in pathogenesis and treatment of epilepsy are still to be explored. Therefore, in this review, we will summarize latest advances concerning the mechanisms of epigenetic regulation in epilepsy, which provide novel insight into therapy and biomarkers for epilepsy.

Background and Purpose: Mitochondrial dysfunction is a driving factor in the development and progression of diabetic kidney disease (DKD). Our laboratory discovered that the 2-adrenoceptor agonist formoterol regulates mitochondrial dynamics in the hyperglycemic renal proximal tubule. Here, we identified signaling mechanisms through which formoterol regulates the mitochondrial fission protein Drp1 and the mitochondrial fusion protein Mfn1. Experimental Approach: Using primary cultures of renal proximal tubule cells (RPTC) exposed to high glucose, we investigated the role of glucose on RhoA/ROCK1/Drp1 and Raf/MEK1/2/ERK1/2/Mfn1 signaling pathways using pharmacological inhibitors, and the effect of formoterol on these pathways. Key Results: In high glucose, RhoA became hyperactive, leading to ROCK1-induced activation of Drp1. Using pharmacological inhibitors, formoterol signals through G subunits of the 2-adrenoceptor to decrease RhoA/ROCK1-mediated activation of Drp1. Formoterol restored this pathway by preventing the interaction of RhoA with the guanine nucleotide exchange factor p114RhoGEF. Inhibition of RhoA/ROCK1/Drp1 restored maximal mitochondrial respiration. Formoterol also restored Mfn1 through a separate G-dependent mechanism composed of Raf/MEK1/2/ERK1/2/Mfn1. RPTC exposed to high glucose exhibited decreased Mfn1 activation, which was restored with formoterol. Pharmacological inhibition of G, Raf and MEK1/2 also restored Mfn1 activity. Conclusion and Implications: We demonstrate that glucose promotes the interaction between RhoA and p114RhoGEF, leading to increased RhoA/ROCK1/Drp1, and glucose decreases Mfn1 activity through activation of Raf/MEK1/2/ERK1/2. Formoterol restores these pathways and mitochondrial function in response to elevated glucose. Formoterol activates three separate integrative pathways that promote mitochondrial biogenesis, decreased fission and increased fusion in RPTC, supporting its potential as a therapeutic for DKD.

Assessing the Feto-Maternal Outcome of Chronic Liver Disease in Pregnancy: An Obstetric Nightmare Isha Wadhawan1, Avir Sarkar2#, Nancy Bhagat3, Prerana Nagabhushana41 - MD, Diplomate ABOG, MRCOG, FMAS, Department of Obstetrics and Gynaecology, ESIC Medical College and Hospital, Faridabad, Haryana, Indiae mail: isha.wadhawan@gmail.com2 - MD, DNB, FMAS, Department of Obstetrics and Gynaecology, ESIC Medical College and Hospital, Faridabad, Haryana, Indiae mail: avirsarkar93@gmail.com3 - MD, DNB, Department of Obstetrics and Gynaecology, Government Medical College, Jammu, Indiae mail: nancygmc29@gmail.com4 - MD, DNB, Department of Obstetrics and Gynaecology, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry, Indiae mail: nprerana1993@gmail.com# Corresponding author: Avir SarkarAddress: House number 140, 3F- NIT, Faridabad, Haryana-121001, Indiae mail: avirsarkar93@gmail.comRunning title: Chronic liver disease in pregnancyConflict of interest: The authors declare that there is no conflict of interest between themFunding: No external funding has been received for this studyEthics approval: Institutional ethics committee approval was obtained prior to the commencement of the study (NK/4910/MD/312)

Objective We compared maternal and foetal outcomes between termination gestational age at 40 0/7-40 6/7 and 41 0/7-41 6/7 weeks. Design Retrospective cohort, observational, single-centre study. Setting Jiangsu Province Hospital, China: January 2020-December 2020 Population 1569 low-risk pregnancies. Methods Maternal medical records and neonatal delivery data were analysed retrospectively. Main outcome measures Difference in adverse outcomes of mothers and babies between termination gestational age at 40 0/7-40 6/7 and 41 0/7-41 6/7 weeks. Results The study included 1569 pregnancies, with 1107 (70.6%) delivered at 40 0/7-40 6/7 weeks and 462 (29.4%) delivered at 41 0/7-41 6/7 weeks. Intrapartum caesarean section (8% versus 16%, P<0.001), meconium-stained amniotic fluid (13% versus 19%, P=0.004), episiotomy (41% versus 49%, P=0.011), and macrosomia (13% versus 18%, P=0.026) were significantly lower at 40 0/7-40 6/7 weeks. The premature rupture of membranes rate(22% versus 12%, P<0.001), spontaneous labour rate(54% versus 20%, P<0.001), vaginal delivery rate of artificial rupture of membrane induction (83% versus 71%, P=0.006) and balloon catheter combined with oxytocin induction (88% versus 79%, P=0.049) were significantly higher at 40 0/7-40 6/7 weeks. Conclusions Low-risk women who delivered at 40 0/7-40 6/7 weeks showed better outcomes in terms of the mother’s and baby’s health, such as decreased rates of intrapartum caesarean section, meconium-stained amniotic fluid, episiotomy, and macrosomia, compared with those who delivered at 41 0/7-41 6/7 weeks. Tweetable abstract Induction at 40 weeks will decrease adverse outcomes of mothers and babies.

Background Although studies have shown that the microbial presence of follicular fluid (FF) can lead to poor IVF outcomes, there is still a lack of consensus. Objective The aim of the study was to synthesize these disparate studies to comprehensively investigate the potential impact of the microbial presence in the FF of infertile women on IVF outcomes. Search strategy Following preliminary searches to find Medical Subject Heading (MeSH) terms plus free terms, a systematic search was performed in PubMed in July 2022. Selection criteria The population was infertile women undergoing IVF treatment. The exposure was the microbiota of FF. The positivity of FF was defined according to the original studies. Primary outcomes included the clinical pregnancy rate and fertilization rate Data Collection and Analysis Data collected for each study were analyzed using RevMan 5.4 software available on the Cochrane website. Main results The FFs of 285 women were detected positively by nonspecific flora detection and specific flora detection. The clinical pregnancy rate of the FF-positive group was significantly lower than that of the FF-negative group in the microbial culture and identification group (OR:0.61, 95% CI:0.21-1.71) and in the ELISA test group (OR:0.41, 95% CI:0.21-0.80). In the IPA test group, which included only one study, the pregnancy rate in the FF-positive group was higher than that in the FF-negative group, but the results were low quality. Conclusions Currently, there is still a lack of evidence for the associations of the presence of microorganisms in FF with IVF outcomes.

This work reports a theoretical study of a novel family of multi-coordinated noble gas (Ng) complexes, Xe(AuF)n (n = 2-4). Geometrical optimization at the LC-ωPBE-D3/def2TZVPP level locates two types of structures based on the bond-bending isomerism induced by an intramolecular competition between Xe-Au covalent bonding and Au···Au aurophilic interactions. They both comprise a center Xe atom serving as an electron donor binding to AuF moieties, but pronouncedly differ in the Au-Au distance and Au-Xe-Au bending angle. Comprehensive chemical bonding analysis undisputedly demonstrates that aurophilic interactions exist and affect the strength of Xe-Au bonds whose covalent nature is evident. By scanning the potential energy surface of Xe(AuF)2 with arbitrary one atom being substituted by its analogue, we found only Xe(AuF)2 and Xe(AuCl)2 feature bond-bending isomerism, due to the highly electronegative F/Cl atom inducing strongly covalent Xe-Au bond via electron donation-feedback mechanism. The present work predicts multi-coordinated Ng-metal complexes and demonstrates the bond-bending isomerism, which could be an interesting addition and call out more attentions to the research field of Ng chemistry.

Pathogenic variants in the ETS Variant Transcription Factor 6 ( ETV6) are associated with inherited thrombocytopenia with predisposition to hematologic malignancy. We report two young sisters who presented with mild thrombocytopenia and mild bleeding symptoms. Further family history led to suspicion of inherited etiology, and genetic sequencing revealed a novel ETV6 variant (c.1085A>G) of paternal origin. Collaboration between clinical and laboratory teams allowed resolution of variant classification to likely pathogenic. Our report demonstrates genetic testing for inherited thrombocytopenia should be considered for children with mild, variable, and non-specific bleeding symptoms.

Abstract Objective To compare the Liverpool Causality Assessment Tool versus Naranjo Scale for screening suspected adverse drug reaction (ADR) cases. Methods We retrospectively reviewed patient charts with a history of suspected ADR, scored using both instruments and determined how each correlates with laboratory and other investigations. 924 charts from the Clinical Pharmacology Clinic at the London Health Sciences Centre were reviewed and 529 charts contained objective findings to support or against the diagnosis of ADR. The participant age ranged from 1 month old to 93 years. We determined the sensitivity and specificity of Liverpool and Naranjo tools for predicting ADRs with scores ranging from “Possible” to “Definite” were considered positive and “Unlikely/Doubtful” as negative for ADR. These results were confirmed by laboratory or clinical (re-challenge) testing in 529 cases. Results Liverpool causality tool had sensitivity (SN) of 97.2% ± 2.4% and specificity (SP) of 2.3% ± 1.57%. The positive (PPV) and negative predictive values (NPV) were 34.1% and 61.5%, respectively. The Naranjo scale had SN of 81.2% ± 5.69% and SP of 13.2% ± 3.56%. PPV and NPV were 32.7% and 57.5%, respectively. Conclusions The Liverpool Causality Assessment Tool is a more sensitive tool than the Naranjo Scale in the assessment of possible ADRs but both tools have poor specificity. The Liverpool Tool can be a useful screening tool in settings where other tests may not be readily available. However the low PPV and NPV of both instruments suggests pursue further testing is needed to confirm or deny an ADR.

Aim: To identify older patients’ risk factors for drug-related readmissions and assess the preventability of older patients’ drug-related revisits. Methods: Post-hoc analysis of a randomised clinical trial with patients aged ≥ 65 years at eight wards within four hospitals in Sweden. The primary outcome used to identify risk factors was drug-related readmission within 12 months post-discharge. A Cox proportional hazards model was made with sociodemographic and clinical baseline characteristics. Four hundred trial participants were randomly selected and their revisits (admissions and emergency department visits) were assessed to identify potentially preventable drug-related revisits, related diseases and causes. Results: Among 2,637 patients (median age (interquartile range) 81 (74–87) years), 582 (22%) experienced a drug-related readmission within 12 months. Sixteen risk factors (hazard ratio > 1, p < 0.05) related to age, previous hospital visits, medication use, multimorbidity and cardiovascular, liver, lung and peptic ulcer disease were identified. The 400 patients experienced a total of 522 hospital revisits, of which 85 (16%) were potentially preventable drug-related revisits. The two most prevalent diseases and causes related to preventable revisits were heart failure (n=24, 28%) and chronic obstructive pulmonary disease (n=13, 15%), and inadequate treatment (n=23, 27%) and insufficient or no follow-up (n=22, 26%). Conclusion: Risk factors for drug-related readmissions in older hospitalised patients were age, previous hospital visits, medication use and multiple diseases. Potentially preventable drug-related hospital revisits are common and might be prevented through adequate medication use and follow-up in older patients with cardiovascular or lung disease.

Background There is evidence gastrointestinal (GI) motility may play a role in the development of GI cancers. Weak opioids (codeine and dihydrocodeine) decrease GI motility, but their effect on GI cancer risk has not been assessed. Aim To assess the association between weak opioids and cancers of the GI tract. Methods A series of nested case-control studies was conducted using Scottish general practice records from the Primary Care Clinical Informatics Unit Research database. Oesophageal (n=2,432), gastric (n=1,443), and colorectal cancer (n=8,750) cases, diagnosed between 1999 and 2011, were identified and matched with up to five controls. Weak opioid use was identified from prescribing records. Odds ratios (OR) and 95% confidence intervals (CI) were calculated using conditional logistic regression, adjusting for relevant comorbidities and medication use. Results There was no association between weak opioids and colorectal cancer (adjusted OR=0.96, CI 0.90, 1.02, p=0.15). There was an increased risk of oesophageal (adjusted OR=1.16, CI 1.04, 1.29, p=0.01) and gastric cancer (adjusted OR=1.26, CI 1.10, 1.45, p=0.001). The associations for oesophageal cancer, but not gastric cancer, were attenuated when weak opioid users were compared with users of another analgesic (adjusted OR=1.03 CI 0.86, 1.22, p=0.76 and adjusted OR=1.29 CI 1.02, 1.64, p=0.04 respectively). Conclusion In this large population-based study, there was no consistent evidence of an association between weak opioids and oesophageal or colorectal cancer risk, but a small increased risk of gastric cancer. Further investigation is required to determine whether this association is causal or reflects residual confounding or confounding by indication.

The recent introduction of the European Medical Device Regulation poses stricter legislation for manufacturers developing medical devices in the EU. Many devices have been placed into a higher risk category, thus requiring more data before market approval, and a much larger focus has also been placed on safety. For implantable and Class III devices, the highest risk class, clinical evidence is a necessity. However, the requirements of clinical study design and developmental outcomes are only described in general terms due to the diversity of devices. A structured approach to determining the requirements for the clinical development of high-risk medical devices is introduced, utilising the question-based development framework, which is already used for pharmaceutical drug development. An example of a novel implantable device for haemodialysis demonstrates how to set up a relevant target product profile defining the device requirements and criteria. This can then be used to define specific questions to be answered during clinical development, based upon 5 general questions as specified by the question-based framework. The result is a clear and evaluable overview of requirements and methodologies to verify and track these requirements in the clinical development phase. Development organisations will be guided to the optimal route, also to abandon projects destined for failure in an early stage to minimise development risks. Moreover, the framework facilitates communication with funding agencies, regulators and clinicians, while highlighting remaining “known unknowns” that are to be answered in the post-market phase after sufficient benefit has been established relative to the risks.

Background Middle East Respiratory Syndrome Coronavirus (MERS-CoV) emerged in the Middle East in 2012 and was associated with significant morbidity and mortality. Considering the role of cytokines in MERS-CoV infection and pathogenesis, this study was performed to assess the plasma levels of proinflammatory cytokines among MERS-CoV patients. Methods A total of 46 MERS-CoV infected patients (19 asymptomatic and 27 with symptoms) were compared to 52 normal healthy controls for the levels of proinflammatory cytokines (IL-1β, TNF-α, IL-17, IL-7, IL-6, IFN-α, IL-15) using a customized luminex kit. Results There was no difference observed between asymptomatic MERS-CoV patients and controls, however; the mean plasma levels among MERS-CoV symptomatic patients were significantly higher than asymptomatic MERS-CoV patients and normal controls: IL-1β (16.89 ± 1.23 pg/mL vs 12.80 ± 0.59 pg/mL; p<0.001), TNF-α (14.04 ± 0.93 pg/mL vs 10.35 ± 0.29 pg/mL; p<0.0001), IL-17 (14.33 ± 0.89 pg/mL vs 11.47 ± 0.61 pg/mL; p<0.001), IL-7 (21.56 ± 1.00 pg/mL vs 16.31 ± 0.30 pg/mL; p<0.0001), IL-6 (156.5 ± 37.90 pg/mL vs 18.60 ± 1.59 pg/mL; p<0.0001), and IFN-α (68.73 ± 13.06 pg/mL vs 23.57 ± 1.05 pg/mL; p<0.0001). The mean plasma levels of IL-15 were no different among the groups. Conclusion Significantly elevated proinflammatory cytokines (IL-1β, TNF-α, IL-17, IL-7, IL-6, IFN-α) among symptomatic MERS-CoV infected patients may contribute to manifestations of cytokine storm frequently observed among critically ill MERS-CoV patients.

Objectives: Patient-prosthesis mismatch (PPM) may impair functional capacity and survival after aortic valve replacement (AVR). A mechanical prosthesis tends to have less PPM than a biological prosthesis, but these differences in clinical outcomes remain unclear. This study aimed to investigate the impact of PPM on long-term survival and quality of life (QoL) after mechanical and biological AVRs. Methods: The presence of PPM was defined in 595 consecutive patients who had undergone isolated AVR. Patients were divided into two groups according to whether they had received a biological or mechanical prosthesis. The groups with and without PPM present were compared with regard to baseline characteristics, operative characteristics, survival, severe complications, freedom from angina and QoL up to 6 years of follow-up. PPM calculation was performed using the EOA value provided by the manufacturer for every prosthesis divided by the patient’s body surface area. Results: The moderate-to-severe PPM rates were 69.8% and 3.7% after biological and mechanical prostheses implantation, respectively. Patients with a biological prosthesis implanted had mean survival significantly shorter in the PPM group (50.2 months, 95% confidence interval [CI] 45.2-55.3) when compared to the no-PPM group (60.1 months, 95% CI 55.7-64.4) (p = 0.035). In the mechanical prosthesis group, there was no difference in mean survival between the PPM group (66.6 months, 95% CI 58.3-74.9) when compared to the no-PPM group (64.9 months, 95% CI 62.6-67.2) (p = 0.50). The physical score of the QoL questionnaire was significantly lower in the PPM group when compared to the no-PPM group with a biological prosthesis (39.4 ± 8.4 vs. 45.7 ± 10.1, p < 0.001) compared to patients with a mechanical prosthesis (43.9 ± 9.4 vs. 46.9 ± 8.3, p = 0.18). Conclusions: PPM is common after biological valve implantation and significantly impacts long-term survival and QoL. If the risk of PPM after implantation of a biological prosthesis is suspected, prospective strategies to avoid PPM at the time of operation are warranted.

Background/Aim: A transposition complex with an interrupted aortic arch (IAA) is rare and surgically challenging because of its anatomical diversity and complexity. Herein, we aimed to present our 20-year experience with one-stage arterial switch surgery associated with IAA repair. Methods: From January 2000 to April 2017, 11 patients were diagnosed with transposition complex and IAA and underwent one-stage repair at our center. These patients were retrospectively reviewed. Two patients had transposition of the great arteries, while the others had double outlet right ventricles, of whom eight had subpulmonary ventricular septal defects (Taussig-Bing anomalies), and one had a non-committed ventricular septal defect. In terms of the IAA, three patients underwent repair by extended end-to-end anastomosis, and one 16-mm prosthetic vascular graft was replaced in an elder patient. The remaining patients underwent autologous pericardial patch enlargement. All the variables were summarized and reported with descriptive statistics. Results: Three early deaths occurred in this study. The median follow-up time was approximately 5 years (range: 3 – 14 years). No late deaths were reported. Only one patient required percutaneous re-intervention for recurrent coarctation. Moderate aortic regurgitation was observed in three patients. However, there was no requirement for aortic valvuloplasty or valve replacement. One patient had more than moderate tricuspid regurgitation. The other survivors are presently healthy. Conclusions: Although one-stage repair for transposition complex and IAA still has non-negligible mortality even in older children, the late outcomes of survivors are acceptable. Owing to the high rate of valve regurgitation, closer follow-up is necessary for these patients.

Laparoscopic surgery is the standard of care for various abdominal pathologies due to apparent advantages. Nevertheless, the initial steps of the Veress needle or trocar are inserted blindly in laparoscopic surgeries, which may cause major vascular, bowel, or urinary tract injuries. We report two cases of vascular laparoscopic entry injuries.

Sweet Syndrome, or acute febrile neutrophilic dermatosis, is characterized by tender erythematous skin lesions (Figure 1 and 2) frequently associated with fever and leukocytosis. Despite being an uncommon inflammatory disease, it is triggered by infections, pregnancy, drugs and malignancy. We report a case of a man diagnosed with Sweet Syndrome.

Suturing the retroperitoneum is a common technique in laparoscopic hysterectomy, which is reported to reduce vaginal cuff infection and organ evisceration in case vaginal cuff dehiscence occurs. However, physicians should take into account that it may cause internal hernia.

One of the serious side effects of COVID-19 vaccines is vaccine-induced immune thrombotic thrombocytopenia (VITT). A young man presented with pulmonary thromboembolism 7 days after receiving inactivated COVID-19 vaccine BIBP developed by Sinopharm/China. Close surveillance of possible adverse reactions a crucial step to encourage population to participate in vaccine campaign.

We report a case of radiation-induced myofibroblastoma of the right nasal cavity in a patient with a remote history of radiotherapy for pediatric retinoblastoma. The patient required maxillectomy and ethmoidectomy. To our knowledge, a rare number of cases have been reported in this location.

Mitigating Esophageal Injury after Atrial Fibrillation Ablation Guided by Ablation Index; CLOSEr to goalJason S. Chinitz, MD1 and Eli Q. Harris, MD21.South Shore University HospitalNorthwell HealthBay Shore, NY2. Nassau University Medical CenterEast Meadow, NYFinancial support : none.Disclosures : Dr. Chinitz serves on the scientific advisory board for Biosense Webster and has received consulting fees