Reduced levels of MRE11 cause disease phenotypes distinct from ataxia telangiectasia-like disorder.

The MRE11/RAD50/NBS1 (MRN) complex plays critical roles in cellular responses to DNA double-strand breaks. MRN is involved in end binding and processing, and it also induces cell cycle checkpoints by activating the ataxia-telangiectasia mutated (ATM) protein kinase. Hypomorphic pathogenic variants in the MRE11, RAD50, or NBS1 genes cause autosomal recessive genome instability syndromes featuring variable degrees of dwarfism, neurological defects, anemia, and cancer predisposition. Disease-associated MRN alleles include missense and nonsense variants, and many cause reduced protein levels of the entire MRN complex. However, the dramatic variability in the disease manifestation of MRN pathogenic variants is not understood. We sought to determine if low protein levels are a significant contributor to disease sequelae and therefore generated a transgenic murine model expressing MRE11 at low levels. These mice display dramatic phenotypes including small body size, severe anemia, and impaired DNA repair. We demonstrate that, distinct from ataxia telangiectasia-like disorder caused by MRE11 pathogenic missense or nonsense variants, mice and cultured cells expressing low MRE11 levels do not display the anticipated defects in ATM activation. Our findings indicate that ATM signaling can be supported by very low levels of the MRN complex and imply that defective ATM activation results from perturbation of MRN function caused by specific hypomorphic disease mutations. These distinct phenotypic outcomes underline the importance of understanding the impact of specific pathogenic MRE11 variants, which may help direct appropriate early surveillance for patients with these complicated disorders in a clinical setting.

Phenotypic effects of mutations observed in the neuraminidase of human origin H5N1 influenza A viruses.

Global spread and regional endemicity of H5Nx Goose/Guangdong avian influenza viruses (AIV) pose a continuous threat for poultry production and zoonotic, potentially pre-pandemic, transmission to humans. Little is known about the role of mutations in the viral neuraminidase (NA) that accompanied bird-to-human transmission to support AIV infection of mammals. Here, after detailed analysis of the NA sequence of human H5N1 viruses, we studied the role of A46D, L204M, S319F and S430G mutations in virus fitness in vitro and in vivo. Although H5N1 AIV carrying avian- or human-like NAs had similar replication efficiency in avian cells, human-like NA enhanced virus replication in human airway epithelia. The L204M substitution consistently reduced NA activity of H5N1 and nine other influenza viruses carrying NA of groups 1 and 2, indicating a universal effect. Compared to the avian ancestor, human-like H5N1 virus has less NA incorporated in the virion, reduced levels of viral NA RNA replication and NA expression. We also demonstrate increased accumulation of NA at the plasma membrane, reduced virus release and enhanced cell-to-cell spread. Furthermore, NA mutations increased virus binding to human-type receptors. While not affecting high virulence of H5N1 in chickens, the studied NA mutations modulated virulence and replication of H5N1 AIV in mice and to a lesser extent in ferrets. Together, mutations in the NA of human H5N1 viruses play different roles in infection of mammals without affecting virulence or transmission in chickens. These results are important to understand the genetic determinants for replication of AIV in mammals and should assist in the prediction of AIV with zoonotic potential.

Reducing Quantitative Uncertainty Caused by Data Processing in Untargeted Metabolomics.

Processing liquid chromatography-mass spectrometry-based metabolomics data using computational programs often introduces additional quantitative uncertainty, termed computational variation in a previous work. This work develops a computational solution to automatically recognize metabolic features with computational variation in a metabolomics data set. This tool, AVIR (short for "Accurate eValuation of alIgnment and integRation"), is a support vector machine-based machine learning strategy (https://github.com/HuanLab/AVIR). The rationale is that metabolic features with computational variation have a poor correlation between chromatographic peak area and peak height-based quantifications across the samples in a study. AVIR was trained on a set of 696 manually curated metabolic features and achieved an accuracy of 94% in a 10-fold cross-validation. When tested on various external data sets from public metabolomics repositories, AVIR demonstrated an accuracy range of 84%-97%. Finally, tested on a large-scale metabolomics study, AVIR clearly indicated features with computational variation and thus guided us to manually correct them. Our results show that 75.3% of the samples with computational variation had a relative intensity difference of over 20% after correction. This demonstrates the critical role of AVIR in reducing computational variation to improve quantitative certainty in untargeted metabolomics analysis.

Itaconate and derivatives reduce interferon responses and inflammation in influenza A virus infection.

Excessive inflammation is a major cause of morbidity and mortality in many viral infections including influenza. Therefore, there is a need for therapeutic interventions that dampen and redirect inflammatory responses and, ideally, exert antiviral effects. Itaconate is an immunomodulatory metabolite which also reprograms cell metabolism and inflammatory responses when applied exogenously. We evaluated effects of endogenous itaconate and exogenous application of itaconate and its variants dimethyl- and 4-octyl-itaconate (DI, 4OI) on host responses to influenza A virus (IAV). Infection induced expression of ACOD1, the enzyme catalyzing itaconate synthesis, in monocytes and macrophages, which correlated with viral replication and was abrogated by DI and 4OI treatment. In IAV-infected mice, pulmonary inflammation and weight loss were greater in Acod1-/- than in wild-type mice, and DI treatment reduced pulmonary inflammation and mortality. The compounds reversed infection-triggered interferon responses and modulated inflammation in human cells supporting non-productive and productive infection, in peripheral blood mononuclear cells, and in human lung tissue. All three itaconates reduced ROS levels and STAT1 phosphorylation, whereas AKT phosphorylation was reduced by 4OI and DI but increased by itaconate. Single-cell RNA sequencing identified monocytes as the main target of infection and the exclusive source of ACOD1 mRNA in peripheral blood. DI treatment silenced IFN-responses predominantly in monocytes, but also in lymphocytes and natural killer cells. Ectopic synthesis of itaconate in A549 cells, which do not physiologically express ACOD1, reduced infection-driven inflammation, and DI reduced IAV- and IFNγ-induced CXCL10 expression in murine macrophages independent of the presence of endogenous ACOD1. The compounds differed greatly in their effects on cellular gene homeostasis and released cytokines/chemokines, but all three markedly reduced release of the pro-inflammatory chemokines CXCL10 (IP-10) and CCL2 (MCP-1). Viral replication did not increase under treatment despite the dramatically repressed IFN responses. In fact, 4OI strongly inhibited viral transcription in peripheral blood mononuclear cells, and the compounds reduced viral titers (4OI>Ita>DI) in A549 cells whereas viral transcription was unaffected. Taken together, these results reveal itaconates as immunomodulatory and antiviral interventions for influenza virus infection.

Correction: Itaconate and derivatives reduce interferon responses and inflammation in influenza A virus infection.

[This corrects the article DOI: 10.1371/journal.ppat.1010219.].

Molecular characterization of the whole genome of H9N2 avian influenza virus isolated from Egyptian poultry farms.

H9N2 avian influenza viruses (AIVs) affect both poultry and humans on a global level, and they are especially prevalent in Egypt. In this study, we sequenced the entire genome of AIV H9N2 isolated from chickens in Egypt in 2021, using next-generation sequencing (NGS) technology. Phylogenetic analysis of the resulting sequences showed that the studied strain was generally monophyletic and grouped within the G1 sublineage of the Eurasian lineage. Four segments (polymerase basic 2 [PB2], polymerase basic 1 [PB1], polymerase acidic [PA], and non-structural [NS]) were related to Egyptian genotype II, while the nucleoprotein (NP), neuraminidase (NA), matrix (M), and haemagglutinin (HA) segments were related to Egyptian genotype I. Molecular analysis revealed that HA protein contained amino acid residues (191H and 234L) that suggested a predilection for attaching to human-like receptors. The antigenic sites of HA had two nonsynonymous mutations: V194I at antigenic site A and M40K at antigenic site B. Furthermore, the R403W and S372A mutations, which have been observed in H3N2 and H2N2 strains that caused human pandemics, were found in the NA protein of the detected strain. The internal proteins contained virulence markers: 504V in the PB2 protein, 622G, 436Y, 207K, and 677T in the PB1 protein, 127V, 550L, and 672L in PA protein, and 64F and 69P in the M protein. These results show that the detected strain had undergone intrasubtype reassortment. Furthermore, it contains changes in the viral proteins that make it more likely to be virulent, raising a question about the tendency of AIV H9N2 to become highly pathogenic in the future for both poultry and humans.

Evaluation of the effect of diode laser application on the hydrophilicity, surface topography, and chemical composition of titanium dental implant surface.

PURPOSE: Attempts have been made to decontaminate the implant surface by using diode lasers. However, the parameters that provide efficient decontamination without altering the topography or surface characteristics of titanium implants are still unclear. The aim of the present study was to evaluate the effect of altering the power of diode laser (940 nm) application on the hydrophilicity, surface topography, and chemical composition of sandblasted, large grit, acid-etched (SLA) treated titanium alloy implant surface. MATERIALS AND METHODS: Thirty-six SLA-treated titanium discs (Dentis Co., Ltd.) were used in this study. The hydrophilicity of all discs was measured by using a contact angle goniometer (190 CA; Rame-hart Co, Ltd). Discs were randomly divided into four groups (n = 9 each) based on the power of the diode laser used. Group I (control, no lasing group), group II: treated with 1 W power, group III: 2 W power, and group IV: 3 W power. The chemical composition of the SLA discs was evaluated by using energy dispersive x-ray spectroscopy (EDX) before laser application. Hydrophilicity was reevaluated after the application of laser irradiation. The surface topography of all discs was examined. Changes in the chemical composition of the titanium discs were investigated following the lasing procedure. Morphometric analysis of the surface area (µm2 ) of the indentations created following laser application was also evaluated. Data were collected and the Shapiro-Wilk test of normality was used. Comparisons between the four study groups were done by using the Kruskal-Wallis test, while that to evaluate the morphometric analysis of the surface area was done by using One-way ANOVA (P < 0.05). RESULTS: The average contact angle of the drop of distilled water to the SLA discs significantly decreased after laser treatment (P < 0.05). The largest contact angle was measured in the control group, followed by the 1 W group, and the 2 W group. The smallest angle was measured in the 3 W group. Considerable surface alterations such as melting and flattening were observed on examination of the surface topography of the 3 W group followed by the 2 W group. The least changes were observed in association with the 1 W group in comparison to the control group. The EDX analysis showed the appearance of peaks of the oxygen and carbon elements after the lasing procedure with the highest percentage in the 3 W group. The average of the surface area of the created indentations significantly increased with increasing the power of the diode laser used (P < 0.05). CONCLUSIONS: The application of diode laser (940 nm) with 2 W and 3 W powers significantly altered the hydrophilicity, the surface topography, and the chemical composition of titanium discs. Diode laser (940 nm) with 1 W power can be safely used on SLA titanium implant surfaces with no damaging effect on the surface topography or hydrophilicity.

Incidence, household transmission, and neutralizing antibody seroprevalence of Coronavirus Disease 2019 in Egypt: Results of a community-based cohort.

SARS-CoV-2 virus is transmitted in closed settings to people in contact with COVID-19 patients such as healthcare workers and household contacts. However, household person-to-person transmission studies are limited. Households participating in an ongoing cohort study of influenza incidence and prevalence in rural Egypt were followed. Baseline enrollment was done from August 2015 to March 2017. The study protocol was amended in April 2020 to allow COVID-19 incidence and seroprevalence studies. A total of 290 households including 1598 participants were enrolled and followed from April to October 2020 in four study sites. When a participant showed respiratory illness symptoms, a serum sample and a nasal and an oropharyngeal swab were obtained. Swabs were tested by RT-PCR for SARS-CoV-2 infection. If positive, the subject was followed and swabs collected on days three, six, nine, and 14 after the first swab day and a serum sample obtained on day 14. All subjects residing with the index case were swabbed following the same sampling schedule. Sera were collected from cohort participants in October 2020 to assess seroprevalence. Swabs were tested by RT-PCR. Sera were tested by Microneutralization Assay to measure the neutralizing antibody titer. Incidence of COVID-19, household secondary attack rate, and seroprevalence in the cohort were determined. The incidence of COVID-19 was 6.9% and the household secondary attack rate was 89.8%. Transmission within households occurred within two-days of confirming the index case. Infections were asymptomatic or mild with symptoms resolving within 10 days. The majority developed a neutralizing antibody titer by day 14 post onset. The overall seroprevalence among cohort participants was 34.8%. These results suggest that within-household transmission is high in Egypt. Asymptomatic or mild illness is common. Most infections seroconvert and have a durable neutralizing antibody titer.

Does dengue and COVID-19 co-infection have worse outcomes? A systematic review of current evidence.

In dengue-endemic regions, the co-infection with SARS-CoV-2 and dengue is a significant health concern. Therefore, we performed a literature search for relevant papers in seven databases on 26 Spetember 2021. Out of 24 articles, the mortality rate and intensive care unit (ICU) admission were 19.1% and 7.8%, respectively. The mean hospital stay was 11.4 days. In addition, we identified two pregnancies with dengue and COVID-19 co-infection; one ended with premature rupture of membrane and intrauterine growth restriction fetus, while the other one ended with maternal mortality and intrauterine fetal death. COVID-19 and dengue co-infection had worse outcomes regarding mortality rates, ICU admission, and prolonged hospital stay. Thus, wise-decision management approaches should be adequately offered to these patients to enhance their outcomes. Establishing an early diagnosis might be the answer to reducing the estimated significant burden of these conditions.

The impact of Parkinson's disease on manifestations and outcomes of Covid-19 patients: A systematic review and meta-analysis.

Parkinson's disease (PD) patients who contracted Coronavirus disease 2019 (Covid-19) had a decline in motor functions; nevertheless, there is limited evidence on whether PD patients have a higher risk for contracting Covid-19 or have worse outcomes. This is the first systematic review and meta-analysis to review the impact of PD on the prognosis of Covid-19 patients. We performed a systematic search through seven electronic databases under the recommendations of the Preferred Reporting Items for Systematic Review and Meta-analyses statement (PRISMA) guidelines. The R software version 4.0.2 was used to calculate pooled sample sizes and their associated confidence intervals (95%CI). Finally, we included 13 papers in this study. The pooled prevalence rate of Covid-19 was 2.12% (95%CI: 0.75-5.98). Fever, cough, fatigue and anorexia were the most common symptoms with a rate of 72.72% (95% CI: 57.3 - 92.29), 66.99% (95% CI: 49.08-91.42), 61.58% (95% CI: 46.69-81.21) and 52.55% (95% CI: 35.09-78.68), respectively. The pooled rates were 39.89% (95% CI: 27.09-58.73) for hospitalisation, 4.7% (95% CI: 1.56-14.16) for ICU admission and 25.1% (95%CI: 16.37-38.49) for mortality. On further comparison of hospitalisation and mortality rates among Covid-19 patients with and without PD, there were no significant differences. In conclusion, the prevalence and prognosis of Covid-19 patients seem comparable in patients with PD and those without it. The increased hospitalisation and mortality may be attributed to old age and co-morbidities.

Early satisfactory results of percutaneous repair in neglected achilles tendon rupture.

PURPOSE: This investigation aimed to study the outcome of percutaneous repair of Achilles tendon ruptures regarding patient-reported and objective outcomes. METHODS: This is a retrospective review of a cohort of patients (n = 24) who underwent percutaneous repair of neglected Achilles rupture in the period between 2013 and 2019. Included patients were adults with closed injuries, presented 4-10 weeks after rupture, with intact deep sensation. All underwent clinical examination, X-rays to exclude bony injury and MRI for diagnosis confirmation. All underwent percutaneous repair by the same surgeon, using the same technique and rehabilitation protocol. The postoperative assessment was done subjectively using ATRS and AOFAS score and objectively using a percentage of heel rise comparison to the normal side and calf circumference difference. RESULTS: The mean follow-up period was 14.85 months ± 3 months. Average AOFAS scores at 6,12 months were 91 and 96, respectively, showing statistically significant improvement from pre-op level (P < 0.001). Percentage of heel rise on the affected side and calf circumference showed statistically significant improvement over the 12 month follow up period (P < 0.001). Superficial infection was reported in two patients (8.3%), and two cases reported transient sural nerve neuritis. CONCLUSION: Percutaneous repair of neglected Achilles rupture using the index technique proved a satisfactory patient-reported and objective measurement at a one-year follow-up. With only minor transient complications.

Mitochondrial DNA copy number as a diagnostic marker and indicator of degree of severity in alopecia areata.

Alopecia areata (AA) is a disorder with several etiologies. The evidence suggests that the absolute copy number of mitochondrial deoxyribonucleic acid (mtDNA), as well as proportion of mutated mtDNA copies, determines disease onset. This study aims to quantify the relative index of the mtDNA copy number in patients with AA and healthy controls and correlate the results with the existing clinical information. This case-control study included 50 patients with AA and 50 age- and sex-coordinated healthy persons as controls. The severity of AA was weighed using the Severity of Alopecia Tool and Kavak's classification. The relative index of the mtDNA copy number was measured by real-time qPCR. Significant statistical difference was observed between cases and controls regarding mean mtDNA copy number, p < .001. There was significant positive correlation with SALT score (p = â€…0.001). A cutoff value of >1.619 N/µL could significantly diagnose AA cases (p < .001), and a cutoff value of > 1.36 N/µL could discriminate mild AA cases from those with moderate AA (p = â€…0.007). The relative index of mtDNA copy number is significantly elevated in AA cases and could be helpful in diagnosing and evaluating AA severity.

Essential Oil of Cestrum diurnum L.: GC/MS Analysis, in Vitro and in Silico Anti-HCoV-229E Effects and Inhibitory Activity against LPS-Induced Inflammation.

Cestrum diurnum L. (Solanaceae) is a fragrant ornamental tree cultivated in different parts around the world. In this study, the essential oil (EO) of the aerial parts was extracted by hydrodistillation (HD), steam distillation (SD) and microwave-assisted hydro-distillation (MAHD). GC/MS analysis of the three EOs revealed that phytol represents the major component in SD-EO and MAHD-EO (40.84 and 40.04 %, respectively); while in HD-EO it only represented 15.36 %. The SD-EO showed a strong antiviral activity against HCoV-229E with IC50 of 10.93 µg/mL, whereas, MAHD-EO and HD-EO showed a moderate activity with IC50 values of 119.9 and 148.2 µg/mL, respectively. The molecular docking of EO major components: phytol, octadecyl acetate and tricosane showed a strong binding to coronavirus 3-CL (pro). Moreover, the three EOs (50 µg/mL) decreased the levels of NO, IL-6 and TNF-α and suppressed IL-6 and TNF-α gene expression in LPS-induced inflammation model in RAW264.7 macrophage cell lines.

Discovery of novel thioquinazoline-N-aryl-acetamide/N-arylacetohydrazide hybrids as anti-SARS-CoV-2 agents: Synthesis, in vitro biological evaluation, and molecular docking studies.

In the current investigation, two novel series of (tetrahydro)thioquinazoline-N-arylacetamides and (tetrahydro)thioquinazoline-N-arylacetohydrazides were designed, synthesized and investigated for their antiviral activity against SARS-CoV-2. The thioquinazoline-N-arylacetamide 17g as well as the tetrahydrothioquinazoline-N-arylacetohydrazides 18c and 18f showed potent antiviral activity with IC50 of 21.4, 38.45 and 26.4 µM, respectively. In addition, 18c and 18f demonstrated potential selectivity toward the SARS-CoV-2 over the host cells with SI of 10.67 and 16.04, respectively. Further evaluation of the mechanism of action of the three derivatives 17g, 18c, and 18f displayed that they can inhibit the virus at the adsorption as well as at the replication stages, in addition to their virucidal properties. In addition, 17g, 18c, and 18f demonstrated satisfactory physicochemical properties as well as drug-likeness properties to be further optimized for the discovery of novel antiviral agents. The docking simulation on Mpro binding site predicted the binding pattern of the target compounds rationalizing their differential activity based on their hydrophobic interaction and fitting in the hydrophobic S2 subsite of the binding site.

GC-MS Determination of Undeclared Phthalate Esters in Commercial Fragrances: Occurrence, Profiles and Assessment of Carcinogenic and Non-Carcinogenic Risk Associated with Their Consumption among Adult Consumers.

Phthalates are chemicals that are extensively used in the manufacturing of cosmetic products. The occurrence of phthalate esters in personal care products may pose adverse effects on consumers' health. In this work, a simple, fast and reliable GC-MS method was developed and validated for concurrent determination of phthalate esters in fragrances. Simple procedures were employed for sample preparation and clean up. The recoveries achieved were in the range of 94.9% to 105.6% with RSD ≤ 4.06. The detection limits were in the range of 0.0010 to 0.0021 µg/mL. The GC-MS method was utilized to investigate the occurrence of phthalate esters in different brands of perfumes sold in the Saudi Arabian market. Diethyl phthalate was detected in all analyzed samples, with a maximum concentration of 5766 µg/mL, and di (2-ethylhexyl) phthalate was detected in the majority of the analyzed samples (95%), with a mean concentration of 55.9 µg/mL and a highest concentration of 377.7 µg/mL. Additionally, the exposure to phthalate esters due to the consumption of perfumes was investigated among the adult Saudi population for the first time. It was found that the systemic exposure dose, measured at mean concentrations, ranged from 4.59 × 10-4 to 4.29 × 10-2 (mg/kg/day) and from 5.00 × 10-4 to 4.68 × 10-2 (mg/kg/day) for male and female users, respectively. Moreover, the non-carcinogenic risk of the investigated phthalate esters and the carcinogenic risk of DEHP were also evaluated. The non-carcinogenic risk values of the detected phthalate esters were greater than 100, which indicates that exposure to these phthalate esters is unlikely to produce non-carcinogenic health effects to consumers. However, at maximum DEHP concentrations, the carcinogenic risk values were 5.49 × 10-5 for male users and 5.98 × 10-5 for female users, which indicates the possibility of DEHP to pose a carcinogenic health effect if present at high levels. Regular monitoring of undeclared chemicals such as phthalate esters in personal care products marketed in Saudi Arabia is extremely important to ensure consumers' safety. To the best of the authors' knowledge, this is the first study to assess the health risk associated with consumption of perfumes in Saudi Arabia.

Synthesis and Molecular Docking Study of Novel Pyrimidine Derivatives against COVID-19.

A novel series of pyrido[2,3-d]pyrimidines; pyrido[3,2-e][1,3,4]triazolo; and tetrazolo[1,5-c]pyrimidines were synthesized via different chemical transformations starting from pyrazolo[3,4-b]pyridin-6-yl)-N,N-dimethylcarbamimidic chloride 3b (prepared from the reaction of o-aminonitrile 1b and phosogen iminiumchloride). The structures of the newly synthesized compounds were elucidated based on spectroscopic data and elemental analyses. Designated compounds are subjected for molecular docking by using Auto Dock Vina software in order to evaluate the antiviral potency for the synthesized compounds against SARS-CoV-2 (2019-nCoV) main protease M pro. The antiviral activity against SARS-CoV-2 showed that tested compounds 7c, 7d, and 7e had the most promising antiviral activity with lower IC50 values compared to Lopinavir, "the commonly used protease inhibitor". Both in silico and in vitro results are in agreement.

Does sequential examination under anaesthesia provide a reliable method to determine a management plan for unstable lateral compression pelvic ring injuries? a prospective study.

PURPOSE: To assess the reliability of sequential examination under anaesthesia (EUA) to determine pelvic instability and to evaluate radiological and functional outcomes in unstable lateral compression (LC) injuries. METHODS: A prospective case series study was conducted from 2020 to 2022 at a university hospital on 43 cases with LC injuries that met the inclusion criteria. Sequential EUA was carried out in three steps. Posterior-only fixation or anterior-posterior fixation was done according to the algorithm. Each patient was followed up for at least 12 months, both radiologically and functionally. RESULTS: Forty cases proved unstable and were fixed. None showed secondary displacement in the anterior-posterior fixation group. However, five cases (19.2%) of the posterior-only fixation group showed secondary displacement with a mean of 5.9 mm. Four cases of them had tetra-ramic injuries. There is a high tendency for secondary displacement at 14.5 mm or more preoperative displacement of the rami. Patients with secondary displacement showed comparable functional outcome scores to patients without secondary displacement. Posterior-only fixation showed shorter operative time, lesser radiological exposure, blood loss and iatrogenic nerve injury than anterior-posterior fixation. CONCLUSION: EUA is a reliable method to determine pelvic instability and management plan for LC fractures with unilateral anterior ring injury. Anterior-posterior fixation is needed if there is a tetra-ramic fracture or initial anterior ring displacement of 14.5 mm or more, irrespective of EUA.

Pleural manometry during thoracocentesis in patients with malignant pleural effusion: A randomized controlled trial.

Background: Large-volume therapeutic thoracocentesis may be associated with pulmonary congestion or a more serious complication; re-expansion pulmonary edema (RPE). We investigated whether monitoring pleural pressure with manometry during thoracocentesis would prevent these pulmonary symptoms/RPE and allow larger volume drainage. Methods: We did a randomized controlled trial involving 110 patients with large malignant pleural effusions. Patients were randomly allocated to obtain thoracocentesis with or without pleural manometry. We measured the incidence of pulmonary congestion symptoms, total fluid aspirated, and pleural pressures in both groups. This trial is listed on ClinicalTrials.gov as NCT04420663. Results: The mean amount of total thoracocentesis fluid withdrawn from the control group was 945.4±78.9 (mL) and 1690.9±681.0 (mL) from the intervention group (P<0.001). Clinical symptoms of pulmonary congestion appeared in (n=20) (36.3%) of patients in the intervention group while no symptoms appeared in controls (P<0.001). The difference between opening and closing pressures between the non-symptomatic cluster and the symptomatic cluster was (32.8±15.6 versus 42.2±13) respectively (P=0.02). Total fluid withdrawn from the non-symptomatic cluster was 1828.5±505 mL in comparison to 1,450±875 mL in the symptomatic cluster (P=0.04). Conclusion: Pleural manometry can be used to increase the volume of fluid removed on each occasion in patients with malignant pleural effusion. In our study, pleural manometry was associated with a larger number of pulmonary congestion symptoms/RPE. We believe that manometry may be a useful tool to not exceed a 17 cm H2O gradient in pleural pressure which should be avoided to prevent pulmonary congestion symptoms or RPE. Pulmonary congestion symptoms/RPE are not related to the amount of volume withdrawn but to the gradient of pleural pressure drop. Our conclusion does support the adoption of pleural manometry whenever large-volume thoracocentesis is intended.

A pathogenic deletion in Forkhead Box L1 (FOXL1) identifies the first otosclerosis (OTSC) gene.

Otosclerosis is a bone disorder of the otic capsule and common form of late-onset hearing impairment. Considered a complex disease, little is known about its pathogenesis. Over the past 20 years, ten autosomal dominant loci (OTSC1-10) have been mapped but no genes identified. Herein, we map a new OTSC locus to a 9.96 Mb region within the FOX gene cluster on 16q24.1 and identify a 15 bp coding deletion in Forkhead Box L1 co-segregating with otosclerosis in a Caucasian family. Pre-operative phenotype ranges from moderate to severe hearing loss to profound sensorineural loss requiring a cochlear implant. Mutant FOXL1 is both transcribed and translated and correctly locates to the cell nucleus. However, the deletion of 5 residues in the C-terminus of mutant FOXL1 causes a complete loss of transcriptional activity due to loss of secondary (alpha helix) structure. FOXL1 (rs764026385) was identified in a second unrelated case on a shared background. We conclude that FOXL1 (rs764026385) is pathogenic and causes autosomal dominant otosclerosis and propose a key inhibitory role for wildtype Foxl1 in bone remodelling in the otic capsule. New insights into the molecular pathology of otosclerosis from this study provide molecular targets for non-invasive therapeutic interventions.

COVID-19 data reporting systems in Africa reveal insights for future pandemics.

Globally, countries have used diverse methods to report data during the COVID-19 pandemic. Using international guidelines and principles of emergency management, we compare national data reporting systems in African countries in order to determine lessons for future pandemics. We analyse COVID-19 reporting practices across 54 African countries through 2020. Reporting systems were diverse and included summaries, press releases, situation reports and online dashboards. These systems were communicated via social media accounts and websites belonging to ministries of health and public health. Data variables from the reports included event detection (cases/deaths/recoveries), risk assessment (demographics/co-morbidities) and response (total tests/hospitalisations). Of countries with reporting systems, 36/53 (67.9%) had recurrent situation reports and/or online dashboards which provided more extensive data. All of these systems reported cases, deaths and recoveries. However, few systems contained risk assessment and response data, with only 5/36 (13.9%) reporting patient co-morbidities and 9/36 (25%) including total hospitalisations. Further evaluation of reporting practices in Cameroon, Egypt, Kenya, Senegal and South Africa as examples from different sub-regions revealed differences in reporting healthcare capacity and preparedness data. Improving the standardisation and accessibility of national data reporting systems could augment research and decision-making, as well as increase public awareness and transparency for national governments.