Search

Abstract Ribosomal DNA (rDNA) repeats harbor ribosomal RNA (rRNA) genes and intergenic spacers (IGS). RNA polymerase (Pol) I transcribes rRNA genes yielding rRNA components of ribosomes. IGS-associated Pol II prevents Pol I from excessively synthesizing IGS non-coding RNAs (ncRNAs) that can disrupt nucleoli and rRNA production. Here, compartment-enriched proximity-dependent biotin identification (compBioID) revealed the TATA-less-promoter-binding TBPL1 and transcription-regulatory PAF1 with nucleolar Pol II. TBPL1 localizes to TCT motifs, driving Pol II and Pol I and maintaining its baseline ncRNA levels. PAF1 promotes Pol II elongation, preventing unscheduled R-loops that hyper-restrain IGS Pol I-associated ncRNAs. PAF1 or TBPL1 deficiency disrupts nucleolar organization and rRNA biogenesis. In PAF1-deficient cells, repressing unscheduled IGS R-loops rescues nucleolar organization and rRNA production. Depleting IGS Pol I-dependent ncRNAs is sufficient to compromise nucleoli. We present the nucleolar interactome of Pol II and show that its regulation by TBPL1 and PAF1 ensures IGS Pol I ncRNAs maintaining nucleolar structure and function.

Abstract Mice transgenic for human P301S tau protein exhibit many characteristics of the human tauopathies, including the formation of abundant hyperphoshorylated tau filaments, the associated neuroinflammation and disease phenotype. However, the exact underpinning mechanisms are still not fully addressed that hinder our understanding of the tauopathy diseases and the development of possible therapeutic targets.Methods: In the current study, hippocampus from three disease time points (2, 4 and 6 months) of P301S mice were further characterized in comparison to the age and sex matched control wild type mice (WT) that do not express the transgene. Different spectrum of hippocampal dependent cognitive tests, biochemical and pathological analysis were conducted to understand the disease progression and the associated changes in each stage. Results: Cognitive impairment was manifested as early as 2 months age, prior to the identification of tau aggregation and phosphorylation by immunostaining. P301S mice manifested an increased pro-inflammatory related changes at mRNA transcription level (IL-1b and IL17A) with the progression of the disease and when compared to the WT mice of the same age. Among the identified genes in the current study, the nuclear factor (erythroid-derived 2)-like 2 (Nrf2) genes expression that is considered as the master regulator of an endogenous inducible defense system was significantly impaired in P301S mice by 4 and 6 months when compared to healthy WT controls. A data that was also supported by the immunostaining of the serial brain sections including the both brain stem and hippocampus. The current result is suggesting that the downregulation of Nrf2 gene and the impaired Nrf2 dependent anti-inflammatory mechanisms in P301S mice brain is possibly contributing -among other factors- in the neuroinflammation and tauopathy, and that modulation of Nrf2 signaling impairments can be further investigated as a promising potential therapeutic target for tauopathy.

Abstract Background Promoting the uptake of vaccination for infectious diseases such as COVID-19 remains a global challenge, necessitating collaborative efforts between public health units (PHUs) and communities. Applied behavioural science can play a crucial role in supporting PHUs’ response by providing insights into human behaviour and informing tailored strategies to enhance vaccination uptake. Community engagement can help broaden the reach of behavioural science research by involving a more diverse range of populations and ensuring that strategies better represent the needs of specific communities. We developed and applied an approach to conducting community-based behavioural science research with ethnically and socioeconomically diverse populations to guide PHUs in tailoring their strategies to promote COVID-19 vaccination. This paper presents the community engagement methodology and the lessons learned in applying the methodology. Methods The community engagement methodology was developed based on integrated knowledge translation (iKT) and community-based participatory research (CBPR) principles. The study involved collaboration with PHUs and local communities in Ontario, Canada to identify priority groups for COVID-19 vaccination, understand factors influencing vaccine uptake and co-design strategies tailored to each community to promote vaccination. Community engagement was conducted across three large urban regions with individuals from Eastern European communities, African, Black, and Caribbean communities and low socioeconomic neighbourhoods. Results We developed and applied a seven-step methodology for conducting community-based behavioural science research: (1) aligning goals with system-level partners; (2) engaging with PHUs to understand priorities; (3) understanding community strengths and dynamics; (4) building relationships with each community; (5) establishing partnerships (community advisory groups); (6) involving community members in the research process; and (7) feeding back and interpreting research findings. Research partnerships were successfully established with members of prioritized communities, enabling recruitment of participants for theory-informed behavioural science interviews, interpretation of findings, and co-design of targeted recommendations for each PHU to improve COVID-19 vaccination uptake. Lessons learned include the importance of cultural sensitivity and awareness of sociopolitical context in tailoring community engagement, being agile to address the diverse and evolving priorities of PHUs, and building trust to achieve effective community engagement. Conclusion Effective community engagement in behavioural science research can lead to more inclusive and representative research. The community engagement approach developed and applied in this study acknowledges the diversity of communities, recognizes the central role of PHUs, and can help in addressing complex public health challenges.

Sea cucumbers are benthic marine invertebrate members of the phylum Echinodermata. Due to the absence of a rigid skeleton, these species have developed chemical defenses based on the production of saponins (triterpene glycosides). These secondary metabolites are bioactive molecules with a broad biological, ecological, and pharmaceutical spectrum. However, the saponin profiles of several species of sea cucumbers are not known yet. The present study aims to highlight the mixture of saponins in two sea cucumber species from the Algerian coast, namely Holothuria (Holothuria) algeriensis, which has been recently described in central and western Algerian waters, and Holothuria (Roweothuria) arguinensis, originating from the Atlantic Ocean and reported in Algeria for the first time in 2014. Saponin extracts from three individuals of H. (H.) algeriensis and two individuals of H. (R.) arguinensis were analyzed using mass spectrometry, i.e., Matrix-assisted Laser Desorption/Ionization mass spectrometry (MALDI-MS), MALDI-High Resolution MS (MALDI-HRMS), Liquid Chromatography MS (LC-MS) and tandem MS (LC-MS/MS). These analyses allow us to detect 11 and 18 elemental compositions for H. (H.) algeriensis and H. (R.) arguinensis, respectively, each presenting several isomers. In total, 13 new saponin structures are proposed, of which four are common between the two species, six are specific to H. (H.) algeriensis and three to H. (R.) arguinensis. The saponin profiles of the two species were compared to those of other species of the same genus existing on the Algerian coast and the results showed that they share non-sulfated saponins with Holothuria (Panningothuria) forskali and Holothuria (Platyperona) sanctori and sulfated saponins with Holothuria (Holothuria) tubulosa and Holothuria (Roweothuria) poli.

Transfection, a nonviral method of nucleic acid delivery, often exhibits poor efficiency in vivo. The needle-based in vivo delivery of transfection reagents can be invasive. Here, we report a noninvasive protocol for in vivo gene delivery via the needle-free MED-JET H4 MULTIJET (MJH4M) device using both “home-made” glucose-based and commercial transfection reagents. The objective of this study was to compare the relative transfection efficiencies of the needle-free system to that of the needle-based delivery method. We observed a 15-fold increase in transfection efficiency using the needle-free MJH4M device when compared to the needle-based delivery method. The highest transfection efficiency was achieved using a 5% glucose solution as the delivery vehicle.

Summary: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) hinders host gene expression, curbing defenses and licensing viral protein synthesis and virulence. During SARS-CoV-2 infection, the virulence factor non-structural protein 1 (Nsp1) targets the mRNA entry channel of mature cytoplasmic ribosomes, limiting translation. We show that Nsp1 also restrains translation by targeting nucleolar ribosome biogenesis. SARS-CoV-2 infection disrupts 18S and 28S ribosomal RNA (rRNA) processing. Expression of Nsp1 recapitulates the processing defects. Nsp1 abrogates rRNA production without altering the expression of critical processing factors or nucleolar organization. Instead, Nsp1 localizes to the nucleolus, interacting with precursor-rRNA and hindering its maturation separately from the viral protein’s role in restricting mature ribosomes. Thus, SARS-CoV-2 Nsp1 limits translation by targeting ribosome biogenesis and mature ribosomes. These findings revise our understanding of how SARS-CoV-2 Nsp1 controls human protein synthesis, suggesting that efforts to counter Nsp1’s effect on translation should consider the protein’s impact from ribosome manufacturing to mature ribosomes.

Preterm deliveries are a major multifactorial public health problem in French Guiana. Desert dust episodes have been associated with preterm delivery in Guadeloupe, a territory with similarities to French Guiana. We thus tried to replicate this finding in the context of French Guiana. A retrospective ecological cohort study combined daily PM10 concentration measurements during pregnancy and term at delivery extracted from French Guiana’s computerized pregnancy delivery registry. Daily PM10 concentrations during the course of pregnancy were analyzed as mean concentrations and as the proportion of intense dust episodes (≥55 μg PM10/m3). These exposure variables were studied in relation to the outcome of preterm delivery. Overall, 3,321 pregnant women with complete daily PM10 measurements were included, of whom 374 (11.26%) delivered prematurely. Among preterm deliveries, 168 (44.9%) were spontaneous deliveries and 206 (55.1%) were induced. Rank-sum tests showed that, for spontaneous and induced spontaneous deliveries, both mean PM10 concentrations and proportions of intense desert dust episodes were significantly greater among preterm births than among term births. Although the proportion of intense desert dust episodes during pregnancy was significantly associated with spontaneous preterm deliveries, the relation was U-shaped, with an adjusted odds ratio (AOR) = 2 (95%CI = 1.2–3.1) for lowest values relative to median values and AOR = 5.4 (95%CI = 3.2–8.9) for the highest values relative to median values. Similarly, the proportion of intense desert dust episodes during pregnancy was also significantly associated with induced preterm deliveries in a U-shaped manner (AOR = 2.7 (95%CI = 1.6–4.5) for the lowest relative to median values and AOR = 6.8 (95%CI = 3.9–11.9) for the highest relative to median values). Although in our study the relation between PM10 concentrations appeared non-linear, the highest mean concentrations and intense desert dust episodes were indeed associated with both spontaneous and induced preterm delivery.

Context: Patients with adrenal insufficiency (AI) have a higher mortality than the general population, possibly because of excess glucocorticoid exposure at inappropriate times. The cortisol circadian rhythm is difficult to mimic with t wice- or thrice-daily hydrocortisone. Prednisolone is a once-daily alternative which may improve patient compliance through its convenience. Objectives: Prednisolone day curves can be used to accurately downtitrate patients to the minimum effective dose. This study aimed to review prednisol one day curves and determine therapeutic ranges at different time points after admi nistration. Methods: Between August 2013 and May 2021, 108 prednisolone day curves from 76 individuals receiving prednisolone replacement were analysed. Prednisolone concentrations were determined by ultra-high-performance liquid chromatography-tandem mass spectrometry. Spearman’s correlation coefficient was used to determine the relationship between 2-, 4-, and 6-h prednisolone levels compared to the previously validated standard 8-h prednisolone level (15–25 μg/L). Results: The median dose was 4 mg of prednisolone once daily. There was a strong correlation between the 4- and 8-h (R = 0.8829, P ≤ 0.0001) and 6- and 8-h prednisolone levels (R = 0.9530, P ≤ 0.0001). Target ranges for prednisolone were 37–62 μg/L at 4 h, 24–39 μg/L at 6 h, and 15–25 μg/L at 8 h. Prednisolone doses were successfully reduced in 21 individuals, and of these, 3 were reduced to 2 mg once daily. All patients were well upon follow-up. Conclusion: This is the largest evaluation of oral prednisolone pharmacokinetics in humans. Low-dose prednisolone of 2–4 mg is safe and effective in most pa tients with AI. Doses can be titrated with either 4-, 6-, or 8-h single time point drug levels.

Multilayer III–V-based solar cells are complex devices consisting of many layers and interfaces. The study and the comprehension of the mechanisms that take place at the interfaces is crucial for efficiency improvement. In this work, we apply frequency-modulated Kelvin probe force microscopy under ambient conditions to investigate the capability of this technique for the analysis of an InP/GaInAs(P) multilayer stack. KPFM reveals a strong dependence on the local doping concentration, allowing for the detection of the surface potential of layers with a resolution as low as 20 nm. The analysis of the surface potential allowed for the identification of space charge regions and, thus, the presence of several junctions along the stack. Furthermore, a contrast enhancement in the surface potential image was observed when KPFM was performed under illumination, which is analysed in terms of the reduction of surface band bending induced by surface defects by photogenerated carrier distributions. The analysis of the KPFM data was assisted by means of theoretical modelling simulating the energy bands profile and KPFM measurements.

The SMN protein recognizes symmetric dimethylarginine by its Tudor domain, and SMN deficiency leads to spinal muscular atrophy. Here, Liu et al. discover a small molecule that binds to the SMN Tudor domain and disrupts the interaction between SMN and RNA Polymerase II.

Introduction: The purpose of this study is to investigate the meta-analysis of published articles on the factors affecting suicide. Method: From 15 selected studies, appropriate statistics were recorded to calculate the effect size and other required information and with CMA2 software, the effect size was calculated and hypotheses were analyzed. Findings: The results of the present study show that in total independent variables are identified Suicide has been effective. The value of the combined effect is 0660 (d = 0660) and is also statistically significant. Since this value is in the range of 0.8 to 0.5, it is considered moderate according to the Cohen classification. The results also show that the mean size of r related to studies that had theoretical foundations was EsrQ = 0.30 and in studies that lacked theoretical foundations was equivalent to ESrQ = 0.20. The results of the z-r difference test in the above study were 4.99. Discussion: Shows that there is a significant difference between the size of the effects obtained. Variables such as having a theoretical basis, level of gender, marriage, self-esteem, family cohesion, early marriage, anxiety, family economic status, had a statistically significant effect on suicide. Is. Part of the research findings indicate that in the social categories, the variable of early marriage has the highest relationship with suicidal tendencies with an effect size of 0.3721, in the psychological aspects of self-esteem research has the highest relationship with suicide with an effect size of 0.6216. Conclusion To combat suicide, one should consider increasing self-esteem, conscious marriage, self-esteem, and family cohesion

Endogenous Cushing’s syndrome (CS) poses considerable diagnostic challenges. Although late-night salivary cortisol (LNSC) is recommended as a first-line screening investigation, it remains the least widely used test in many countries. The combined measurement of LNSC and late-night salivary cortisone (LNS cortisone) has shown to further improve diagnostic accuracy. We present a retrospective study in a tertiary referral centre comparing LNSC, LNS cortisone, overnight dexamethasone suppression test, low-dose dexamethasone suppression test and 24-h urinary free cortisol results of patients investigated for CS. Patients were categorised into those who had CS (21 patients) and those who did not (33 patients). LNSC had a sensitivity of 95% and a specificity of 91%. LNS cortisone had a specificity of 100% and a sensitivity of 86%. With an optimal cut-off for LNS cortisone of >14.5 nmol/L the sensitivity was 95.2%, and the specificity was 100% with an area under the curve of 0.997, for diagnosing CS. Saliva collection is non-invasive and can be carried out at home. We therefore advocate simultaneous measurement of LNSC and LNS cortisone as the first-line screening test to evaluate patients with suspected CS.

Abstract Background Many prominent UK medical organisations have identified a need for more generalist clinicians to address the complex requirements of an aging society. We sought to clarify attitudes towards “Specialists” and “Generalists” amongst medical students and junior doctors at Imperial College School of Medicine. Methods A survey exploring medical students’ beliefs was followed up by qualitative analysis of focus groups of medical students and Imperial-graduate foundation year doctors. Results First year medical students associated specialists with academia and higher income, and generalists with ease of training and job availability. Senior (Years 5/6) medical students associated specialists even more firmly with broader influence and academic work, whilst generalists were assigned lower prestige but the same workload as specialists. The medical student focus group discussed concepts of Generalism pertaining only to Primary Care. In contrast, the foundation year doctor focus group revealed that Generalism was now seen to include some hospital care, and the perception that generalists sat lower in a knowledge hierarchy had been challenged. Conclusion Perceptions that Generalism is associated with lower prestige in the medical profession are already present at the very start of medical school and seem to be reinforced during undergraduate training. In early postgraduate clinical practice, the perceived knowledge and prestige hierarchy lessens. These findings can help inform curriculum redesign and the promotion of Generalism as a rewarding career aspiration.

Summary: Modulating R-loop triplex nucleic acid structures reveals their roles across the genome. However, common approaches cannot ascribe functions to R-loops in a locus-associated manner. This protocol presents the use of a locus-associated R-loop-modulating system (dubbed LasR), which employs an inducible RNaseH1-EGFP-dCas9 chimaera. We detail the in silico design of sgRNAs and their transfection with the chimaera, and outline steps confirming RNaseH1-EGFP-dCas9 expression, localization, locus-targeted association, and R-loop modulation in cis or trans using immunoblotting, microscopy, and chromatin and DNA-RNA immunoprecipitation.For complete details on the use and execution of this protocol, please refer to Abraham et al. (2020). : Publisher’s note: Undertaking any experimental protocol requires adherence to local institutional guidelines for laboratory safety and ethics.

The book Public Policy Making Process written by respected professors Dr. Gholamreza Esghandari, Karim Eskandari, and Rasoul Eskandari has been an attempt to reduce the resources of the policy-making process. The purpose of this article is to analyze and express the strengths and weaknesses of the book content. The book has advantages, but it also suffers from some shortcomings, the elimination of which can add to the richness of the book's topics. The authors of the book have been careful in the use of specialized terms and equivalence of foreign words, except for a few cases, and are acceptable in terms of compliance with the approved chapters. The content is compatible with scientific values and theories are not addressed.

Objective: Dexamethasone is a known treatment for lymphoma, but the potency and rapidity of its effect have not been recognized. We present a case of bilateral adrenal lymphoma that significantly reduced in size after a single dose of dexamethasone. Methods: We present the clinical course and investigations, including adrenocorticotropic hormone, cortisol, short synacthen test, computed tomography (CT), and adrenal biopsy results. Results: A 52-year-old man had a fall and was incidentally found to have bilateral adrenal masses (left, 6 cm; right, 5 cm) on CT. His adrenal function tests included plasma metanephrines (normetanephrine, 830 pmol/L [normal,

Laflamme and Mekhail discuss emerging nuclear roles for LLPS in genome organization, gene expression and DNA repair, highlighting the emerging notion that biomolecular condensates regulate the sequential engagement of molecules in multistep biological processes.

Objectives: Primary aldosteronism is one of the most common causes of secondary hypertension. Distinguishing unilateral from bilateral disease is essential as those with unilateral adrenal disease will benefit from adrenalectomy. This is best achieved by adrenal vein sampling (AVS) which may be a difficult procedure with significant radiation to both patient and operator. This study aims to measure the radiation dose during AVS before and after the installation of a new angiography platform. Materials and Methods: The dose area product (DAP), air kerma, and fluoroscopy time were collected retrospectively together with demographic data for the first ten patients who underwent AVS between April and September 2018 following the installation of the Philips Azurion 7 M20 interventional platform. These results were compared with those from ten patients who underwent AVS before the installation of the new machine using the Philips Allura Xper FD20 platform. Mann–Whitney test was used to compare DAP, air kerma, and fluoroscopy time. P < 0.05 was considered statistically significant. Results: Successful bilateral adrenal vein catheterization was achieved in all cases in both groups. There was no significant difference in fluoroscopy time: 5.5 (3.3–10.8) min (new) versus 5.3 (4.5–8.4) min (old) (P = 0.9502). The DAP and air kerma were both significantly lower on the new machine: 11.3 (5.2–26.7) Gy.cm2 versus 45.5 (17.2–56.5) Gy.cm2 (P = 0.0089) and 201.5 (88.1–464.0) mGy versus 682.5 (300.5–998.5) mGy (P = 0.0115), respectively. Conclusion: The installation of the Philips Azurion 7 M20 interventional platform has allowed a significant reduction in radiation dose during AVS.

Genome dynamics allow cells to repair DNA double-strand breaks (DSBs), which are highly toxic DNA lesions. Here the authors reveal that in S. cerevisiae, Rad52 DNA repair proteins assemble in liquid droplets that work with dynamic nuclear microtubules to relocalize lesions to the nuclear periphery for repair.

BackgroundSeveral studies report an increased susceptibility to SARS-CoV-2 infection in cancer patients. However, data in the intensive care unit (ICU) are scarce.Research QuestionWe aimed to investigate the association between active cancer and mortality among patients requiring organ support in the ICU.Study Design and MethodsIn this ambispective study encompassing 17 hospitals in France, we included all adult active cancer patients with SARS-CoV-2 infection requiring organ support and admitted in ICU. For each cancer patient, we included 3 non cancer patients as controls. Patients were matched at the same ratio using the inverse probability weighting approach based on a propensity score assessing the probability of cancer at admission. Mortality at day 60 after ICU admission was compared between cancer patients and non-cancer patients using primary logistic regression analysis and secondary multivariable analyses.ResultsBetween March 12, 2020 and March 8, 2021, 2608 patients were admitted with SARS-CoV-2 infection in our study, accounting for 2.8% of the total population of patients with SARS-CoV-2 admitted in all French ICUs within the same period. Among them, 105 (n=4%) presented with cancer (51 patients had hematological malignancy and 54 patients had solid tumors). 409 of 420 patients were included in the propensity score matching process, of whom 307 patients in the non-cancer group and 102 patients in the cancer group. 145 patients (35%) died in the ICU at day 60, 59 (56%) with cancer and 86 (27%) without cancer. In the primary logistic regression analysis, the odds ratio for death associated to cancer was 2.3 (95%CI 1.24 – 4.28, p=0.0082) higher for cancer patients than for a non-cancer patient at ICU admission. Exploratory multivariable analyses showed that solid tumor (OR: 2.344 (0.87-6.31), p=0.062) and hematological malignancies (OR: 4.144 (1.24-13.83), p=0.062) were independently associated with mortality.InterpretationPatients with cancer and requiring ICU admission for SARS-CoV-2 infection had an increased mortality, hematological malignancy harboring the higher risk in comparison to solid tumors.

Background: Anticoagulation (AC) adherence after acute pulmonary embolism (PE) is vital to prevent mortality and future recurrence of venous thromboembolism (VTE). We aimed to analyze factors affecting AC adherence after acute PE. Methods: Consecutive adult patients with CT angiography or V/Q scan confirmed acute PE were included in a single-center retrospective study from April 2016 to May 2020. Adherence data, including AC refill dates, were collected from pharmacies, and adherence measures including Continuous Measure of Medication Acquisition (CMA), Proportion of Days Covered (PDC), and Optimal Medication Adherence (OMA) were calculated per standardized formulas. Univariable and multivariable linear and logistic regression was used to analyze different variables affecting AC adherence. Results: A total of 118 out of 144 patients had sufficient follow-up data to measure adherence and were included in the final analysis. Mean age was 60 ± 15 years, with 64 (54.2%) women; 70 (59.3%) White, 26 (22%) African American, 13 (11%) Hispanic; 58 (49.2%) patients had private insurance, 48 (40.7%) Medicare, 11 (9.3%) Medicaid. Type of AC comprised of 57 (48.3%) apixaban, 17 (14.4%) rivaroxaban, 8 (6.8%) warfarin, 6 (5.1%) enoxaparin, and 30 (25.4%) patients with changing AC. In univariable regression, African American and Medicaid-insured patients had significantly lower adherence, while advancing age, apixaban usage, and 30-day follow-up clinic visit showed a higher adherence. However, in multivariable regression, African American race (PDC -0.135, p = 0.006, CI (−0.231, −0.040) | OMA Adjusted OR 0.166, p = 0.030, CI (0.033, 0.837)) and other non-White, non-Hispanic races (PDC -0.314, p = 0.009, CI (−0.548, −0.080)) were associated with lower AC adherence. Conclusion: In our study, African American and other minority race patients showed lower AC adherence after hospital admission for acute PE. Further studies are needed to address underlying contributors and improve adherence in this population.

In this work we employ the transfer matrix method for the analysis of optical materials properties to simulate and optimize monolithic tandem solar cell devices based on CuIn _1− _x Ga _x Se _2 , CI(G)S, and perovskite (PVK) absorbers. By finding models that fit well the experimental data of the CI(G)S solar cell, the semitransparent perovskite solar cell (PSC) and the PVK/CI(G)S monolithic tandem solar cell, we were able to perform a detailed optical loss analysis that allowed us to determine sources of parasitic absorption. We found better substitute materials for the transport layers to increase the power conversion efficiency and, in case of semitransparent PSCs, sub-bandgap transmittance. Our results set guidelines for the monolithic PVK/CI(G)S tandem solar cells development, predicting an achievable efficiency of 30%.

Background: Stress-induced hyperprolactinemia can be difficult to differentiate from true hyperprolactinema and may result in patients having unnecessary investigations and imaging. We report the results of cannulated prolactin tests with serial prolactin measurements from an indwelling catheter to differentiate true from stress-induced hyperprolactinemia in patients with persistently mildly elevated prolactin levels in both referral and repeat samples. Methods: Data were collected for 42 patients who had a cannulated prolactin test between January 2017 and May 2018. After cannula insertion, prolactin was measured at 0, 60, and 120 minutes. Normalization is defined as a decline in prolactin to gender-defined normal ranges. Results: The mean age was 33.8 years ( SD ± 9.9), and 37 (88%) were female. Menstrual irregularities were the main presenting symptom in 28.57% of the patients. Prolactin normalized in 12 (28.6%) patients of whom cannulated prolactin test was done. Repeat random prolactin levels were significantly higher in patients whose prolactin did not normalize during the cannulated prolactin test. MRI of the pituitary gland showed an abnormality in 23 out of 28 (82%) patients who did not normalize prolactin, a microadenoma in the majority of patients (18 patients). Conclusion: The cannulated prolactin test was useful in excluding true hyperprolactinemia in 28.6% of patients with previously confirmed mildly elevated random prolactin on two occasions, thus avoiding over-diagnosis and unnecessary imaging.

Background/AimsThere is no universal consensus on the practical implementation and evaluation of the Amsterdam Declaration on Graves Orbitopathy in a Multidisciplinary Thyroid Eye Disease (MDTED) pathway. Recent recommendations from the UK TEAMeD-5 and BOPSS initiative highlight the importance of prevention, screening, and prompt referral of patients with moderate to severe and sight-threatening thyroid eye disease to multidisciplinary (MDTED) clinics and recommends annual auditing. We propose a practical service evaluation model with Key Performance Indicators (KPI) that are achievable and could be implemented across most TED pathways.Material and MethodsWe conducted a service evaluation from an integrated TED pathway in London with three MDTED clinics. Data was collected retrospectively from consecutive TED patients included: 1) Patient demographics, 2) Referral to first appointment time, 3) Documented smoking cessation and selenium supplementation advice, 4) Presenting disease activity and severity, 5) Investigations and treatments, including radio-iodine, 6) Time from decision to treatment initiation, 7) Initial and subsequent thyroid status.ResultsThe median age was 49.0 yrs, 77.5% (183/236) were female and 49.5% (101/204) Afro-Caribbean or Asian. At their first clinic attendance, 47.6% (110/231) were biochemically euthyroid and 76.7% (79/103) at discharge. All 23.1% (52/225) current smokers received smoking cessation advice and 64.8% (153/236) received selenium supplementation advice. Intravenous methylprednisolone was given to 33.9% (80/236) patients and 12.7% (30/236) received second-line immunosuppression. All 7.2% (17/236) patients with sight-threatening disease received treatment within two weeks of diagnosis.ConclusionsThis study forms a waymark for other units using TEAMeD-5 and BOPSS audit criteria. Dedicated electronic patient records with ongoing data capture, including quality of life assessments, and diagnostic coding would significantly aid future auditing, improve patient care, and facilitate a national audit of TED management. A future survey when the TED standards have become embedded would be instructive to see whether this has improved TED care.

BackgroundCortisol levels in response to stress are highly variable. Baseline and stimulated cortisol levels are commonly used to determine adrenal function following unilateral adrenalectomy. We report the results of synacthen stimulation testing following unilateral adrenalectomy in a tertiary referral center.MethodsData were collected retrospectively for 36 patients who underwent synacthen stimulation testing one day post unilateral adrenalectomy. None of the patients had clinical signs of hypercortisolism preoperatively. No patient received pre- or intraoperative steroids. Patients with overt Cushing’s syndrome were excluded.ResultsThe median age was 58 (31-79) years. Preoperatively, 16 (44%) patients had a diagnosis of pheochromocytoma, 12 (33%) patients had primary aldosteronism and 8 (22%) patients had non-functioning adenomas with indeterminate/atypical imaging characteristics necessitating surgery. Preoperative overnight dexamethasone suppression test results revealed that 6 of 29 patients failed to suppress cortisol to

BackgroundThyroid eye disease (TED) is a potentially disfiguring and sight-threatening autoimmune (AI) orbitopathy, affecting up to 400,000 people in the UK. There are no accurate early predictors of TED severity. Although polyautoimmunity has been shown to affect AI disease severity, its influence on TED severity has never been investigated. The prevalence of polyautoimmunity among TED patients is also unclear, with discordant results reported in the literature. This study evaluates the prevalence of non-thyroid/“other” AI (OAI) conditions in an ethnically diverse TED cohort and assesses how polyautoimmunity affects TED severity and activity.MethodsA retrospective study of patients presenting to multidisciplinary TED clinics across three North-West London hospitals between 2011 and 2019. Data collected included: 1) demographics; 2) OAI conditions and management; 3) endocrine management of thyroid dysfunction; 4) details of TED and clinical activity score at presentation.ResultsTwo hundred and sixty-seven patients with a median age of 46 (35–54) years were included, 79.4% were female and 55% were Black, Asian and minority ethnic (BAME). Thirty-seven patients (13.9%) had OAI conditions, with rheumatoid arthritis (3.7%), vitiligo (3.0%) and psoriasis (3.0%) among the most prevalent. Of patients with OAI conditions, 43.2% (16/37) required immunosuppression prior to TED onset. Non-immunosuppressed patients with OAI conditions had a significantly higher clinical activity score at presentation than TED-only and previously immunosuppressed patients (p=0.02). No significant differences were observed in thyroid receptor antibody titers between these groups.ConclusionsThis study finds a 13.9% prevalence of OAI conditions among TED patients. Patients with OAI conditions overall have a tendency for more severe and significantly more clinically active TED than those without OAI conditions. Larger, prospective studies are warranted to further evaluate polyautoimmunity as an early predictor of TED severity.

The introduction of adrenocortical extract in 1930 improved the life expectancy of hyhpoadrenal patients, with further increases seen after the introduction of cortisone acetate from 1948. Most patients are now treated with synthetic hydrocortisone, and incremental advances have been made with optimisation of daily dosing and the introduction of multidose regimens. There remains a significant mortality gap between individuals with treated hypoadrenalism and the general population. It is unclear whether this gap is a result of glucocorticoid over-replacement, under-replacement or loss of the circadian and ultradian rhythm of cortisol secretion, with the risk of detrimental excess glucocorticoid exposure at later times in the day. The way forwards will involve replacement of the diurnal cortisol rhythm with better glucocorticoid replacement regimens. The steroid profile produced by both predn isolone and dual-release hydrocortisone (Plenadren), provide a smoother glucocorticoid profile of cortisol than standard oral multidose regimens of hydrocortisone and cortisone acetate. The individualisation of prednisolone doses and lower bioavailability of Plenadren offer reductions in total steroid exposure. Although there is emerging evidence of both treatments offering better cardiometabolic outcomes than standard glucocorticoid replacement regimens, there is a paucity of evidence involving very low dose prednisolone (2–4 mg daily) compared to the larger doses (~7.5 mg) historically used. Data from upcoming clinical studies on prednisolone will therefore be of key importance in informing future practice.

Background: The mass vaccination campaign against SARS-CoV-2 was started in Tunisia on 13 March 2021 by using progressively seven different vaccines approved for emergency use. Herein, we aimed to evaluate the humoral and cellular immunity in subjects aged 40 years and over who received one of the following two-dose regimen vaccines against SARS-CoV-2, namely mRNA-1273 or Spikevax (Moderna), BNT162B2 or Comirnaty (Pfizer-BioNTech), Gam-COVID-Vac or Sputnik V (Gamaleya Research Institute), ChAdOx1-S or Vaxzevria (AstraZeneca), BIBP (Sinopharm), and Coronavac (Sinovac). Material and methods: For each type of vaccine, a sample of subjects aged 40 and over was randomly selected from the national platform for monitoring COVID-19 vaccination and contacted to participate to this study. All consenting participants were sampled for peripheral blood at 3–7 weeks after the second vaccine dose to perform anti-S and anti-N serology by the Elecsys® (Lenexa, KS, USA) anti-SARS-CoV-2 assays (Roche® Basel, Switzerland). The CD4 and CD8 T cell responses were evaluated by the QuantiFERON® SARS-CoV-2 (Qiagen® Basel, Switzerland) for a randomly selected sub-group. Results: A total of 501 people consented to the study and, of them, 133 were included for the cellular response investigations. Both humoral and cellular immune responses against SARS-CoV-2 antigens differed significantly between all tested groups. RNA vaccines induced the highest levels of humoral and cellular anti-S responses followed by adenovirus vaccines and then by inactivated vaccines. Vaccines from the same platform induced similar levels of specific anti-S immune responses except in the case of the Sputnik V and the AstraZeneca vaccine, which exhibited contrasting effects on humoral and cellular responses. When analyses were performed in subjects with negative anti-N antibodies, results were similar to those obtained within the total cohort, except for the Moderna vaccine, which gave a better cellular immune response than the Pfizer vaccine and RNA vaccines, which induced similar cellular immune responses to those of adenovirus vaccines. Conclusion: Collectively, our data confirmed the superiority of the RNA-based COVID-19 vaccines, in particular that of Moderna, for both humoral and cellular immunogenicity. Our results comparing between different vaccine platforms in a similar population are of great importance since they may help decision makers to adopt the best strategy for further national vaccination programs.

The spinal cord is a major structure of the central nervous system allowing, among other things, the transmission of afferent sensory and efferent motor information. During spinal surgery, such as scoliosis correction, this structure can be damaged, resulting in major neurological damage to the patient. To date, there is no direct way to monitor the oxygenation of the spinal cord intraoperatively to reflect its vitality. This is essential information that would allow surgeons to adapt their procedure in case of ischemic suffering of the spinal cord. We report the development of a specific device to monitor the functional status of biological tissues with high resolution. The device, operating with multiple wavelengths, uses Near-InfraRed Spectroscopy (NIRS) in combination with other additional sensors, including ElectroNeuroGraphy (ENG). In this paper, we focused primarily on aspects of the PhotoPlethysmoGram (PPG), emanating from four different light sources to show in real time and record biological signals from the spinal cord in transmission and reflection modes. This multispectral system was successfully tested in in vivo experiments on the spinal cord of a pig for specific medical applications.

Objective: Graves' disease is the commonest cause of hyperthyroidism in populations with sufficient dietary iodine intake. Anti-thyroid drugs (ATD) are often used as the initial treatment for Graves' hyperthyroidism, however there is a paucity of data relating the dose of ATD therapy to the effect on thyroid hormone levels, increasing the risk of both over- and under-treatment. We aimed to determine the pharmacodynamic response to the ATD carbimazole.Design: Retrospective cohort study.Methods: Participants were patients (n = 441) diagnosed with Graves' disease at Imperial College Healthcare NHS Trust between 2009 and 2018. The main outcome measure was change in thyroid hormone levels in response to ATD.Results: Baseline thyroid hormone levels were positively associated with TSH receptor antibody titres (P < 0.0001). Baseline free triiodothyronine (fT3) were linearly related to free thyroxine (fT4) levels in the hyperthyroid state (fT3 = fT4*0.97–11), and fell proportionately with carbimazole. The percentage falls in fT4 and fT3 per day were associated with carbimazole dose (P < 0.0001). The magnitude of fall in thyroid hormones after the same dose of carbimazole was lower during follow up than at the initiation visit. The fall in thyroid hormone levels approximated to a linear response if assessed at least 3 weeks after commencement of carbimazole. Following withdrawal of antithyroid drug treatment, the risk of relapse was greater in patients with higher initial fT4, initial TSH receptor antibody titre, males, smokers, and British Caucasian ethnicity.Conclusion: We identify a dose-response relationship for fall in thyroid hormones in response to carbimazole to aid in the selection of dose for Graves' hyperthyroidism.

Purpose: To review the clinical and biochemical characteristics and clinical outcome of patients presenting with pituitary apoplexy to a tertiary centre. Methods: We retrospectively reviewed the clinical features, predisposing factors, biochemistry and clinical outcome of patients presenting with pituitary apoplexy to Imperial College Healthcare NHS Trust between 1991 and 2015. Results: We identified 64 patients with pituitary apoplexy (more complete clinical records were available in 52 patients). The median age at presentation was 46.7 years (IQR 31.5–57.0 years). Pituitary apoplexy was the first presentation of pituitary disease in 38/52 of patients and predisposing factors were identified in 28/52. Pituitary apoplexy predominantly occurred in patients with non-functioning pituitary adenomas (47/52). Headache was most commonly described as sudden onset, severe, lateralising to the frontal or temporal regions. Symptoms of meningeal irritation were reported in 7/18 and visual abnormalities in 22/35. A pre-treatment serum cortisol

Following DNA damage, different processes come to action to aid repair. The authors here find that microtubule filaments within the cell nucleus capture and non-randomly mobilize damaged chromatin to mediate DNA repair.

Symptomatic pituitary adenomas occur with a prevalence of approximately 0.1% in the general population. It is estimated that 5% of pituitary adenomas occur in a familial setting, either in isolated or syndromic form. Recently, loss-of-function mutations in genes encoding succinate dehydrogenase subunits (SDHx) or MYC-associated factor X (MAX) have been found to predispose to pituitary adenomas in co-existence with paragangliomas or phaeochromocytomas. It is rare, however, for a familial SDHx mutation to manifest as an isolated pituitary adenoma. We present the case of a pituitary lactotroph adenoma in a patient with a heterozygous germline SDHB mutation, in the absence of concomitant neoplasms. Initially, the adenoma showed biochemical response but poor tumour shrinkage in response to cabergoline; therefore, transsphenoidal surgery was performed. Following initial clinical improvement, tumour recurrence was identified 15 months later. Interestingly, re-initiation of cabergoline proved successful and the lesion demonstrated both biochemical response and tumour shrinkage. Our patient’s SDHB mutation was identified when we realised that her father had a metastatic paraganglioma, prompting genetic testing. Re-inspection of the histopathological report of the prolactinoma confirmed cells with vacuolated cytoplasm. This histological feature is suggestive of an SDHx mutation and should prompt further screening for mutations by immunohistochemistry and/or genetic testing. Surprisingly, immunohistochemistry of this pituitary adenoma demonstrated normal SDHB expression, despite loss of SDHB expression in the patient’s father’s paraganglioma.

Due to the continuous increase in data traffic, it is becoming imperative to develop communication systems capable of meeting the throughput requirements. Monolithic Opto-Electronic Integrated Circuits (OEICs) are ideal candidates to meet these demands. With that in mind, we propose a compact and computationally efficient model for Uni-Traveling Carrier Photodiodes (UTC-PDs) which are a key component of OEICs because of their high bandwidth and RF output power. The developed compact model is compatible with existing SPICE design software, enabling the design of beyond 5G and terahertz (THz) communication circuits and systems. By introducing detailed physical equations describing, in particular, the dark current, the intrinsic series resistance, and the junction capacitance, the model accurately captures the physical characteristics of the UTC-PD. The model parameter extraction follows a scalable extraction methodology derived from that of the bipolar and CMOS technologies. A detailed description of the de-embedding process is presented. Excellent agreement between the compact model and measurements has been achieved, showing model versatility across various technologies and scalability over several geometries.

Introduction: Patients who need glucocorticoid replacement in both primary and secondary adrenal insufficiency (AI) have the choice of either once-daily prednisolone or thrice-daily hydrocortisone. A recent European study found no difference between prednisolone and hydrocortisone users in several markers including glucose, weight, body mass index, systolic and diastolic blood pressure and waist circumference, although an increase in cholesterol and low-density lipoprotein (LDL) was suggested in a subgroup of these patients. The aim of this study was to expand the evidence base for the use of these agents as replacement therapy. Methods: Data from 82 patients on hydrocortisone and 64 patients on prednisolone for AI at Imperial College Healthcare NHS Trust were analysed. Results: There was no significant difference in total cholesterol, LDL levels or any other risk factors between hydrocortisone and prednisolone patients. Prednisolone was subjectively significantly more convenient than hydrocortisone (P = 0.048). Conclusions: Prednisolone once daily is more convenient than hydrocortisone thrice daily, and there is no difference in the markers of cardiovascular risk measured. Because prednisolone mimics the circadian rhythm better than other glucocorticoids, it should be considered as an alternative to hydrocortisone for AI.

Genetic loci are non-randomly arranged in the nucleus of the cell. This order, which is important to overall genome expression and stability, is maintained by a growing number of factors including the nuclear envelope, various genetic elements and dedicated protein complexes. Here, we review evidence supporting roles for non-coding RNAs (ncRNAs) in the regulation of spatial genome organization and its impact on gene expression and cell survival. Specifically, we discuss how ncRNAs from single-copy and repetitive DNA loci contribute to spatial genome organization by impacting perinuclear chromosome tethering, major nuclear compartments, chromatin looping, and various chromosomal structures. Overall, our analysis of the literature highlights central functions for ncRNAs and their transcription in the modulation of spatial genome organization with connections to human health and disease.

Objectives The study aimed to compare candidate performance between traditional best-of-five single-best-answer (SBA) questions and very-short-answer (VSA) questions, in which candidates must generate their own answers of between one and five words. The primary objective was to determine if the mean positive cue rate for SBAs exceeded the null hypothesis guessing rate of 20%.Design This was a cross-sectional study undertaken in 2018.Setting 20 medical schools in the UK.Participants 1417 volunteer medical students preparing for their final undergraduate medicine examinations (total eligible population across all UK medical schools approximately 7500).Interventions Students completed a 50-question VSA test, followed immediately by the same test in SBA format, using a novel digital exam delivery platform which also facilitated rapid marking of VSAs.Main outcome measures The main outcome measure was the mean positive cue rate across SBAs: the percentage of students getting the SBA format of the question correct after getting the VSA format incorrect. Internal consistency, item discrimination and the pass rate using Cohen standard setting for VSAs and SBAs were also evaluated, and a cost analysis in terms of marking the VSA was performed.Results The study was completed by 1417 students. Mean student scores were 21 percentage points higher for SBAs. The mean positive cue rate was 42.7% (95% CI 36.8% to 48.6%), one-sample t-test against ≤20%: t=7.53, p

Objective To assess the utility and ability of the novel prescribing very short answer (VSA) question format to identify the sources of undergraduate prescribing errors when compared with the conventional single best answer (SBA) question format and assess the acceptability of machine marking prescribing VSAs.Design A prospective study involving analysis of data generated from a pilot two-part prescribing assessment.Setting Two UK medical schools.Participants 364 final year medical students took part. Participation was voluntary. There were no other inclusion or exclusion criteria.Outcomes (1) Time taken to mark and verify VSA questions (acceptability), (2) differences between VSA and SBA scores, (3) performance in VSA and (4) SBA format across different subject areas and types of prescribing error made in the VSA format.Results 18 200 prescribing VSA questions were marked and verified in 91 min. The median percentage score for the VSA test was significantly lower than the SBA test (28% vs 64%, p

To promote the nutritional and pharmacological values of four sea cucumber species (Holothuria poli, H. tubulosa, H. arguinensis, and H. sanctori), harvested from the Algerian coast, we aimed to study their proximate composition, fatty acid profile and angiotensin-converting enzyme (ACE) inhibitory activity. Their phospholipids were also used to elaborate nanoliposomes and to encapsulate peptides obtained from the same source. After the physico-chemical characterization of nanoliposomes and peptides, in vitro analyses were realized. The four holothurian species showed a high amount of protein (49.26–69.34%), and an impressive lipid profile of 27 fatty acids, mainly composed of polar fatty acids (91.16–93.85%), with a high polyunsaturated fatty acids (PUFA) content (50.90–71.80%), particularly eicosapentaenoic acid (EPA) (5.07–8.76%) and docosahexaenoic acid (DHA) (4.86–7.25%). A high phospholipids amount was also found (55.20–69.85%), mainly composed of phosphatidylcholine (PC) (51.48–58.56%). Their peptide fractions exhibited a high ACE inhibitory activity (IC50 0.30 to 0.51 mg/mL). The results also showed that the nanoliposomes do not induce cytotoxicity and cell death in human MSCs and no perturbation of proliferation for all the times and the tested concentrations, as well as the combined nanoliposomes and hydrolysates (HTS) at a concentration of 0.1 mg/mL. All four sea cucumbers show potential as a new source for omega-3, omega-6, and bioactive peptides.

Eukaryotic genomes are non-randomly arranged inside the nucleus. Despite this ordered spatial genome organization, damaged DNA exhibits increased random mobility within nuclear space. This increased random movement is thought to promote DNA repair by facilitating homology search, allowing targeting to repair-conducive nuclear domains, or releasing damage from repair-repressive locations. Recent studies focusing on the relationship between telomeres, DNA repair processes, and nuclear organization have revealed that the disruption of motor proteins or microtubules, which typically mediate the directed motion of cargo, disrupts the random mobility of damaged DNA. These findings define a new biological paradox. Here, I define this as the damaged DNA mobility paradox, describe how it uncovers key gaps in knowledge, and highlight key questions to help guide us toward paradox resolution.

As of June 19, 2015, the World Health Organization had received 1,338 notifications of laboratory-confirmed infection with Middle East respiratory syndrome coronavirus (MERS-CoV). Little is known about the course of or treatment for MERS-CoV in pregnant women. We report a fatal case of MERS-CoV in a pregnant woman administered combination ribavirin–peginterferon-α therapy.

Elbow arthroscopy is a useful tool for managing diseases of the elbow, including valgus extension overload, when conservative treatments have failed. Arthroscopic access to the elbow in the supine-suspended position is simple and reproducible with the technique described in this report. Synovial tissue can be cleared, optimizing visualization of the anatomic structures in the elbow including the posterior ulnohumeral joint. This report describes, in detail, arthroscopy of the elbow in the supine-suspended position and basic principles for arthroscopic decompression of the posterior elbow for valgus extension overload.

Descriptive, trans-sectional, correlated study of the main caretaker (MC) for ill terminal patients, included in the Programme for Pain Allaying, Palliative Care Chillán. The study implied 170 patients, with a sample of 50 individuals. The aim was to determine the existing relationship between socio-demographic characteristics and health characteristics in MC, and the perception of satisfaction in basic needs of patient. A questionnaire prepared by the authors was applied between January and May 2004. Data processing were gathered according to Programme EpiInfo 6,0 and checked with Programme Infostast. Statistical tests of square Chi and Fisher Test were applied. The results were as followis: 62 % of the MC were around 41 years and older; 86 % of the MC were women; 52 % were single or with no steady-boyfriend or commonlaw-husband; 82 % were patient’s relatives; 66 % of MC have financial income less to Pesos 100.000; 94 % were aware of their patient’s prognosis; 80 % dedicated all their time to their patient’s care; 78 % of the patients were dependant. It was observed that the social and demographic variables and those of health when related to perception of satisfaction of basic needs had no statistical significance in this study.