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Cellular exposure to hypoxia results in altered gene expression in a range of physiologic and pathophysiologic states. Discrete cohorts of genes can be either up- or down-regulated in response to hypoxia. While the Hypoxia-Inducible Factor (HIF) is the primary driver of hypoxia-induced adaptive gene expression, less is known about the signalling mechanisms regulating hypoxia-dependent gene repression. Using RNA-seq, we demonstrate that equivalent numbers of genes are induced and repressed in human embryonic kidney (HEK293) cells. We demonstrate that nuclear localization of the Repressor Element 1-Silencing Transcription factor (REST) is induced in hypoxia and that REST is responsible for regulating approximately 20% of the hypoxia-repressed genes. Using chromatin immunoprecipitation assays we demonstrate that REST-dependent gene repression is at least in part mediated by direct binding to the promoters of target genes. Based on these data, we propose that REST is a key mediator of gene repression in hypoxia.

A long-term (1995-2016) survey for novae in the nearby Andromeda galaxy (M31) was conducted as part of the Research-Based Science Education initiative. During the course of the survey 180 nights of observation were completed at Kitt Peak, Arizona. A total of 262 novae were either discovered or confirmed, 40 of which have not been previously reported. Of these, 203 novae form a spatially-complete sample detected by the KPNO/WIYN 0.9-m telescope within a \\(20'\\times20'\\) field centered on the nucleus of M31. An additional 50 novae are part of a spatially-complete sample detected by the KPNO 4-m telescope within a larger \\(36'\\times36'\\) field. Consistent with previous studies, it is found that the spatial distribution of novae in both surveys follows the bulge light of M31 somewhat more closely than the overall background light of the galaxy. After correcting for the limiting magnitude and the spatial and temporal coverage of the surveys, a final nova rate in M31 is found to be \\(R=40^{+5}_{-4}\\) yr\\(^{-1}\\), which is considerably lower than recent estimates. When normalized to the \\(K\\)-band luminosity of M31, this value yields a luminosity-specific nova rate, \\(\\nu_K = 3.3\\pm0.4\\) yr\\(^{-1} [10^{10} L_{\\odot,K}]^{-1}\\). By scaling the M31 nova rate using the relative infrared luminosities of M31 and our Galaxy, a nova rate of \\(R_\\mathrm{G}=28^{+5}_{-4}\\) is found for the Milky Way.

Although HIV infection and its associated co-morbidities remain the commonest reason for hospitalisation in Africa, their impact on economic costs and health-related quality of life (HRQoL) are not well understood. This information is essential for decision-makers to make informed choices about how to best scale-up anti-retroviral treatment (ART) programmes. This study aimed to quantify the impact of HIV infection and ART on economic outcomes in a prospective cohort of hospitalised patients with high HIV prevalence. Sequential medical admissions to Queen Elizabeth Central Hospital, Malawi, between June-December 2014 were followed until discharge, with standardised classification of medical diagnosis and estimation of healthcare resources used. Primary costing studies estimated total health provider cost by medical diagnosis. Participants were interviewed to establish direct non-medical and indirect costs. Costs were adjusted to 2014 US$ and INT$. HRQoL was measured using the EuroQol EQ-5D. Multivariable analyses estimated predictors of economic outcomes. Of 892 eligible participants, 80.4% (647/892) were recruited and medical notes found. In total, 447/647 (69.1%) participants were HIV-positive, 339/447 (75.8%) were on ART prior to admission, and 134/647 (20.7%) died in hospital. Mean duration of admission for HIV-positive participants not on ART and HIV-positive participants on ART was 15.0 days (95%CI: 12.0-18.0) and 12.2 days (95%CI: 10.8-13.7) respectively, compared to 10.8 days (95%CI: 8.8-12.8) for HIV-negative participants. Mean total provider cost per hospital admission was US$74.78 (bootstrap 95%CI: US$25.41-US$124.15) higher for HIV-positive than HIV-negative participants. Amongst HIV-positive participants, the mean total provider cost was US$106.87 (bootstrap 95%CI: US$25.09-US$106.87) lower for those on ART than for those not on ART. The mean total direct non-medical and indirect cost per hospital admission was US$87.84. EQ-5D utility scores were lower amongst HIV-positive participants, but not significantly different between those on and not on ART. HIV-related hospital care poses substantial financial burdens on health systems and patients; however, per-admission costs are substantially lower for those already initiated onto ART prior to admission. These potential cost savings could offset some of the additional resources needed to provide universal access to ART.

Approximately 11% of people reported to have tuberculosis (TB) have previously received treatment. Clinical outcomes are consistently poor on retreatment regimens, however reasons for this are unclear. This study aimed to explore factors which may contribute to unsuccessful outcomes in retreatment TB. A prospective cohort of consecutive patients starting WHO Category II retreatment regimen was recruited at a central hospital in Malawi. Participants were evaluated at baseline, after completion of the intensive phase at 2-months, and at the end of the 8-month treatment course. Patients were assessed for respiratory co-morbidity; anaemia; renal impairment; diabetes; Anti-retroviral (ART) failure; and drug toxicity. Amongst 158 patients entering TB care at the point of a recurrent episode, only 92 (58%) had a microbiologically confirmed diagnosis. The prevalence of drug resistance was low (9.6%). Of the 158 patients, 131 (83%) were HIV-positive, of whom 96 (73%) were on ART. Of 63 patients on ART >1 year, 24 (38%) had ART failure. Chronic lung disease was found in 88% on CT thorax, including scarring (80%), bronchiectasis (61%), COPD (22%), and destroyed lung (19%). Spirometry revealed restrictive deficit in 60%, and obstructive deficit in 7% of patients. Anaemia and renal impairment were common (34% and 45% respectively). Ototoxicity developed in 32%, and nephrotoxicity in 15%. 40% of patients reported peripheral neuropathy. Liver injury developed in 4%. If outcomes are to be improved in retreatment TB, there is an urgent need to address the impact of other co-morbid medical conditions including chronic lung disease, HIV and ART failure.

BackgroundPeople with recurrent or drug-resistant TB require long courses of intramuscular injections. We evaluate a novel system in which patient-nominated lay carers were trained to deliver intramuscular injections to patients in their own homes.MethodsA pragmatic, individually randomised non-inferiority trial was conducted at two hospitals in Malawi. Adults starting TB retreatment were recruited. Patients randomised to the intervention received home-based care from patient-nominated lay people trained to deliver intramuscular streptomycin. Patients receiving standard care were admitted to hospital for 2 months of streptomycin. The primary outcome was successful treatment (alive and on treatment) at the end of the intervention.ResultsOf 456 patients screened, 204 participants were randomised. The trial was terminated early due to futility. At the end of the intervention, 97/101 (96.0%) in the hospital arm were still alive and on treatment compared with 96/103 (93.2%) in the home-based arm (risk difference −0.03 (95% CI −0.09 to 0.03); p value 0.538). There were no differences in the proportion completing 8 months of anti-TB treatment; or the proportion experiencing 2-month sputum culture conversion. The mean cost of hospital-based management was US$1546.3 per person, compared to US$729.2 for home-based management. Home-based care reduced risk of catastrophic household costs by 84%.ConclusionsAlthough this trial failed to meet target recruitment, the available data demonstrate that training patient-nominated lay people has potential to provide a feasible solution to the operational challenges associated with delivering long-term-injectable drugs to people with recurrent or drug-resistant TB in resource-limited settings, and substantially reduce costs. Further data under operational conditions are required.Trial registration number ISRCTN05815615.

Laryngocoele is a rare entity, defined as an abnormal cystic dilatation of saccule of the laryngeal ventricle. Three types of laryngocele have been described, based on their relation to the thyrohyoid membrane: internal, external or mixed type. Symptoms are variable, including neck swelling, shortness of breath, dysphonia and fever, if the laryngocoele becomes infected. Patients may also present in extremis with airway obstruction. We present the case of a healthy 34-year-old gentleman with acute airway obstruction due to a mixed infected laryngocoele. Flexible nasoendoscopy showed a large cystic swelling arising from the laryngeal ventricle. Computed tomography of neck confirmed a right paraglottic collection extending into the ventricle and glottis, causing significant airway compromise. The patient was managed with microlaryngoscopy and cystic decompression. At outpatient follow up, he was completely asymptomatic and is currently under surveillance. Endoscopic decompression is a safe and effective initial management for mixed laryngocoele.

Paranasal sinus mucoceles are benign, locally expansile masses of the paranasal sinuses that are lined by epithelial cells. They result from obstruction of sinus ostia. The close proximity of paranasal sinus mucoceles to the orbit and skull base predisposing the patient to significant morbidity. We describe the case of a previously healthy 23-year-old gentleman presenting with a five-day history of unilateral (left) eye pain and swelling with an obvious deformity. There was also no history of trauma or prior surgery. He underwent a CT sinus, which showed near complete opacification of the left anterior ethmoid sinus with bony destruction and obvious displacement of the orbit both laterally and anteriorly. This was assessed as to be in keeping with an ethmoid mucocele. Endoscopic marsupialization has become the preferred surgical approach over obliterative procedures for the treatment of paranasal sinus mucoceles. Primary ethmoid mucocele is an uncommon entity, especially in the absence of prior ear, nose and throat (ENT) complaints, and therefore should remain an important differential when a patient presents with a unilateral swelling causing proptosis.

ObjectivesAcute appendicitis is the most common surgical condition in children. In the UK, appendicectomy is the most common treatment with non-operative management unusual. Due to concerns about the risk of SARS-CoV-2 transmission during surgical procedures, surgeons were advised to consider non-operative treatment and avoid laparoscopy where possible. This study aims to report management and outcomes, to date, of children with appendicitis in the UK and Ireland during the COVID-19 pandemic.DesignSurvey of consultant surgeons who treat children with appendicitis that informed a prospective multicentre observational cohort study.SettingData were collected from centres in the UK and Ireland for cases admitted between 1 April and 31 May 2020 (first 2 months of the COVID-19 pandemic) at both general surgical and specialist paediatric surgical centres.ParticipantsThe study cohort includes 838 children with a clinical and/or radiological diagnosis of acute appendicitis of which 527 (63%) were male.Main outcomes measuredPrimary outcome was treatment strategy used for acute appendicitis. Other outcomes reported include change in treatment strategy over time, use of diagnostic imaging and important patient outcomes to 30 days following hospital admission.ResultsFrom very early in the pandemic surgeons experienced a change in their management of children with appendicitis and almost all surgeons who responded to the survey anticipated further changes during the pandemic. Overall, 326/838 (39%) were initially treated non-operatively of whom 81/326 (25%) proceeded to appendicectomy within the initial hospital admission. Of cases treated initially surgically 243/512 (48%) were performed laparoscopically. Diagnostic imaging was used in 445/838 (53%) children. Cases treated non-operatively had a shorter hospital stay than those treated surgically but hospital readmissions within 30 days were similar between groups. In cases treated surgically the negative appendicectomy rate was 4.5%. There was a trend towards increased use of surgical treatment and from open to laparoscopic appendicectomy as the pandemic progressed.ConclusionNon-operative treatment of appendicitis has been widely used for the first time in children in the UK and Ireland and is safe and effective in selected patients. Overall patient outcomes do not appear to have been adversely impacted by change in management during the pandemic thus far.