Sleep insufficiency, circadian rhythms, and metabolomics: the connection between metabolic and sleep disorders.

PURPOSE: US adults who report experiencing insufficient sleep are more likely to suffer from metabolic disorders such as hyperlipidemia, diabetes, and obesity than those with sufficient sleep. Less is understood about the underlying molecular mechanisms connecting these phenomena. A systematic, qualitative review of metabolomics studies exploring metabolic changes in response to sleep insufficiency, sleep deprivation, or circadian disruption was conducted in accordance with PRISMA guidelines. METHODS: An electronic literature review in the PubMed database was performed considering publications through May 2021 and screening and eligibility criteria were applied to articles retrieved. The following keywords were used: "metabolomics" and "sleep disorders" or "sleep deprivation" or "sleep disturbance" or "circadian rhythm." After screening and addition of studies included from reference lists of retrieved studies, 16 records were identified for review. RESULTS: Consistent changes in metabolites were observed across studies between individuals experiencing sleep deprivation compared to non-sleep deprived controls. Significant increases in phosphatidylcholines, acylcarnitines, sphingolipids, and other lipids were consistent across studies. Increased levels of amino acids such as tryptophan and phenylalanine were also noted. However, studies were limited to small samples of young, healthy, mostly male participants conducted in short inpatient sessions, limiting generalizability. CONCLUSION: Changes in lipid and amino acid metabolites accompanying sleep deprivation and/or circadian rhythms may indicate cellular membrane and protein breakdown underlying the connection between sleep disturbance, hyperlipidemia, and other metabolic disorders. Larger epidemiological studies examining changes in the human metabolome in response to chronic insufficient sleep would help elucidate this relationship.

Sphinganine is associated with 24-h MAP in the non-sleepy with OSA.

INTRODUCTION: Excessive daytime sleepiness is a debilitating symptom of obstructive sleep apnea (OSA) linked to cardiovascular disease, and metabolomic mechanisms underlying this relationship remain unknown. We examine whether metabolites from inflammatory and oxidative stress-related pathways that were identified in our prior work could be involved in connecting the two phenomena. METHODS: This study included 57 sleepy (Epworth Sleepiness Scale (ESS) ≥ 10) and 37 non-sleepy (ESS < 10) participants newly diagnosed and untreated for OSA that completed an overnight in-lab or at home sleep study who were recruited from the Emory Mechanisms of Sleepiness Symptoms Study (EMOSS). Differences in fasting blood samples of metabolites were explored in participants with sleepiness versus those without and multiple linear regression models were utilized to examine the association between metabolites and mean arterial pressure (MAP). RESULTS: The 24-h MAP was higher in sleepy 92.8 mmHg (8.4) as compared to non-sleepy 88.8 mmHg (8.1) individuals (P = 0.03). Although targeted metabolites were not significantly associated with MAP, when we stratified by sleepiness group, we found that sphinganine is significantly associated with MAP (Estimate = 8.7, SE = 3.7, P = 0.045) in non-sleepy patients when controlling for age, BMI, smoking status, and apnea-hypopnea index (AHI). CONCLUSION: This is the first study to evaluate the relationship of inflammation and oxidative stress related metabolites in sleepy versus non-sleepy participants with newly diagnosed OSA and their association with 24-h MAP. Our study suggests that Sphinganine is associated with 24 hour MAP in the non-sleepy participants with OSA.

The risk of reverse zoonotic transmission to pet animals during the current global monkeypox outbreak, United Kingdom, June to mid-September 2022.

We report results of surveillance between June and mid-September 2022 of pet animals living in households of confirmed human monkeypox (MPX) cases. Since surveillance commenced, 154 animals from 40 households with a confirmed human MPX case were reported to the United Kingdom Animal and Plant Health Agency. No animals with clinical signs of MPX were identified. While a risk of transmission exists to pets from owners with a confirmed MPX virus infection, we assess this risk to be low.

Case-Control Study of Risk Factors for Acquired Hepatitis E Virus Infections in Blood Donors, United Kingdom, 2018-2019.

Hepatitis E virus (HEV) is the most common cause of acute viral hepatitis in England. Substantial yearly increases of autochthonous infections were observed during 2003-2016 and again during 2017-2019. Previous studies associated acute HEV cases with consumption of processed pork products, we investigated risk factors for autochthonous HEV infections in the blood donor population in England. Study participants were 117 HEV RNA-positive blood donors and 564 HEV RNA-negative blood donors. No persons with positive results were vegetarian; 97.4% of persons with positive results reported eating pork products. Consuming bacon (OR 3.0, 95% CI 1.7-5.5; p<0.0001), cured pork meats (OR 3.5, 95% CI 2.2-5.4; p<0.0001), and pigs' liver (OR 2.9, 95% CI 1.0-8.3; p = 0.04) were significantly associated with HEV infection. Our findings confirm previous links to pork products and suggest that appropriate animal husbandry is essential to reduce the risk for HEV infection.

Family cluster of three cases of monkeypox imported from Nigeria to the United Kingdom, May 2021.

Most reported cases of human monkeypox occur in Central and West Africa, where the causing virus is endemic. We describe the identification and public health response to an imported case of West African monkeypox from Nigeria to the United Kingdom (UK) in May 2021. Secondary transmission from the index case occurred within the family to another adult and a toddler. Concurrent COVID-19-related control measures upon arrival and at the hospital, facilitated detection and limited the number of potential contacts.

Human-to-Human Transmission of Monkeypox Virus, United Kingdom, October 2018.

In September 2018, monkeypox virus was transmitted from a patient to a healthcare worker in the United Kingdom. Transmission was probably through contact with contaminated bedding. Infection control precautions for contacts (vaccination, daily monitoring, staying home from work) were implemented. Of 134 potential contacts, 4 became ill; all patients survived.

A probable case of tick-borne encephalitis (TBE) acquired in England, July 2019.

The United Kingdom (UK) has thus far been considered to be free from tick-borne encephalitis (TBE), yet in July 2019, a German infant developed serologically diagnosed TBE following a tick bite in southern England. This first report of a probable human case together with recent findings of TBE virus in ticks in foci in England suggest that TBE may be acquired in parts of England and should be considered in patients with aetiologically-unexplained neurological manifestations.

Bovine tuberculosis in working foxhounds: lessons learned from a complex public health investigation.

In 2017, Public Health England South East Health Protection Team (HPT) were involved in the management of an outbreak of Mycobacterium bovis (the causative agent of bovine tuberculosis) in a pack of working foxhounds. This paper summarises the actions taken by the team in managing the public health aspects of the outbreak, and lessons learned to improve the management of future potential outbreaks. A literature search was conducted to identify relevant publications on M. bovis. Clinical notes from the Public Health England (PHE) health protection database were reviewed and key points extracted. Animal and public health stakeholders involved in the management of the situation provided further evidence through unstructured interviews and personal communications. The PHE South East team initially provided 'inform and advise' letters to human contacts whilst awaiting laboratory confirmation to identify the infectious agent. Once M. bovis had been confirmed in the hounds, an in-depth risk assessment was conducted, and contacts were stratified in to risk pools. Eleven out of 20 exposed persons with the greatest risk of exposure were recommended to attend TB screening and one tested positive, but had no evidence of active TB infection. The number of human contacts working with foxhound packs can be large and varied. HPTs should undertake a comprehensive risk assessment of all potential routes of exposure, involve all other relevant stakeholders from an early stage and undertake regular risk assessments. Current guidance should be revised to account for the unique risks to human health posed by exposure to infected working dogs.

Two cases of monkeypox imported to the United Kingdom, September 2018.

In early September 2018, two cases of monkeypox were reported in the United Kingdom (UK), diagnosed on 7 September in Cornwall (South West England) and 11 September in Blackpool (North West England). The cases were epidemiologically unconnected and had recently travelled to the UK from Nigeria, where monkeypox is currently circulating. We describe the epidemiology and the public health response for the first diagnosed cases outside the African continent since 2003.

Insidious Risk of Severe Mycobacterium chimaera Infection in Cardiac Surgery Patients.

BACKGROUND: An urgent UK investigation was launched to assess risk of invasive Mycobacterium chimaera infection in cardiothoracic surgery and a possible association with cardiopulmonary bypass heater-cooler units following alerts in Switzerland and The Netherlands. METHODS: Parallel investigations were pursued: (1) identification of cardiopulmonary bypass-associated M. chimaera infection through national laboratory and hospital admissions data linkage; (2) cohort study to assess patient risk; (3) microbiological and aerobiological investigations of heater-coolers in situ and under controlled laboratory conditions; and (4) whole-genome sequencing of clinical and environmental isolates. RESULTS: Eighteen probable cases of cardiopulmonary bypass-associated M. chimaera infection were identified; all except one occurred in adults. Patients had undergone valve replacement in 11 hospitals between 2007 and 2015, a median of 19 months prior to onset (range, 3 months to 5 years). Risk to patients increased after 2010 from <0.2 to 1.65 per 10000 person-years in 2013, a 9-fold rise for infections within 2 years of surgery (rate ratio, 9.08 [95% CI, 1.81-87.76]). Endocarditis was the most common presentation (n = 11). To date, 9 patients have died. Investigations identified aerosol release through breaches in heater-cooler tanks. Mycobacterium chimaera and other pathogens were recovered from water and air samples. Phylogenetic analysis found close clustering of strains from probable cases. CONCLUSIONS: We identified low but escalating risk of severe M. chimaera infection associated with heater-coolers with cases in a quarter of cardiothoracic centers. Our investigations strengthen etiological evidence for the role of heater-coolers in transmission and raise the possibility of an ongoing, international point-source outbreak. Active management of heater-coolers and heightened clinical awareness are imperative given the consequences of infection.

Management of Zika virus in pregnancy: a review.

INTRODUCTION/BACKGROUND: Since 2015, an epidemic of Zika virus spread across the Americas. This coincided with an increased incidence of microcephaly reported at birth in Brazil, with subsequent evidence of a causal association. SOURCES OF DATA: Systemic reviews, observational studies, public health organizations. AREAS OF AGREEMENT: Zika virus causes microcephaly and brain abnormalities in infants born to mothers infected during or shortly before pregnancy. Zika virus is a trigger for Guillain Barre Syndrome. Whilst mosquito bite is the main route of transmission, sexual transmission is another confirmed route. AREAS OF CONTROVERSY: Uncertainty remains regarding the proportion of Zika-infected pregnancies that will give rise to a significantly affected infant. GROWING POINTS: The development of a vaccine remains a priority whilst public health efforts continue to educate at risk populations on reducing transmission. AREAS TIMELY FOR DEVELOPING RESEARCH: Follow-up studies of affected infants are vital to inform on prognosis and guide screening programmes of the future.

Cyclosporiasis in travellers returning to the United Kingdom from Mexico in 2017: lessons from the recent past to inform the future.

During the summers of 2015 and 2016, the United Kingdom experienced large outbreaks of cyclosporiasis in travellers returning from Mexico. As the source of the outbreaks was not identified, there is the potential for a similar outbreak to occur in 2017; indeed 78 cases had already been reported as at 27 July 2017. Early communication and international collaboration is essential to provide a better understanding of the source and extent of this recurring situation.

Hepatitis E virus in blood components: a prevalence and transmission study in southeast England.

BACKGROUND: The prevalence of hepatitis E virus (HEV) genotype 3 infections in the English population (including blood donors) is unknown, but is probably widespread, and the virus has been detected in pooled plasma products. HEV-infected donors have been retrospectively identified through investigation of reported cases of possible transfusion-transmitted hepatitis E. The frequency of HEV transmission by transfusion and its outcome remains unknown. We report the prevalence of HEV RNA in blood donations, the transmission of the virus through a range of blood components, and describe the resulting morbidity in the recipients. METHODS: From Oct 8, 2012, to Sept 30, 2013, 225,000 blood donations that were collected in southeast England were screened retrospectively for HEV RNA. Donations containing HEV were characterised by use of serology and genomic phylogeny. Recipients, who received any blood components from these donations, were identified and the outcome of exposure was ascertained. FINDINGS: 79 donors were viraemic with genotype 3 HEV, giving an RNA prevalence of one in 2848. Most viraemic donors were seronegative at the time of donation. The 79 donations had been used to prepare 129 blood components, 62 of which had been transfused before identification of the infected donation. Follow-up of 43 recipients showed 18 (42%) had evidence of infection. Absence of detectable antibody and high viral load in the donation rendered infection more likely. Recipient immunosuppression delayed or prevented seroconversion and extended the duration of viraemia. Three recipients cleared longstanding infection after intervention with ribavirin or alteration in immunosuppressive therapy. Ten recipients developed prolonged or persistent infection. Transaminitis was common, but short-term morbidity was rare; only one recipient developed apparent but clinically mild post-transfusion hepatitis. INTERPRETATION: Our findings suggest that HEV genotype 3 infections are widespread in the English population and in blood donors. Transfusion-transmitted infections rarely caused acute morbidity, but in some immunosuppressed patients became persistent. Although at present blood donations are not screened, an agreed policy is needed for the identification of patients with persistent HEV infection, irrespective of origin, so that they can be offered antiviral therapy. FUNDING: Public Health England and National Health Service Blood and Transplant.

The implementation of a municipal indoor ice skating helmet policy: effects on helmet use, participation and attitudes.

RELEVANT LOCAL INJURY EPIDEMIOLOGY: In Ottawa, between 2005 and 2009 there was an annual average of 47.2 head injuries due to ice skating in children and youth (1-19 years of age) requiring a visit to the emergency department, with the highest rates among those aged 5-14 years. Between 2002 and 2007, only 6% of children were wearing a helmet during ice skating when the head injury occurred. During indoor public skating sessions, 93% of children (<10 years)-57% aged 10-12 years, 20% aged 13-17 years and 9% adults-wore helmets in the absence of a policy. Support for a helmet policy was high from public health, medical, political and community perspectives. BEST PRACTICE: Helmet policies in relation to cycling have demonstrated increases in helmet use and reduction of head injuries without decreasing physical activity. However, no known studies have examined the effect of indoor ice skating helmet policy coupled with education and promotional activities on helmet use, participation and attitudes towards helmet use. IMPLEMENTATION: An ice skating helmet policy for children (<11 years of age) and those with limited skating experience at indoor rinks during public skating sessions was developed, implemented and evaluated. Supportive activities such as discount coupons, promotional materials, a media launch, social marketing and staff training are described. DISCUSSION: The helmet policy was associated with increased helmet use for young children and for older children, youth and adults not included in the policy, without decreasing attendance to public skating sessions.

The first three reported cases of Sporothrix brasiliensis cat-transmitted sporotrichosis outside South America.

An epidemic of cat-transmitted sporotrichosis caused by Sporothrix brasiliensis has emerged as a major public health threat in Brazil in recent decades. We report the first three cases of cat-transmitted sporotrichosis caused by Sporothrix brasiliensis outside South America, and the first ever cases of cat-transmitted sporotrichosis in the United Kingdom. We outline the public health implications and outbreak response and encourage clinicians and veterinarians worldwide to be vigilant for sporotrichosis in cats and cat owners.

Variability in firearm injury among major pediatric trauma centers across the USA.

Objectives: In 2020, firearm injuries surpassed automobile collisions as the leading cause of death in US children. Annual automobile fatalities have decreased during 40 years through a multipronged approach. To develop similarly targeted public health interventions to reduce firearm fatalities, there is a critical need to first characterize firearm injuries and their outcomes at a granular level. We sought to compare firearm injuries, outcomes, and types of shooters at trauma centers in four pediatric health systems across the USA. Methods: We retrospectively extracted data from each institution's trauma registry, paper and electronic health records. Study included all patients less than 19 years of age with a firearm injury between 2003 and 2018. Variables collected included demographics, intent, resources used, and emergency department and hospital disposition. Descriptive statistics were reported using medians and IQRs for continuous data and counts with percentages for categorical data. χ2 test or Fisher's exact test was conducted for categorical comparisons. Results: Our cohort (n=1008, median age 14 years) was predominantly black and male. During the study period, there was an overall increase in firearm injuries, driven primarily by increases in the South (S) site (ß=0.11 (SE 0.02), p=<0.001) in the setting of stable rates in the West and decreasing rates in the Northeast and Mid-Atlantic sites (ß=-0.15 (SE 0.04), p=0.002; ß=-0.19 (SE0.04), p=0.001). Child age, race, insurance type, resource use, injury type, and shooter type all varied by regional site. Conclusion: The incidence of firearm-related injuries seen at four sites during 15 years varied by site and region. The overall increase in firearm injuries was predominantly driven by the S site, where injuries were more often unintentional. This highlights the need for region-specific data to allow for the development of targeted interventions to impact the burden of injury.Level of Evidence: II, retrospective study.

Three Pediatric Siblings With CADASIL.

BACKGROUND: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a congenital small vessel disease of the brain due to NOTCH3 gene mutations. Although adult-onset CADASIL is well documented, more cases are being described within the pediatric population. We describe three siblings with NOTCH3 mutations with various symptomatic presentations of early-onset CADASIL and one sibling with concurrent moyamoya syndrome. METHODS: Review of electronic medical records of identified patients. RESULTS: A 19-year-old male who has experienced behavioral dysregulation, hallucinations, and memory loss along with a hyperintense signal abnormality in his temporal lobe; his 15-year-old sister who has the mildest presentation in terms of normal imaging results but experiences severe headaches, anxiety, and depression; and the youngest sibling, a 13-year-old with first reported case of a NOTCH3 mutation associated with moyamoya syndrome and a TREX1 gene mutation of uncertain clinical significance. She had multiple strokes before age five years. CONCLUSION: Our set of siblings share many similarities with other reported pediatric cases of CADASIL, all with NOTCH3 gene mutations and with early-onset symptoms that range from abnormalities in the cognitive/behavioral/psychiatric field to neurological deficits, migraines, and strokes. Gene testing and imaging studies in symptomatic children with a family history suggestive of CADASIL might aid in early diagnosis, even though there is no effective therapy. We believe that the correlation of clinical presentations and gene mutations together with increased research into the molecular mechanisms underlying CADASIL (and related arteriopathies such as moyamoya syndrome) are critical to the eventual development of targeted therapies.

A comparison of placebo and nocebo effects on objective and subjective postural stability: a double-edged sword?

Background: Positive expectations (i.e., placebo effect) can improve postural control during quiet standing. This raises an important question: if postural control is susceptible to positive expectations, is it possible to elicit the opposite, a decline in postural stability, simply by suggesting a performance impairment (i.e., nocebo) will take place? Yet no studies have examined the nocebo effect on balance performance. To better understand both phenomena, comparative studies, which include both placebo and nocebo conditions, are needed. Method: Forty-two healthy adults were initially assessed for objective (center of pressure movement) and subjective (perceived) postural stability and performance expectations. Participants were then randomly assigned in equal numbers to a placebo (positive expectation), nocebo (negative expectation) or control (no suggestion) group. Participants in the placebo/nocebo groups were deceptively administered an inert capsule described as a potent supplement which would either positively or negatively influence their balance performance. Objective and subjective postural stability, and performance expectations were reassessed 20 min later. Results: The nocebo procedure evoked an increase in COP sway movements and reduced perceived stability compared to a control group. The placebo group presented with reductions COP sway movements and increased perceived stability following expectation manipulation. Compared to the control group, the placebo group showed a significantly higher performance expectation whilst the nocebo group showed a significantly lower performance expectation. Regression analyses also revealed that performance expectations following the placebo/nocebo procedure significantly predicted perceptions of postural instability (i.e., perceived performance), accounting for around 50% of the variance. These results remained even when controlling for actual performance (i.e., objective postural stability). Conclusion: Our findings indicate that positive and negative performance expectations evoked by instructional manipulation can profoundly influence both objective and subjective postural stability. Postural control-and perceptions regarding such-are clearly susceptible to expectation manipulation, which could have important practical implications and repercussions on testing, training interventions and rehabilitation programs. Positive and negative expectancies are a double-edged sword for postural control.

Case Report: Toxigenic Corynebacterium ulcerans Diphtheria-Like Infection in a Horse in the United Kingdom.

Corynebacterium ulcerans (C. ulcerans) may cause diphtheria in humans and can be carried by a wide range of animal species including dairy cows and, more recently, dogs and cats that have been increasingly involved in zoonotic trasmission. We isolated and characterized, by WGS, a toxigenic C. ulcerans strain from a diseased horse in the United Kingdom showing clinical signs of respiratory diphtheria comparable to those seen in people. Our results indicate a role for horses as reservoirs for zoonotic C. ulcerans.

Very low energy electrons transform the cyclobutane-pyrimidine dimer into a highly reactive intermediate.

Electrons with virtually no kinetic energy (close to 0 eV) trigger the decomposition of cytotoxic cyclobutane-pyrimidine dimer (CPD) into a surprisingly large variety of fragment ions plus their neutral counterparts. The response of CPD to low energy electrons is thus comparable to that of explosives like trinitrotoluene (TNT). The dominant unimolecular reaction is the splitting into two thymine like units, which can be considered as the essential molecular step in the photolyase of CPD. We find that CPD is significantly more sensitive towards low energy electrons than its thymine building blocks. It is proposed that electron attachment at very low energy proceeds via dipole bound states, supported by the large dipole moment of the molecule (6.2 D). These states act as effective doorways to dissociative electron attachment (DEA).