Perspectives of Interstitial Lung Disease Patients and Carers During COVID-19.

Aim To gain an understanding of the impact of COVID-19 on the daily life, healthcare needs, mental wellbeing and outlook of patients with Interstitial Lung Disease (ILD) and their caregivers. Methods ILD patients and caregivers were invited to participate in a quantitative survey. Respondents could self-select to then participate in in-depth structured telephone interviews. Survey data was compared to Department of Health COVID-19 public opinion tracker findings for the comparable time period. Results There were 170 survey respones (111 patients and 59 caregivers) and 14 in-depth interview participants. 32% (n=36) of patients and 42% (n=25) of caregivers expressed extreme worry regarding COVID-19 on a 1-10 scale. 83% (n=92) of patients expressed concern about safe hospital access, 33% (n=37) had received a telephone consultation with their clinician, 43% (n=48) reported test delays, 47% (n=52) were exercising less, 23% (n=26) reported worse sleep and 15% (n=17) reported being financially worse off. Carers reported that sleep was worse for 58% (n=34), 42% (n=25) reported being worse off financially, and 40% (n=24) reported a worse diet. Worry (66%, n=39), stress (51%, n=30), anxiety (49%, n=29) were commonly reported by carers. Discussion ILD patients and caregivers reported higher levels of worry regarding COVID-19 compared to the general public. Alternative pathways for quality ILD patient care and interventions to reduce the burden of care on ILD caregivers are required.

Surveillance optimisation to detect poliovirus in the pre-eradication era: a modelling study of England and Wales.

Surveillance for acute flaccid paralysis (AFP) cases are essential for polio eradication. However, as most poliovirus infections are asymptomatic and some regions of the world are inaccessible, additional surveillance tools require development. Within England and Wales, we demonstrate how inclusion of environmental sampling (ENV) improves the sensitivity of detecting both wild and vaccine-derived polioviruses (VDPVs) when compared to current surveillance. Statistical modelling was used to estimate the spatial risk of wild and VDPV importation and circulation in England and Wales. We estimate the sensitivity of each surveillance mode to detect poliovirus and the probability of being free from poliovirus, defined as being below a pre-specified prevalence of infection. Poliovirus risk was higher within local authorities in Manchester, Birmingham, Bradford and London. The sensitivity of detecting wild poliovirus within a given month using AFP and enterovirus surveillance was estimated to be 0.096 (95% CI 0.055-0.134). Inclusion of ENV in the three highest risk local authorities and a site in London increased surveillance sensitivity to 0.192 (95% CI 0.191-0.193). The sensitivity of ENV strategies can be compared using the framework by varying sites and the frequency of sampling. The probability of being free from poliovirus slowly increased from the date of the last case in 1993. ENV within areas thought to have the highest risk improves detection of poliovirus, and has the potential to improve confidence in the polio-free status of England and Wales and detect VDPVs.

Evolving epidemiology of poliovirus serotype 2 following withdrawal of the serotype 2 oral poliovirus vaccine.

Although there have been no cases of serotype 2 wild poliovirus for more than 20 years, transmission of serotype 2 vaccine-derived poliovirus (VDPV2) and associated paralytic cases in several continents represent a threat to eradication. The withdrawal of the serotype 2 component of oral poliovirus vaccine (OPV2) was implemented in April 2016 to stop VDPV2 emergence and secure eradication of all serotype 2 poliovirus. Globally, children born after this date have limited immunity to prevent transmission. Using a statistical model, we estimated the emergence date and source of VDPV2s detected between May 2016 and November 2019. Outbreak response campaigns with monovalent OPV2 are the only available method to induce immunity to prevent transmission. Yet our analysis shows that using monovalent OPV2 is generating more paralytic VDPV2 outbreaks with the potential for establishing endemic transmission. A novel OPV2, for which two candidates are currently in clinical trials, is urgently required, together with a contingency strategy if this vaccine does not materialize or perform as anticipated.

The influence of androgens on hibernation phenology of free-living male arctic ground squirrels.

Free-living ground squirrel species are sexually dimorphic in hibernation phenology. The underlying causes of these differences are not yet known. Androgens, testosterone (T) in particular, inhibit hibernation. To determine the influence of endogenous androgens on annual timing of hibernation we first measured circulating levels of T and dehydroepiandrosterone (DHEA), an adrenal androgen implicated in non-mating season aggression in other species, in free-living male arctic ground squirrels (Urocitellus parryii, AGS). We also manipulated endogenous androgen levels by surgical castration, and consequently compared body temperature records from intact (n=24) and castrated (n=9) males to elucidate the influence of endogenous androgens on annual body temperature cycles. The highest T levels (0.53±0.10ng/mL) were in reproductively mature male AGS in spring; whereas, both immature males in spring and all males in late summer had T levels an order of magnitude lower (0.07±0.01 and 0.06±0.00ng/mL, respectively). DHEA levels were higher in males during the late summer compared to reproductively mature males in spring (120.6±18.9 and 35.9±2.3pg/mL, respectively). Eliminating gonadal androgens via castration resulted in males delaying euthermy by extending heterothermy significantly in spring (Apr 22 ±2.9) than reproductive males (Mar 28 ±3.9) but did not change the timing of hibernation onset (castrate: Oct 12 ±1.0 vs. intact: Oct 3 ±3.1). We conclude that while androgens play a significant role in spring hibernation phenology of males, their role in fall hibernation onset is unclear.

A New Method for Estimating the Coverage of Mass Vaccination Campaigns Against Poliomyelitis From Surveillance Data.

Mass vaccination campaigns with the oral poliovirus vaccine targeting children aged <5 years are a critical component of the global poliomyelitis eradication effort. Monitoring the coverage of these campaigns is essential to allow corrective action, but current approaches are limited by their cross-sectional nature, nonrandom sampling, reporting biases, and accessibility issues. We describe a new Bayesian framework using data augmentation and Markov chain Monte Carlo methods to estimate variation in vaccination coverage from children's vaccination histories investigated during surveillance for acute flaccid paralysis. We tested the method using simulated data with at least 200 cases and were able to detect undervaccinated groups if they exceeded 10% of all children and temporal changes in coverage of ±10% with greater than 90% sensitivity. Application of the method to data from Pakistan for 2010-2011 identified undervaccinated groups within the Balochistan/Federally Administered Tribal Areas and Khyber Pakhtunkhwa regions, as well as temporal changes in coverage. The sizes of these groups are consistent with the multiple challenges faced by the program in these regions as a result of conflict and insecurity. Application of this new method to routinely collected data can be a useful tool for identifying poorly performing areas and assisting in eradication efforts.

An audit of the management of heart murmurs on the postnatal wards.

BACKGROUND: Investigation and management of neonatal heart murmurs varies widely and is dependent on local resources. In order to standardise the management of heart murmurs in our hospital a guideline (based on clinical examination with selective cardiology review) was introduced. AIMS: To establish adherence to and safety of the guideline; to review workload implications and to define the causes of neonatal heart murmurs in our population. METHODS: Patients were prospectively identified over a 2-year period (August 2006 to July 2008). Case notes were reviewed and examination findings, investigations, follow up and diagnosis recorded. RESULTS: 89 babies were identified. The guideline was generally well adhered to. In total 51 (57%) of babies were referred for cardiology assessment. In 40 babies this assessment included an echocardiogram. 30 babies (34%) had an underlying cardiac malformation: 25 were identified before discharge home. 15/30 (50%) of the babies with a cardiac malformation remain under cardiology follow up at the age of 1 year. No baby discharged from follow up without cardiology review subsequently presented with a cardiac problem. CONCLUSION: A significant minority of babies with a heart murmur have an underlying cardiac malformation. Our guideline appears to ensure the timely identification of these babies and rationalises our use of specialist services.

Associations between the presence of virulence determinants and the epidemiology and ecology of zoonotic Escherichia coli.

The severity of human infection with pathogenic Escherichia coli depends on two major virulence determinants (eae and stx) that, respectively, produce intimin and Shiga toxin. In cattle, both may enhance colonization, but whether this increases fitness by enhancing cattle-to-cattle transmission in the field is unknown. In E. coli O157, the almost uniform presence of the virulence determinants in cattle isolates prevents comparative analysis. The availability to this study of extensive non-O157 E. coli data, with much greater diversity in carriage of virulence determinants, provides the opportunity to gain insight into their potential impact on transmission. Dynamic models were used to simulate expected prevalence distributions for serogroups O26 and O103. Transmission parameters were estimated by fitting model outputs to prevalence data from Scottish cattle using a Bayesian Markov chain Monte Carlo (MCMC) approach. Despite similar prevalence distributions for O26 and O103, their transmission dynamics were distinct. Serogroup O26 strains appear well adapted to the cattle host. The dynamics are characterized by a basic reproduction ratio (R(0)) of >1 (allowing sustained cattle-to-cattle transmission), a relatively low transmission rate from environmental reservoirs, and substantial association with eae on transmission. The presence of stx(2) was associated with reduced transmission. In contrast, serogroup O103 appears better adapted to the noncattle environment, characterized by an R(0) value of <1 for plausible test sensitivities, a significantly higher transmission rate from noncattle sources than serogroup O26, and an absence of fitness benefits associated with the carriage of eae. Thus, the association of eae with enhanced transmission depends on the E. coli serogroup. Our results suggest that the capacity of E. coli strains to derive fitness benefits from virulence determinants influences the prevalence in the cattle population and the ecology and epidemiology of the host organism.

The control of Corynebacterium pseudotuberculosis infection in sheep flocks: a mathematical model of the impact of vaccination, serological testing, clinical examination and lancing of abscesses.

A mathematical model of Corynebacterium pseudotuberculosis infection in sheep flocks was used to evaluate strategies for control and elimination of caseous lymphadenitis (CLA). Control strategies tested were vaccination, serological testing and removal of seropositives, clinical examination and removal of sheep with abscesses, lancing abscesses, and appropriate combinations. Three different infection rates with and without replacement of culled ewes were used to evaluate the control options. Controls were either implemented immediately after infection was detected in a flock or once CLA was at endemic equilibrium, and with different frequencies of examination or testing. Elimination of infection was defined as 99% confidence that no sheep were infected with C. pseudotuberculosis. The control strategies were evaluated by estimating the reduction in infection or probability of elimination and the number of ewes culled from the flock. Lancing abscesses reduced the prevalence of infection when the initial prevalence was <0.60, but elimination was unlikely. A vaccine efficacy of 0.79 or more led to elimination of infection from the flock, provided that the endemic prevalence of infection was <0.60. A combination of vaccination and clinical examination reduced the prevalence of infection at a faster rate than using clinical examination or vaccination alone where five rounds of clinical examination were done. Serological testing led to elimination of infection after five tests, but was highly dependent upon the diagnostic test sensitivity and specificity and management options used: a test sensitivity of 0.90 always resulted in elimination. A test specificity greater than 0.90 prevented removal of many false positive ewes and consequently prevented a large reduction in lamb production. Elimination was most likely using a serological test with sensitivity and specificity >0.90, but vaccination combined with clinical examination reduced infection rapidly with little impact on lamb productivity. Further research is required to develop a diagnostic test with at least 0.90 specificity and sensitivity under field conditions before any methods of control can be recommended with confidence.

Parameter estimation and simulations of a mathematical model of Corynebacterium pseudotuberculosis transmission in sheep.

Caseous lymphadenitis (CLA) is an infectious disease of sheep caused by Corynebacterium pseudotuberculosis. It is prevalent in most sheep producing countries and was introduced into the UK sheep population in 1991. The pathogen invades the host through epithelium and forms an abscess in the local draining lymph node. Typically, disease presents as clinical, with overt (externally visible) swollen lymph nodes (the parotid, submandibular, prefemoral, prescapular, popliteal or mammary) or sub-clinical, with abscesses in the lungs and associated thoracic (bronchial and mediastinal) lymph nodes. We present a mathematical model in which disease is categorised as overt and/or respiratory (sub-clinical), using the above groupings. In both situations sheep may be infected and may or may not be infectious. In the model, overt abscesses may resolve and respiratory abscesses are considered to be present for life. Using the location of the abscesses, three routes of transmission are postulated: overt to overt, respiratory to overt and respiratory to respiratory. Data from four naturally infected flocks were used to describe populations of sheep with epidemic CLA and to estimate transmission coefficients for each of the postulated transmission routes. The infection process parameters were derived from literature where possible. Parameters were estimated using maximum likelihood methods and compared to the data using a multinomial distribution. The distribution of abscesses in the flocks was similar to endemic data reported in other studies. In the model most infected sheep developed abscesses, and approximately 36% of sheep with overt abscesses recovered from infection. The average time for respiratory abscesses to become infectious was 41 days. In these data, overt to overt transmission was the most frequent route of transmission since it had the highest coefficient in the model compared with respiratory to overt and respiratory to respiratory transmission. Transmission coefficients specific for each flock significantly (P<0.05) improved the model fit to the data. In simulations using values of best-fitting parameter combinations, the proportion of sheep infected was between 0.39 and 0.60 at equilibrium. This is the first mathematical model of C. pseudotuberculosis infection, the parameter estimates indicate that aspects of the infection process could be utilised to design control strategies.

Factors associated with preweaning mortality on commercial pig farms in England and Wales.

Data from 67 pig farms with a variety of farrowing systems were used to identify factors associated with preweaning mortality in British pig herds. The median mortality reported by the farmers was 10.7 per cent (interquartile range 8.5 to 14 per cent). There was a significantly higher mortality when the pigs were weaned when they were older. A multivariable Poisson model was developed into which the types of farrowing system on each farm and the age at weaning were forced. Factors associated with a lower preweaning mortality rate were insulating the farrowing building, providing extra heat at farrowing, giving the piglets iron injections, dipping their navels, using fan ventilation and using artificial lighting systems. Factors associated with a higher mortality rate were a later weaning age, the use of infra-red lamps rather than other forms of supplementary heat, and the use of a creep without any bedding.

Investigation of risk factors for clinical mastitis in British dairy herds with bulk milk somatic cell counts less than 150,000 cells/ml.

A sample of dairy farms in Great Britain with a monthly bulk milk somatic cell count of less than 150,000 cells/ml was enrolled into a 12-month prospective study. At the end of the study, a questionnaire on milking practice and other farm management practices was sent to the 482 farmers who had collected data on the occurrence of mastitis throughout the 12 months. The response rate was 93 per cent. The reported mean incidence of clinical mastitis was 36.9 cases per 100 cow-years. Factors associated with an increase in the incidence of clinical mastitis were cleaning out the straw yard less frequently than every six weeks, more than 5 per cent of cows leaking milk outside the parlour, checking the foremilk, wearing gloves during milking, an average annual milk yield of more than 7000 litres per cow, dipping or spraying teats before milking and keeping milk with a high somatic cell count out of the bulk tank. Factors associated with a decrease in the incidence of clinical mastitis were using a cloth to dry the teats after washing them as part of premilking preparation, using calving boxes for less than 40 per cent of calvings, and using both cubicles and straw yards to house dry cows, as opposed to other housing.

A case of steroid responsive pulmonary hyalinising granuloma: complicated by deep venous thrombosis.

A case of pulmonary hyalinising granuloma (PHG) complicated by deep venous thrombosis (DVT) is presented. The DVT was associated with the presence of a lupus anticoagulant. In the past PHG has been linked to various auto-antibodies, but to the best of the authors' knowledge, this is the first case reporting PHG in association with a lupus anticoagulant and clinically significant venous thrombosis. Historically, PHG has been regarded as poorly corticosteroid responsive. However, the patient in this case study responded dramatically to prednisone. This case study suggests that in selected patients with pulmonary hyalinising granuloma experiencing disabling symptoms and worsening pulmonary function, a trial of corticosteroids may be warranted.

Ecological factors underlying the adrenocortical response to capture stress in arctic-breeding shorebirds.

Birds breeding in the Arctic must carefully balance survival and reproduction because of the often extreme environmental conditions and the very brief breeding season. Acute elevation of plasma corticosterone is one mechanism that birds apparently use to alter the balance in favor of survival at the expense of reproduction when faced with stressors such as storms, predators, or low food availability. To examine this relationship, we applied a standardized stressor, capture and handling, to four species of shorebirds (Scolopacidae) during their breeding season in the Arctic and measured the increase in corticosterone between 3 min and 30 min after capture (hereafter called the stress response). We tested two hypotheses in an effort to explain the individual variation observed in the stress response. The first hypothesis states that individuals most responsible for parental care have a lower stress response than individuals less responsible for parental care. In species with uniparental care (Pectoral Sandpiper Calidris melanotos, Red Phalarope Phalaropus fulicaria), the caregivers had a lower stress response than the opposite sex, although in the latter species the difference was not significant (P = 0.016 and P = 0.102, respectively). In a species with equal biparental care (Semipalmated Sandpiper C. pusilla), the stress response did not differ between the sexes (P = 0.99, Barrow population). In a species with unequal biparental care (Western Sandpiper C. mauri), the more parental sex (males) had a much lower stress response than the less parental sex (P = 0.002). The second hypothesis states that individuals breeding in the high Arctic have a lower stress response than individuals breeding in the low Arctic. The stress response in a low-Arctic population of Semipalmated Sandpipers (Nome) was higher than that in a high-Arctic population (Barrow, P < 0.05). Individuals at an additional high-Arctic location (Prudhoe Bay) exhibited stress responses most similar to those of the Barrow population (P > 0.05). Taken together, these results provide evidence of a mechanism that birds may use to breed in environments with a brief breeding season and under conditions that might be perceived as stressful, if not for their reduced sensitivity to potential stressors.

Fibrosis of the lung and other tissues: new concepts in pathogenesis and treatment.

Tissue fibrosis can lead to significant organ dysfunction and resulting patient morbidity and mortality. Unfortunately, the therapeutic repertoire is currently limited, nonspecific, and largely ineffective. While the pathogenesis is incompletely understood, evidence is accumulating that immune and cytokine mediated mechanisms are critical. In this review, data will be provided to support the role of Type 2 cytokines in the pathogenesis of fibrosis. The importance of the role of the pro-fibrogenic cytokine TGF-beta and CD40-CD40 ligand mediated fibroblast activation will also be evaluated. Finally, novel therapeutic options based on inhibiting these pathways will be described.

Hormones and territorial behavior during breeding in snow buntings (Plectrophenax nivalis): an Arctic-breeding songbird.

We examined hormonal profiles and behavior associated with maintaining a single-purpose territory in an Arctic-breeding songbird-the snow bunting (Plectrophenax nivalis). Snow buntings differ from many other Arctic-breeding passerines by using nest cavities, an uncommon and defended resource, but not relying upon the surrounding territory for forage. Circulating levels of testosterone in males were high when territories were established and then decreased over the breeding season. LH secretion was enhanced in females while laying eggs, followed by detectable levels of estradiol during incubation. Both sexes showed equivalent corticosterone responses to the stress of being captured and held. Male snow buntings vigorously defended territories in response to a simulated territorial intrusion both when initiating breeding and when feeding young. Exogenous testosterone implants surprisingly inhibited physical aggression but enhanced singing when birds were feeding young, thus suggesting that song and physical aggression are mediated by different hormonal mechanisms at this time of year. Together, these results contrast with hormonal profiles and behavior in other Arctic-breeding passerines.

Lethal presentation of mosaic tetrasomy 12p (Pallister-Killian) syndrome.

A lethally malformed neonate with mosaic tetrasomy 12p is presented. This is the third reported case of mosaic tetrasomy 12p to have died in the neonatal period. These three babies have shown a consistent phenotype characterized by dysmorphic facies and large diaphragmatic hernia. Mosaic tetrasomy 12p is usually not detectable from lymphocyte investigation, indicating that chromosome studies from cultured fibroblasts should be undertaken in neonates with multiple malformations which include a diaphragmatic defect.

Etiological heterogeneity in sirenomelia.

Two babies with sirenomelia are described. Case 1, one of twins, showed the full sirenomelia sequence in conjunction with atelencephaly and cebocephaly. Case 2 had malformations consistent with a diagnosis of the VATER association. Review of the literature indicates that the basic defect in sirenomelia and the VATER association lies in the formation and differentiation of mesodermal tissue and that sirenomelia, the VATER association, and monozygotic twinning show a complex etiological interrelationship.