Analysis of the yearly transition function in measles disease modeling.

Globally, there were an estimated 9.8 million measles cases and 207 500 measles deaths in 2019. As the effort to eliminate measles around the world continues, modeling remains a valuable tool for public health decision-makers and program implementers. This study presents a novel approach to the use of a yearly transition function that formulates mathematically the vaccine schedules for different age groups while accounting for the effects of the age of vaccination, the timing of vaccination, and disease seasonality on the yearly number of measles cases in a country. The methodology presented adds to an existing modeling framework and expands its analysis, making its utilization more adjustable for the user and contributing to its conceptual clarity. This article also adjusts for the temporal interaction between vaccination and exposure to disease, applying adjustments to estimated yearly counts of cases and the number of vaccines administered that increase population immunity. These new model features provide the ability to forecast and compare the effects of different vaccination timing scenarios and seasonality of transmission on the expected disease incidence. Although the work presented is applied to the example of measles, it has potential relevance to modeling other vaccine-preventable diseases.

Palliative care for persons with late-stage Alzheimer's and related dementias and their caregivers: protocol for a randomized clinical trial.

BACKGROUND: Limited access to specialized palliative care exposes persons with late-stage Alzheimer's disease and related dementias (ADRD) to burdensome treatment and unnecessary hospitalization and their caregivers to avoidable strain and financial burden. Addressing this unmet need, the purpose of this study was to conduct a randomized clinical trial (RCT) of the ADRD-Palliative Care (ADRD-PC) program. METHODS: The study will use a multisite, RCT design and will be set in five geographically diverse US hospitals. Lead investigators and outcome assessors will be masked. The study will use 1:1 randomization of patient-caregiver dyads, and sites will enroll N = 424 dyads of hospitalized patients with late-stage ADRD with their family caregivers. Intervention dyads will receive the ADRD-PC program of (1) dementia-specific palliative care, (2) standardized caregiver education, and (3) transitional care. Control dyads will receive publicly available educational material on dementia caregiving. Outcomes will be measured at 30 days (interim) and 60 days post-discharge. The primary outcome will be 60-day hospital transfers, defined as visits to an emergency department or hospitalization ascertained from health record reviews and caregiver interviews (aim 1). Secondary patient-centered outcomes, ascertained from 30- and 60-day health record reviews and caregiver telephone interviews, will be symptom treatment, symptom control, use of community palliative care or hospice, and new nursing home transitions (aim 2). Secondary caregiver-centered outcomes will be communication about prognosis and goals of care, shared decision-making about hospitalization and other treatments, and caregiver distress (aim 3). Analyses will use intention-to-treat, and pre-specified exploratory analyses will examine the effects of sex as a biologic variable and the GDS stage. DISCUSSION: The study results will determine the efficacy of an intervention that addresses the extraordinary public health impact of late-stage ADRD and suffering due to symptom distress, burdensome treatments, and caregiver strain. While many caregivers prioritize comfort in late-stage ADRD, shared decision-making is rare. Hospitalization creates an opportunity for dementia-specific palliative care, and the study findings will inform care redesign to advance comprehensive dementia-specific palliative care plus transitional care. TRIAL REGISTRATION: ClinicalTrials.gov NCT04948866. Registered on July 2, 2021.

Evolution of a minimal cell.

Possessing only essential genes, a minimal cell can reveal mechanisms and processes that are critical for the persistence and stability of life1,2. Here we report on how an engineered minimal cell3,4 contends with the forces of evolution compared with the Mycoplasma mycoides non-minimal cell from which it was synthetically derived. Mutation rates were the highest among all reported bacteria, but were not affected by genome minimization. Genome streamlining was costly, leading to a decrease in fitness of greater than 50%, but this deficit was regained during 2,000 generations of evolution. Despite selection acting on distinct genetic targets, increases in the maximum growth rate of the synthetic cells were comparable. Moreover, when performance was assessed by relative fitness, the minimal cell evolved 39% faster than the non-minimal cell. The only apparent constraint involved the evolution of cell size. The size of the non-minimal cell increased by 80%, whereas the minimal cell remained the same. This pattern reflected epistatic effects of mutations in ftsZ, which encodes a tubulin-homologue protein that regulates cell division and morphology5,6. Our findings demonstrate that natural selection can rapidly increase the fitness of one of the simplest autonomously growing organisms. Understanding how species with small genomes overcome evolutionary challenges provides critical insights into the persistence of host-associated endosymbionts, the stability of streamlined chassis for biotechnology and the targeted refinement of synthetically engineered cells2,7-9.

Studies on the novel effects of electron beam treated pollen on colony reproductive output in commercially-reared bumblebees (Bombus terrestris) for mass pollination applications.

Commercially-reared bumblebees provide an important pollinator service that helps support food production and security. The deployment of an appropriate non-thermal disinfection technology for the bulk treatment of pollen collected from honeybees for the feeding of commercial bumblebees is important in order to mitigate against complex diseases and unwanted pathogen spillover to native bees. High level disinfection of pollen was achieved using an electron (e)-beam dose of 100 kGy that corresponded to 78 % loss of cellular viability of bee pathogens before feeding to bumblebees as measured by the novel in vitro use of flow cytometry (FCM). Novel findings showed that e-beam treated-pollen that was fed to bumblebees produced fewer females, gynes and exhibited an absence of males when compared to control bumblebee colonies that were fed untreated commercial pollen. A similar trend emerged in bumblebee colony reproductive outputs when using membrane filtered washed pollen. Proteomic analysis of bumblebees from individual colonies fed with treated-pollen revealed a differential abundance of proteins associated with stress, immunity and metabolism when compared to the untreated pollen control group. Microbiome analysis of the bumblebee gut content revealed differences in microbiota between treated and untreated pollen in bumblebee colony studies. This novel study evaluated the impact of industrial e-beam treated-pollen on complex bee disease mitigation where physically treated-pollen fed to bumblebees was shown to substantially affect colony reproductive outputs.

SARS-CoV-2 Testing and Patient Waiting Times in the Emergency Department.

Aim Emergency Departments (EDs) were impacted early in the coronavirus disease 2019 (COVID-19) pandemic, with high attendance numbers. EDs relied upon SARS-CoV-2 reverse-transcriptase polymerase chain reaction (RT-PCR) tests to triage patients and facilitate admission to appropriate wards, meaning positive patients were isolated as early as possible. In October 2020, we introduced a 24-hour SARS-CoV-2 testing service. We examined the impact of this on patient experience times (PETs) in the ED, and on healthcare-associated (HA) COVID-19 infections. Methods Data on PETs before and after the introduction of 24-hour testing were available from the ED. HA COVID-19 infections were reported weekly to the Health Services Executive as a key performance indicator. Results Mean PET prior to the pandemic was 20 hours and dropped to 10 and 13 hours respectively in the first and second wave. A surge in case numbers and ED attendances during the third wave was not reflected in a rise in PETs, with a mean PET of 11 hours, significantly below pre-pandemic levels. HA-COVID-19 infections remained stable between wave one and three (83 v 92). Conclusion The introduction of 24-hour SARS-CoV-2 testing in our ED contributed to a reduction in PETs, facilitated appropriate patient placement at ward level, and kept HA-COVID-19 infections at acceptably low levels.

Early detection and intervention for young children with early developmental disabilities in Western Uganda: a mixed-methods evaluation.

BACKGROUND: Early support for children with developmental disabilities is crucial but frequently unavailable in low-resource settings. We conducted a mixed-methods evaluation to assess the feasibility, acceptability, and impact of a programme of early detection and intervention for young children with developmental disabilities in Western Uganda. METHODS: Early child development training for healthcare workers (HCWs) was implemented in three rural districts, and attendance was tracked. HCW knowledge and confidence were assessed pre-/post-intervention, and referral numbers tracked to evaluate impact. Facilitators were trained and mentored to deliver a participatory, group, early intervention programme (EIP) for young children with developmental disabilities and their families. Facilitators were tracked as they were identified, trained, and delivered the intervention, and attendance of families was tracked. Pre-/post-intervention assessments evaluated changes in family quality of life (PedsQL 2.0, Family Impact Module), and child nutritional outcomes. Focus group discussions with stakeholders also assessed feasibility, acceptability and impact. RESULTS: Overall, 93 HCWs from 45 healthcare facilities received training. In the pre-/post-evaluation, median knowledge and confidence scores increased significantly (from 4.0 to 7.0 and from 2.7 to 4.7, respectively (p < 0.001)). HCWs reported feeling empowered to refer and offer care for families with a young child with disability. Referral rates increased significantly from 148 to 251 per annum (70%; p = 0.03). Eleven EIP facilitators were trained, and all delivered the intervention; 84 families were enrolled, of which 78% attended at least 6 out of 10 modules. Amongst those with paired pre-/post-intervention data (n = 48), total family quality of life scores increased significantly (21%, p < 0.001). Improvements were seen across all domains of quality of life, with the largest impacts on emotional functioning and social functioning (p < 0.001). The programme was acceptable to caregivers and facilitators. Caregivers reported improved knowledge, family relationships, hope, emotional wellbeing, and reduced self-stigma. CONCLUSIONS: A programme of early detection and intervention for children with early developmental disabilities and their families was feasible and acceptable in a rural community-based Ugandan setting. HCW training positively impacted knowledge, confidence, attitudes, and referral rates. Families enrolled to the EIP reported significant improvements in quality of life. Important programmatic barriers identified included geographical spread, poverty, gender inequality, and stigma.

Effect of supplement crude protein concentration on milk production over the main grazing season and on nitrogen excretion in late-lactation grazing dairy cows.

The objectives of this study are to evaluate the effects of (1) a potential interaction between supplement crude protein (CP) concentration and differing cow genotypes on milk production, (2) differing cow genotypes on milk production, and (3) decreasing the supplement CP concentration on milk production and N excretion during the main grazing season within a spring-calving herd. A 2 × 2 factorial arrangement experiment, with 2 feeding strategies [14%; n = 30 (lower CP; LCP) and 18%; n = 28 (higher CP; HCP) CP concentrate supplements] offered at varying levels according to pasture availability and days in milk (DIM) was conducted over the main grazing season from April 3 to September 3, 2019, at University College Dublin Lyons Farm. Cows were also grouped into 2 genotype groups: lower milk genotype; n = 30 [LM; milk kg predicted transmitting ability (PTA): 45 ± 68.6 (mean ± SD); fat kg PTA: 10 ± 4.9; and protein kg PTA: 7 ± 2.3] and higher milk genotype; n = 28 [HM; milk kg PTA: 203 ± 55.0; fat kg PTA: 13 ± 3.8; and protein kg PTA: 10 ± 2.4]. A total of 46 multiparous and 12 primiparous (total; 58) Holstein Friesian dairy cows were blocked on parity and balanced on DIM, body condition score, and Economic Breeding Index. Cows were offered a basal diet of grazed perennial ryegrass pasture. The N partitioning study took place from August 25 to 30, 2019 (187 ± 15.2 DIM). No interactions were observed for any milk production or milk composition parameter. No effect of supplement CP concentration was observed for any total accumulated milk production, daily milk production, or milk composition parameter measured. The HM cows had increased daily milk yield (+1.9 kg), fat and protein (+0.15 kg), and energy-corrected milk (+1.7 kg), compared with the LM cows. Furthermore, HM cows had decreased milk protein concentration (-0.1%) compared with LM cows. For the N partitioning study, cows offered LCP had increased pasture dry matter intake (PDMI; +0.9 kg/d), dietary N intake (+0.022 kg/d), feces N excretion (+0.016 kg/d), and decreased N partitioning to milk (-2%), and N utilization efficiency (-2.3%). In conclusion, offering cows LCP had no negative influence on milk production or milk composition over the main grazing season where high pasture quality was maintained. However, any potential negative effects of offering LCP on milk production may have been offset by the increased PDMI. Furthermore, offering cows LCP decreased N utilization efficiency due to the higher PDMI and feed N intake associated with cows on this treatment in our study.

Genome dependent Cas9/gRNA search time underlies sequence dependent gRNA activity.

CRISPR-Cas9 is a powerful DNA editing tool. A gRNA directs Cas9 to cleave any DNA sequence with a PAM. However, some gRNA sequences mediate cleavage at higher efficiencies than others. To understand this, numerous studies have screened large gRNA libraries and developed algorithms to predict gRNA sequence dependent activity. These algorithms do not predict other datasets as well as their training dataset and do not predict well between species. Here, to better understand these discrepancies, we retrospectively examine sequence features that impact gRNA activity in 44 published data sets. We find strong evidence that gRNA sequence dependent activity is largely influenced by the ability of the Cas9/gRNA complex to find the target site rather than activity at the target site and that this drives sequence dependent differences in gRNA activity between different species. This understanding will help guide future work to understand Cas9 activity as well as efforts to identify optimal gRNAs and improve Cas9 variants.

Mitigation policies, community mobility, and COVID-19 case counts in Australia, Japan, Hong Kong, and Singapore.

OBJECTIVES: The objective of the study was to characterize the timing and trends of select mitigation policies, changes in community mobility, and coronavirus disease 2019 (COVID-19) epidemiology in Australia, Japan, Hong Kong, and Singapore. STUDY DESIGN: Prospective abstraction of publicly available mitigation policies obtained from media reports and government websites. METHODS: Data analyzed include seven kinds of mitigation policies (mass gathering restrictions, international travel restrictions, passenger screening, traveler isolation/quarantine, school closures, business closures, and domestic movement restrictions) implemented between January 1 and April 26, 2020, changes in selected measures of community mobility assessed by Google Community Mobility Reports data, and COVID-19 epidemiology in Australia, Japan, Hong Kong, and Singapore. RESULTS: During the study period, community mobility decreased in Australia, Japan, and Singapore; there was little change in Hong Kong. The largest declines in mobility were seen in places that enforced mitigation policies. Across settings, transit-associated mobility declined the most and workplace-associated mobility the least. Singapore experienced an increase in cases despite the presence of stay-at-home orders, as migrant workers living in dormitories faced challenges to safely quarantine. CONCLUSIONS: Public policies may have different impacts on mobility and transmission of severe acute respiratory coronavirus-2 transmission. When enacting mitigation policies, decision makers should consider the possible impact of enforcement measures, the influence on transmission of factors other than movement restrictions, and the differential impact of mitigation policies on subpopulations.

A survey analysis of farmer practices and perceptions of zero-grazing on Irish dairy farms.

Zero-grazing (ZG; the mechanical harvesting and feeding of fresh grass) is increasingly used in grass-based milk production systems alongside conventional grazing. It allows farmers to supply fresh grass from land parcels that are outside of the main grazing block during seasonal shortages and periods when climatic conditions limit animal grazing opportunities. The objective of this study was to establish an understanding of current ZG practices on Irish dairy farms, to capture farmer perceptions on the implementation of this management practice, and to identify farmer knowledge requirements on ZG. An online survey was distributed and completed by 130 dairy farmers who use or have used ZG. Zero-grazing was used alongside conventional grazing by 92% of respondents. These farms were particularly fragmented, with between 1 and 14 separate land blocks. Respondents felt ZG helped them overcome fragmentation, increase grass use, and extend grass feeding in spring and autumn. However, extra cost and time input associated with ZG were recognized as key challenges. The majority of respondents rated current technical information available on ZG in the Republic of Ireland as "poor" or "very poor," and knowledge deficits were identified in the areas of cost analysis, grass management and productivity, cow productivity, cow health and nutrition, and soil fertility.

The effect of nutritional management in early lactation and dairy cow genotype on milk production, metabolic status, and uterine recovery in a pasture-based system.

High levels of milk production coupled with low feed intake cause negative energy balance in early lactation, especially in the first month postpartum (PP). Therefore, specific nutritional management at this time may improve nutritional and metabolic status with the possibility of contrasting genotypes responding differently. Thus, the objective of this study was to compare the effects of nutritional management strategies and dairy cow genotype on milk production, metabolic status, and some fertility parameters during early lactation in a pasture-based system. Sixty Holstein Friesian cows were blocked on parity and genotype [low-fertility high-milk (LFHM) and high-fertility low-milk (HFLM)] and were randomly assigned to 1 of 2 treatments in a 2 × 2 factorial arrangement, in a randomized complete block design based on calving date, previous 305-d milk yield, and precalving body condition score (BCS). The nutritional management treatments were: (1) ad libitum access to fresh pasture plus an allowance of 3 kg of concentrates per day (CTR, n = 30); and (2) ab libitum access to a tailored total mixed ration (TMR, n = 30). These diets were offered for the first 30 d PP. Following the first 30 d PP, cows fed TMR joined the CTR treatment and were managed similarly until 100 d PP. Blood samples were taken at d 7, 14, 21, and 28 PP to determine metabolic status. Milk samples for composition analysis were collected weekly and BCS assessed every 2 wk. Genotype had a significant effect on milk output, whereas LFHM had increased fat (+0.28 kg/d) and fat-plus-protein (+0.17 kg/d) yield in the first 30 d PP compared with HFLM cows. The LFHM group also exhibited higher protein and lactose yields over the first 100 d PP. Nutritional management did create significant differences in milk composition in the first 30 d: TMR cows had lower protein, milk urea nitrogen, and casein concentration and higher lactose concentration than CTR cows. Over the first 100 d PP, TMR cows had higher fat-plus-protein and lactose yields. Feeding TMR reduced concentrations of nonesterified fatty acids (-0.12 mmol/L) and ß-hydroxybutyric acid (-0.10 mmol/L) compared with the CTR group. Cows fed TMR had smaller BCS losses from calving to 60 d PP. There was no effect of any treatment on uterine recovery. Cows in the LFHM group demonstrated greater milk production in the first 30 and 100 d in milk. These results demonstrate that feeding cows a TMR for the first month of lactation has positive effects on milk output, metabolic status, and BCS profile.

Genome-wide surveillance of transcription errors in response to genotoxic stress.

Mutagenic compounds are a potent source of human disease. By inducing genetic instability, they can accelerate the evolution of human cancers or lead to the development of genetically inherited diseases. Here, we show that in addition to genetic mutations, mutagens are also a powerful source of transcription errors. These errors arise in dividing and nondividing cells alike, affect every class of transcripts inside cells, and, in certain cases, greatly exceed the number of mutations that arise in the genome. In addition, we reveal the kinetics of transcription errors in response to mutagen exposure and find that DNA repair is required to mitigate transcriptional mutagenesis after exposure. Together, these observations have far-reaching consequences for our understanding of mutagenesis in human aging and disease, and suggest that the impact of DNA damage on human physiology has been greatly underestimated.

Opportunities for the application of real-time bacterial cell analysis using flow cytometry for the advancement of sterilization microbiology.

Medical devices provide critical care and diagnostic applications through patient contact. Sterility assurance level (SAL) may be defined as the probability of a single viable micro-organism occurring on an item after a sterilization process. Sterilization microbiology often relies upon using an overkill validation method where a 12-log reduction in recalcitrant bacterial endospore population occurs during the process that exploits conventional laboratory-based culture media for enumeration. This timely review explores key assumptions underpinning use of conventional culture-based methods in sterilization microbiology. Consideration is given to how such methods may limit the ability to fully appreciate the inactivation kinetics of a sterilization process such as vaporized hydrogen peroxide (VH2O2) sterilization, and consequently design efficient sterilization processes. Specific use of the real-time flow cytometry (FCM) is described by way of elucidating the practical relevance of these limitation factors with implications and opportunities for the sterilization industry discussed. Application of FCM to address these culture-based limitation factors will inform real-time kinetic inactivation modelling and unlock potential to embrace emerging opportunities for pharma, medical device and sterilization industries including potentially disruptive applications that may involve reduced usage of sterilant.

Applications and future directions for optical coherence tomography in dermatology.

Optical coherence tomography (OCT) is a noninvasive optical imaging method that can generate high-resolution en face and cross-sectional images of the skin in vivo to a maximum depth of 2 mm. While OCT holds considerable potential for noninvasive diagnosis and disease monitoring, it is poorly understood by many dermatologists. Here we aim to equip the practising dermatologist with an understanding of the principles of skin OCT and the potential clinical indications. We begin with an introduction to the technology and discuss the different modalities of OCT including angiographic (dynamic) OCT, which can image cutaneous blood vessels at high resolution. Next we review clinical applications. OCT has been most extensively investigated in the diagnosis of keratinocyte carcinomas, particularly basal cell carcinoma. To date, OCT has not proven sufficiently accurate for the robust diagnosis of malignant melanoma; however, the evaluation of abnormal vasculature with angiographic OCT is an area of active investigation. OCT, and in particular angiographic OCT, also shows promise in monitoring the response to therapy of inflammatory dermatoses, such as psoriasis and connective tissues disease. We additionally discuss a potential role for artificial intelligence in improving the accuracy of interpretation of OCT imaging data.

Examining the Effects of Whole Crop Wheat Silage on Ewe Performance during Late Gestation Compared to Traditional Grass Silage across Three Prolific Breed Types.

Provision of adequate nutrient intake in late gestation of the ewe is an important determinant of dam and offspring performance. A 2 × 3 factorial design experiment examining two forage types, whole crop wheat silage (WCWS) or grass silage (GS) offered to one of three prolific breed types, (Belclare X, Lleyn X, Mule (Bluefaced Leicester × Blackface Mountain)), was conducted. Forage type had no impact on dry matter (DM) or metabolizable energy (ME) intake, body weight and body condition score change, or colostrum production (p > 0.05). Ewes offered WCWS had lower crude protein (CP) intake (p < 0.0001) and a lower combined litter weight (p < 0.05). Mule ewes consumed less DM, CP, (p < 0.05), and ME (p < 0.01) compared to Belclare X and Lleyn X ewes however, water intake per kg DM consumed did not differ with breed type (p > 0.05). Colostrum yield over the first 18 h postpartum was lower for Mule ewes compared to other breed types (p < 0.05). In conclusion, results from this study suggest nutrient concentration and balance as opposed to forage type is important for late gestation nutrition and breed type can impact feed intake and colostrum yield.

Do established infection prevention and control measures prevent spread of SARS-CoV-2 to the hospital environment beyond the patient room?

The role of the hospital environment in the transmission of infection is well described. With an emerging infection whose mode of transmission is under investigation, strict infection prevention and control measures, including patient isolation, hand hygiene, personal protective equipment that is doffed on exiting the patient room, and environmental cleaning should be implemented to prevent spread. Environmental testing demonstrated that COVID-19 patients contaminated the patient area (11/26, 42.3% of tests) but contamination of general ward areas was minimal (1/30, 3%) and the virus was detected after cleaning on one item only (1/25, 4%) which was noted to be in disrepair.