Improving community antibiotic prescribing to keep antibiotics working in Aotearoa New Zealand.

Antibiotic resistance, principally a consequence of the human use of antibiotics dispensed in the community, is a relentlessly growing threat to human health in Aotearoa New Zealand. Reducing the prescription of antibiotics for conditions in which they confer no benefit is the most effective method of slowing the spread of antibiotic resistance. In Aotearoa New Zealand, as in many other nations, antibiotic "treatment" of acute respiratory tract infections is the most important component of unnecessary antibiotic use. Because of the ethnic inequities in the incidence and consequences of infectious diseases in Aotearoa New Zealand, Maori and Pacific patients should receive antibiotic treatment more frequently than patients of other ethnicities. However, Maori and Pacific people who present to their doctor with conditions that do not require antibiotic treatment deserve the same excellent treatment as anyone else and should not be prescribed an antibiotic when it will provide no benefit. Setting annual goals for reductions in community antibiotic dispensing has been an effective method to encourage sustained improvements in antibiotic prescribing in other nations, and may help to quickly reduce inappropriate antibiotic prescribing in Aotearoa New Zealand.

Benchmarking of human Y-chromosomal haplogroup classifiers with whole-genome and whole-exome sequence data.

In anthropological, medical, and forensic studies, the nonrecombinant region of the human Y chromosome (NRY) enables accurate reconstruction of pedigree relationships and retrieval of ancestral information. Using high-throughput sequencing (HTS) data, we present a benchmarking analysis of command-line tools for NRY haplogroup classification. The evaluation was performed using paired Illumina data from whole-genome sequencing (WGS) and whole-exome sequencing (WES) experiments from 50 unrelated donors. Additionally, as a validation, we also used paired WGS/WES datasets of 54 individuals from the 1000 Genomes Project. Finally, we evaluated the tools on data from third-generation HTS obtained from a subset of donors and one reference sample. Our results show that WES, despite typically offering less genealogical resolution than WGS, is an effective method for determining the NRY haplogroup. Y-LineageTracker and Yleaf showed the highest accuracy for WGS data, classifying precisely 98% and 96% of the samples, respectively. Yleaf outperforms all benchmarked tools in the WES data, classifying approximately 90% of the samples. Yleaf, Y-LineageTracker, and pathPhynder can correctly classify most samples (88%) sequenced with third-generation HTS. As a result, Yleaf provides the best performance for applications that use WGS and WES. Overall, our study offers researchers with a guide that allows them to select the most appropriate tool to analyze the NRY region using both second- and third-generation HTS data.

Changing Mindsets About Side Effects of the COVID-19 Vaccination: A Randomized Controlled Trial.

BACKGROUND: Side-effect concerns are a major barrier to vaccination against COVID-19 and other diseases. Identifying cost- and time-efficient interventions to improve vaccine experience and reduce vaccine hesitancy-without withholding information about side effects-is critical. PURPOSE: Determine whether a brief symptom as positive signals mindset intervention can improve vaccine experience and reduce vaccine hesitancy after the COVID-19 vaccination. METHODS: English-speaking adults (18+) were recruited during the 15-min wait period after receiving their second dose of the Pfizer COVID-19 vaccination and were randomly allocated to the symptom as positive signals mindset condition or the treatment as usual control. Participants in the mindset intervention viewed a 3:43-min video explaining how the body responds to vaccinations and how common side effects such as fatigue, sore arm, and fever are signs that the vaccination is helping the body boost immunity. The control group received standard vaccination center information. RESULTS: Mindset participants (N = 260) versus controls (N = 268) reported significantly less worry about symptoms at day 3 [t(506)=2.60, p=.01, d=0.23], fewer symptoms immediately following the vaccine [t(484)=2.75, p=.006, d=0.24], and increased intentions to vaccinate against viruses like COVID-19 in the future [t(514)=-2.57, p=.01, d=0.22]. No significant differences for side-effect frequency at day 3, coping, or impact. CONCLUSIONS: This study supports the use of a brief video aimed at reframing symptoms as positive signals to reduce worry and increase future vaccine intentions. CLINICAL TRIAL INFORMATION: Australian New Zealand Clinical Trials Registry: ACTRN12621000722897p.

Side-effect concerns are a major barrier to vaccination against COVID-19 and other diseases. Therefore, the purpose of this study was to determine whether a brief symptom as positive signals mindset intervention could improve vaccine experience and reduce vaccine hesitancy after the COVID-19 vaccination. Participants were recruited during the 15-min wait period after receiving their second dose of the Pfizer COVID-19 vaccination and were randomly allocated to a treatment as usual control condition or to a mindset intervention condition which entailed watching a 3:43-min video explaining how the body responds to vaccinations and how common side effects such as fatigue, sore arm, and fever are signs that the vaccination is helping the body boost immunity. Compared with participants in the control condition, participants in the mindset intervention condition reported significantly less worry about symptoms at day 3, fewer symptoms immediately following the vaccine and increased intentions to vaccinate against viruses like COVID-19 in the future. No significant differences emerged for side-effect frequency at day 3, coping, or impact. These finding provide initial support for cost- and time-efficient interventions to improve vaccine experience and reduce vaccine hesitancy without withholding information about side effects.

Long-Term Impact of a Smartphone App on Prescriber Adherence to Antibiotic Guidelines for Adult Patients With Community-Acquired Pneumonia: Interrupted Time-Series Study.

BACKGROUND: Mobile health platforms like smartphone apps that provide clinical guidelines are ubiquitous, yet their long-term impact on guideline adherence remains unclear. In 2016, an antibiotic guidelines app, called SCRIPT, was introduced in Auckland City Hospital, New Zealand, to provide local antibiotic guidelines to clinicians on their smartphones. OBJECTIVE: We aimed to assess whether the provision of antibiotic guidelines in a smartphone app resulted in sustained changes in antibiotic guideline adherence by prescribers. METHODS: We analyzed antibiotic guideline adherence rates during the first 24 hours of hospital admission in adults diagnosed with community-acquired pneumonia using an interrupted time-series study with 3 distinct periods post app implementation (ie, 3, 12, and 24 months). RESULTS: Adherence increased from 23% (46/200) at baseline to 31% (73/237) at 3 months and 34% (69/200) at 12 months, reducing to 31% (62/200) at 24 months post app implementation (P=.07 vs baseline). However, increased adherence was sustained in patients with pulmonary consolidation on x-ray (9/63, 14% at baseline; 23/77, 30% after 3 months; 32/92, 35% after 12 month; and 32/102, 31% after 24 months; P=.04 vs baseline). CONCLUSIONS: An antibiotic guidelines app increased overall adherence, but this was not sustained. In patients with pulmonary consolidation, the increased adherence was sustained.

Dense sampling of ethnic groups within African countries reveals fine-scale genetic structure and extensive historical admixture.

Previous studies have highlighted how African genomes have been shaped by a complex series of historical events. Despite this, genome-wide data have only been obtained from a small proportion of present-day ethnolinguistic groups. By analyzing new autosomal genetic variation data of 1333 individuals from over 150 ethnic groups from Cameroon, Republic of the Congo, Ghana, Nigeria, and Sudan, we demonstrate a previously underappreciated fine-scale level of genetic structure within these countries, for example, correlating with historical polities in western Cameroon. By comparing genetic variation patterns among populations, we infer that many northern Cameroonian and Sudanese groups share genetic links with multiple geographically disparate populations, likely resulting from long-distance migrations. In Ghana and Nigeria, we infer signatures of intermixing dated to over 2000 years ago, corresponding to reports of environmental transformations possibly related to climate change. We also infer recent intermixing signals in multiple African populations, including Congolese, that likely relate to the expansions of Bantu language-speaking peoples.

Genomes from a medieval mass burial show Ashkenazi-associated hereditary diseases pre-date the 12th century.

We report genome sequence data from six individuals excavated from the base of a medieval well at a site in Norwich, UK. A revised radiocarbon analysis of the assemblage is consistent with these individuals being part of a historically attested episode of antisemitic violence on 6 February 1190 CE. We find that four of these individuals were closely related and all six have strong genetic affinities with modern Ashkenazi Jews. We identify four alleles associated with genetic disease in Ashkenazi Jewish populations and infer variation in pigmentation traits, including the presence of red hair. Simulations indicate that Ashkenazi-associated genetic disease alleles were already at appreciable frequencies, centuries earlier than previously hypothesized. These findings provide new insights into a significant historical crime, into Ashkenazi population history, and into the origins of genetic diseases associated with modern Jewish populations.

Evidence of the interplay of genetics and culture in Ethiopia.

The rich linguistic, ethnic and cultural diversity of Ethiopia provides an unprecedented opportunity to understand the level to which cultural factors correlate with-and shape-genetic structure in human populations. Using primarily new genetic variation data covering 1,214 Ethiopians representing 68 different ethnic groups, together with information on individuals' birthplaces, linguistic/religious practices and 31 cultural practices, we disentangle the effects of geographic distance, elevation, and social factors on the genetic structure of Ethiopians today. We provide evidence of associations between social behaviours and genetic differences among present-day peoples. We show that genetic similarity is broadly associated with linguistic affiliation, but also identify pronounced genetic similarity among groups from disparate language classifications that may in part be attributable to recent intermixing. We also illustrate how groups reporting the same culture traits are more genetically similar on average and show evidence of recent intermixing, suggesting that shared cultural traits may promote admixture. In addition to providing insights into the genetic structure and history of Ethiopia, we identify the most important cultural and geographic predictors of genetic differentiation and provide a resource for designing sampling protocols for future genetic studies involving Ethiopians.

The Impact of the Auckland Cellulitis Pathway on Length of Hospital Stay, Mortality Readmission Rate, and Antibiotic Stewardship.

BACKGROUND: The Dundee classification of cellulitis severity, previously shown to predict disease outcomes, provides an opportunity to improve the management of patients with cellulitis. METHODS: We developed and implemented a pathway to guide the management of adults with cellulitis based on their Dundee severity class, and measured its effect on patient outcomes. We compared the outcomes in patients admitted to Auckland City Hospital (ACH) between July 2014 and July 2015 (the baseline cohort) with those in patients admitted between June 2017 and June 2018 (the intervention cohort). RESULTS: The median length of stay was shorter in the intervention cohort (0.7 days, interquartile range (IQR) 0.1 to 3.0 days) than in the baseline cohort (1.8 days, IQR 0.1 to 4.4 days; P < .001). The 30-day mortality rate declined from 1.8% (19/1092) in the baseline cohort to 0.7% (10/1362; P = .02) in the intervention cohort. The 30-day cellulitis readmission rate increased from 6% in the baseline cohort to 11% (P < .001) in the intervention cohort. Adherence to the ACH cellulitis antibiotic guideline improved from 38% to 48% (P < .01) and was independently associated with reduced length of stay. CONCLUSIONS: The implementation of the Auckland cellulitis pathway, readily generalizable to other settings, improved the outcomes in patients with cellulitis, and resulted in an annual saving of approximately 1000 bed days.

Directly modelling population dynamics in the South American Arid Diagonal using 14C dates.

Large anthropogenic 14C datasets are widely used to generate summed probability distributions (SPDs) as a proxy for past human population levels. However, SPDs are a poor proxy when datasets are small, bearing little relationship to true population dynamics. Instead, more robust inferences can be achieved by directly modelling the population and assessing the model likelihood given the data. We introduce the R package ADMUR which uses a continuous piecewise linear (CPL) model of population change, calculates the model likelihood given a 14C dataset, estimates credible intervals using Markov chain Monte Carlo, applies a goodness-of-fit test, and uses the Schwarz Criterion to compare CPL models. We demonstrate the efficacy of this method using toy data, showing that spurious dynamics are avoided when sample sizes are small, and true population dynamics are recovered as sample sizes increase. Finally, we use an improved 14C dataset for the South American Arid Diagonal to compare CPL modelling to current simulation methods, and identify three Holocene phases when population trajectory estimates changed from rapid initial growth of 4.15% per generation to a decline of 0.05% per generation between 10 821 and 7055 yr BP, then gently grew at 0.58% per generation until 2500 yr BP. This article is part of the theme issue 'Cross-disciplinary approaches to prehistoric demography'.

Low Prevalence of Lactase Persistence in Bronze Age Europe Indicates Ongoing Strong Selection over the Last 3,000 Years.

Lactase persistence (LP), the continued expression of lactase into adulthood, is the most strongly selected single gene trait over the last 10,000 years in multiple human populations. It has been posited that the primary allele causing LP among Eurasians, rs4988235-A [1], only rose to appreciable frequencies during the Bronze and Iron Ages [2, 3], long after humans started consuming milk from domesticated animals. This rapid rise has been attributed to an influx of people from the Pontic-Caspian steppe that began around 5,000 years ago [4, 5]. We investigate the spatiotemporal spread of LP through an analysis of 14 warriors from the Tollense Bronze Age battlefield in northern Germany (∼3,200 before present, BP), the oldest large-scale conflict site north of the Alps. Genetic data indicate that these individuals represent a single unstructured Central/Northern European population. We complemented these data with genotypes of 18 individuals from the Bronze Age site Mokrin in Serbia (∼4,100 to ∼3,700 BP) and 37 individuals from Eastern Europe and the Pontic-Caspian Steppe region, predating both Bronze Age sites (∼5,980 to ∼3,980 BP). We infer low LP in all three regions, i.e., in northern Germany and South-eastern and Eastern Europe, suggesting that the surge of rs4988235 in Central and Northern Europe was unlikely caused by Steppe expansions. We estimate a selection coefficient of 0.06 and conclude that the selection was ongoing in various parts of Europe over the last 3,000 years.

Ancient West African foragers in the context of African population history.

Our knowledge of ancient human population structure in sub-Saharan Africa, particularly prior to the advent of food production, remains limited. Here we report genome-wide DNA data from four children-two of whom were buried approximately 8,000 years ago and two 3,000 years ago-from Shum Laka (Cameroon), one of the earliest known archaeological sites within the probable homeland of the Bantu language group1-11. One individual carried the deeply divergent Y chromosome haplogroup A00, which today is found almost exclusively in the same region12,13. However, the genome-wide ancestry profiles of all four individuals are most similar to those of present-day hunter-gatherers from western Central Africa, which implies that populations in western Cameroon today-as well as speakers of Bantu languages from across the continent-are not descended substantially from the population represented by these four people. We infer an Africa-wide phylogeny that features widespread admixture and three prominent radiations, including one that gave rise to at least four major lineages deep in the history of modern humans.

A 3,000-year-old Egyptian emmer wheat genome reveals dispersal and domestication history.

Tetraploid emmer wheat (Triticum turgidum ssp. dicoccon) is a progenitor of the world's most widely grown crop, hexaploid bread wheat (Triticum aestivum), as well as the direct ancestor of tetraploid durum wheat (T. turgidum subsp. turgidum). Emmer was one of the first cereals to be domesticated in the old world; it was cultivated from around 9700 BC in the Levant1,2 and subsequently in south-western Asia, northern Africa and Europe with the spread of Neolithic agriculture3,4. Here, we report a whole-genome sequence from a museum specimen of Egyptian emmer wheat chaff, 14C dated to the New Kingdom, 1130-1000 BC. Its genome shares haplotypes with modern domesticated emmer at loci that are associated with shattering, seed size and germination, as well as within other putative domestication loci, suggesting that these traits share a common origin before the introduction of emmer to Egypt. Its genome is otherwise unusual, carrying haplotypes that are absent from modern emmer. Genetic similarity with modern Arabian and Indian emmer landraces connects ancient Egyptian emmer with early south-eastern dispersals, whereas inferred gene flow with wild emmer from the Southern Levant signals a later connection. Our results show the importance of museum collections as sources of genetic data to uncover the history and diversity of ancient cereals.

A Rare Deep-Rooting D0 African Y-Chromosomal Haplogroup and Its Implications for the Expansion of Modern Humans Out of Africa.

Present-day humans outside Africa descend mainly from a single expansion out ∼50,000-70,000 years ago, but many details of this expansion remain unclear, including the history of the male-specific Y chromosome at this time. Here, we reinvestigate a rare deep-rooting African Y-chromosomal lineage by sequencing the whole genomes of three Nigerian men described in 2003 as carrying haplogroup DE* Y chromosomes, and analyzing them in the context of a calibrated worldwide Y-chromosomal phylogeny. We confirm that these three chromosomes do represent a deep-rooting DE lineage, branching close to the DE bifurcation, but place them on the D branch as an outgroup to all other known D chromosomes, and designate the new lineage D0. We consider three models for the expansion of Y lineages out of Africa ∼50,000-100,000 years ago, incorporating migration back to Africa where necessary to explain present-day Y-lineage distributions. Considering both the Y-chromosomal phylogenetic structure incorporating the D0 lineage, and published evidence for modern humans outside Africa, the most favored model involves an origin of the DE lineage within Africa with D0 and E remaining there, and migration out of the three lineages (C, D, and FT) that now form the vast majority of non-African Y chromosomes. The exit took place 50,300-81,000 years ago (latest date for FT lineage expansion outside Africa - earliest date for the D/D0 lineage split inside Africa), and most likely 50,300-59,400 years ago (considering Neanderthal admixture). This work resolves a long-running debate about Y-chromosomal out-of-Africa/back-to-Africa migrations, and provides insights into the out-of-Africa expansion more generally.

Long-Term Stable Bone Mineral Density in HIV-Infected Men Without Risk Factors for Osteoporosis Treated with Antiretroviral Therapy.

INTRODUCTION: Most prospective studies of bone mineral density (BMD) in HIV-infected cohorts taking antiretroviral therapy (ART) have been of short duration, typically < 3 years. Such studies have reported short-term stable or increasing BMD. We assessed whether this BMD stability persists for > 10 years in middle-aged and older men established on ART. METHODS: A 12-year, prospective, longitudinal study in 44 HIV-infected men treated with ART who had measurements of BMD at the lumbar spine, proximal femur and total body at baseline, 2, 6 and 12 years. RESULTS: At baseline, the mean age of participants was 49 years, the mean duration of HIV infection was 8 years, and the mean duration of ART was 50 months. After 12 years, BMD increased by 6.9% (95% CI 3.4 to 10.3) at the lumbar spine, and remained stable (range of BMD change: - 0.6% to 0.0%) at the total hip, femoral neck and total body. Only two individuals had a decrease of > 10% in BMD at any site during follow-up and both decreases in BMD were explained by co-morbid illnesses. CONCLUSIONS: BMD remained stable over 12 years in middle-aged and older HIV-infected men treated with ART. Monitoring BMD in men established on ART who do not have risk factors for BMD loss is not necessary.

Genetic diversity of CHC22 clathrin impacts its function in glucose metabolism.

CHC22 clathrin plays a key role in intracellular membrane traffic of the insulin-responsive glucose transporter GLUT4 in humans. We performed population genetic and phylogenetic analyses of the CHC22-encoding CLTCL1 gene, revealing independent gene loss in at least two vertebrate lineages, after arising from gene duplication. All vertebrates retained the paralogous CLTC gene encoding CHC17 clathrin, which mediates endocytosis. For vertebrates retaining CLTCL1, strong evidence for purifying selection supports CHC22 functionality. All human populations maintained two high frequency CLTCL1 allelic variants, encoding either methionine or valine at position 1316. Functional studies indicated that CHC22-V1316, which is more frequent in farming populations than in hunter-gatherers, has different cellular dynamics than M1316-CHC22 and is less effective at controlling GLUT4 membrane traffic, altering its insulin-regulated response. These analyses suggest that ancestral human dietary change influenced selection of allotypes that affect CHC22's role in metabolism and have potential to differentially influence the human insulin response.