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The Conservation Reserve Program (CRP) is a primary tool for restoring grassland in the United States, in part as wildlife habitat, which has benefited declining grassland bird populations. Among potential mid-contract management practices used to maintain early-successional CRP grasslands, cattle grazing had been prohibited and is currently disincentivized during the primary nesting season for birds (much of the growing season), despite the important role that large herbivores historically played in structuring grassland ecosystems. Conservative grazing of CRP grasslands could increase spatial heterogeneity in vegetation structure and plant diversity, potentially supporting higher densities of some grassland bird species and higher bird diversity. Our objective was to determine the effect of experimental cattle grazing on species-specific relative abundance and occupancy, species diversity, and community dissimilarity of grassland birds on CRP grasslands across the longitudinal extent of Kansas, USA (a 63.5-cm precipitation gradient) during the 2017–2019 avian breeding seasons. Fifty-three of 108 fields were grazed by cattle during the growing seasons of 2017 and 2018 and all fields were rested from grazing in 2019. For all analyses, we examined separate model sets for semiarid western versus more mesic eastern Kansas. Using data from line transect surveys, we modeled relative abundances of 5 songbird species: grasshopper sparrow (Ammodramus savannarum), dickcissel (Spiza americana), eastern meadowlark (Sturnella magna), western meadowlark (Sturnella neglecta), and brown-headed cowbird (Molothrus ater). Grazing had delayed yet positive effects on abundances of grasshopper sparrow in western Kansas, and eastern meadowlark in eastern Kansas, but negative effects on dickcissel abundance in western Kansas and especially on burned fields in eastern Kansas. Somewhat counterintuitively, brown-headed cowbirds in western Kansas were more abundant on ungrazed versus grazed fields in the years after grazing began. In addition, we modeled multi-season occupancy of 3 gamebird species (ring-necked pheasant [Phasianus colcicus], northern bobwhite [Colinus virginianus], mourning dove [Zenaida macroura]) and Henslow’s sparrow (Centronyx henslowii); grazing did not affect occupancy of these species. In eastern Kansas, species diversity was highest in grazed, unburned fields. In western Kansas, bird communities in grazed and ungrazed fields were dissimilar, as determined from multivariate analysis. Though regionally variable, conservative stocking of cattle on CRP grasslands during the nesting season as a mid-contract management tool might increase bird species diversity by restructuring habitat that accommodates a greater variety of species and decreasing abundances of species associated with taller, denser stands of vegetation.

Bird populations in grasslands have experienced declines coinciding with loss and fragmentation of prairies. The United States Department of Agriculture (USDA)-administered Conservation Reserve Program (CRP) is the most extensive grassland restoration program in North America and it has especially benefitted grassland birds. Grazing by domestic cattle has been restricted in CRP during avian nesting seasons despite the potential improvements in structuring habitat for a greater diversity of grassland bird species. Potential negative consequences of grazing in CRP grasslands include trampling of nests by cattle, reductions in nest concealment from predators, and attraction of brood-parasitic brown-headed cowbirds (Molothrus ater). We designed an experiment to test for effects of cattle grazing in CRP fields during the nesting season on nest survival and brood parasitism of 5 bird species that commonly nest in CRP grasslands: mourning dove (Zenaida macroura), grasshopper sparrow (Ammodramus savannarum), dickcissel (Spiza americana), and eastern (Sturnella magna) and western (S. neglecta) meadowlarks. Grazing was implemented during summers 2017 and 2018 on 17 of 36 fields followed by a year of rest on all fields in 2019. Of the 879 nests on grazed fields, only 4 were likely trampled by cattle (vs. 54% of all nests estimated as failing because of depredation). Experimental grazing (grazed vs. ungrazed fields) had variable effects on nest survival and cowbird parasitism among the bird species analyzed. Negative effects of grazing on daily nest survival of dickcissel and meadowlarks were apparent, at least in some years. We found no direct effects of grazing on nest survival of mourning dove or grasshopper sparrow. Probability and intensity (cowbird offspring/nest) of cowbird parasitism in dickcissel nests was higher on grazed versus ungrazed sites but only in conservation practice (CP) CP2 (vs. CP25 fields). Parasitism probability of grasshopper sparrow nests by cowbirds was higher on grazed fields in the 2 years after introduction of cattle in 2017. Greater vegetative concealment around nest sites was associated with reduced cowbird parasitism of meadowlark and grasshopper sparrow nests and higher nest survival for grasshopper sparrows. Reductions in vegetative height caused by longer-term or high-intensity grazing might therefore have negative consequences for some grassland birds by increasing nest site visibility and exposure to cowbird parasitism. Our results indicate that cattle grazing in CRP fields during the nesting season might have some negative effects on reproductive success of some grassland bird species, at least in the short term; however, the potential improvements of structuring habitat to accommodate more grassland bird species and increasing landowner participation in the CRP are considerable.

Identifying how plant species diversity varies across environmental gradients remains a controversial topic in plant community ecology because of complex interactions among putative factors. This is especially true for grasslands where habitat loss has limited opportunities for systematic study across broad spatial scales. Here we overcome these limitations by examining restored plant community responses to a large-scale precipitation gradient under two common Conservation Reserve Program (CRP) restoration approaches. The two restoration strategies examined were CP2, which seeds a relatively low number of species, and CP25, which seeds a higher number of species. We sampled plant communities on 55 CRP fields distributed along a broad precipitation gradient (410–1,170 mm mean annual precipitation) spanning 650 km within the grassland biome of North America. Mean annual precipitation (MAP) was the most important predicator of plant species richness and had a positive, linear response across the gradient. To a lesser degree, restoration practices also played a role in determining community diversity. The linear increase in species richness across the precipitation gradient reflects the species pool increase from short to tallgrass prairie communities and explained most of the richness variation. These findings provide insight into the diversity constraints and fundamental drivers of change across a large-scale gradient representing a wide variety of grassland habitats. Across a broad environmental gradient, initial planting differences between restoration practices had lower effects on plant diversity than expected. This suggests that new strategies are needed to effectively establish diverse plant communities on large-scale restorations such as these.

Treatment burden is the effort required of patients to look after their health and the impact this has on their functioning and wellbeing. It is likely treatment burden changes over time as circumstances change for patients and health services. However, there are a lack of population-level studies of treatment burden change and factors associated with this change over time. Furthermore, there are currently no practical screening tools for treatment burden in time-pressured clinical settings or at population level. This is a three-year follow-up of a cross-sectional survey of 723 people with multimorbidity (defined as three or more long-term conditions; LTCs) registered at GP practices in in Dorset, England. The survey will repeat collection of information on treatment burden (using the 10-item Multimorbidity Treatment Burden Questionnaire (MTBQ) and a novel single-item screening tool), sociodemographics, medications, LTCs, health literacy and financial resource, as at baseline. Descriptive statistics will be used to compare change in treatment burden since the baseline survey in 2019 and associations of treatment burden change will be assessed using regression methods. Diagnostic test accuracy metrics will be used to evaluate the single-item treatment burden screening tool using the MTBQ as the gold-standard. Routine primary care data (including demographics, medications, LTCs, and healthcare usage data) will be extracted from medical records for consenting participants. A forward-stepwise, likelihood-ratio logistic regression model building approach will be employed in order to assess the utility of routine data metrics in quantifying treatment burden in comparison to self-reported treatment burden using the MTBQ. To the authors' knowledge, this will be the first study investigating longitudinal aspects of treatment burden. Findings will improve understanding of the extent to which treatment burden changes over time for people with multimorbidity and factors contributing to this change, as well as allowing better identification of people at risk of high treatment burden.

Paul Boutros, Robert Bristow and colleagues report a molecular analysis of the spatial heterogeneity of clinically localized, multifocal prostate cancer. They find that multifocal tumors are highly heterogeneous, and they identify a novel recurrent amplification of MYCL1 . Herein we provide a detailed molecular analysis of the spatial heterogeneity of clinically localized, multifocal prostate cancer to delineate new oncogenes or tumor suppressors. We initially determined the copy number aberration (CNA) profiles of 74 patients with index tumors of Gleason score 7. Of these, 5 patients were subjected to whole-genome sequencing using DNA quantities achievable in diagnostic biopsies, with detailed spatial sampling of 23 distinct tumor regions to assess intraprostatic heterogeneity in focal genomics. Multifocal tumors are highly heterogeneous for single-nucleotide variants (SNVs), CNAs and genomic rearrangements. We identified and validated a new recurrent amplification of MYCL , which is associated with TP53 deletion and unique profiles of DNA damage and transcriptional dysregulation. Moreover, we demonstrate divergent tumor evolution in multifocal cancer and, in some cases, tumors of independent clonal origin. These data represent the first systematic relation of intraprostatic genomic heterogeneity to predicted clinical outcome and inform the development of novel biomarkers that reflect individual prognosis.

Nuclear mutations are well known to drive tumor incidence, aggression and response to therapy. By contrast, the frequency and roles of mutations in the maternally inherited mitochondrial genome are poorly understood. Here we sequence the mitochondrial genomes of 384 localized prostate cancer patients, and identify a median of one mitochondrial single-nucleotide variant (mtSNV) per patient. Some of these mtSNVs occur in recurrent mutational hotspots and associate with aggressive disease. Younger patients have fewer mtSNVs than those who diagnosed at an older age. We demonstrate strong links between mitochondrial and nuclear mutational profiles, with co-occurrence between specific mutations. For example, certain control region mtSNVs co-occur with gain of the MYC oncogene, and these mutations are jointly associated with patient survival. These data demonstrate frequent mitochondrial mutation in prostate cancer, and suggest interplay between nuclear and mitochondrial mutational profiles in prostate cancer. In prostate cancer, the role of mutations in the maternally-inherited mitochondrial genome are not well known. Here, the authors demonstrate frequent, age-dependent mitochondrial mutation in prostate cancer. Strong links between mitochondrial and nuclear mutational profiles are associated with clinical aggressivity.

Background: Interaction between maternal obesity, intrauterine environment and adverse clinical outcomes of newborns has been described. Methods: Using statewide birth certificate data, this retrospective, matched-control cohort study compared paired birth weights and complications of infants born to women before and after Roux-en-Y gastric bypass surgery (RYGB) and to matched obese non-operated women in several different groups. Women who had given birth to a child before and after RYGB (group 1; n =295 matches) and women with pregnancies after RYGB (group 2; n =764 matches) were matched to non-operated women based on age, body mass index (BMI) prior to both pregnancy and RYGB, mother’s race, year of mother/s birth, date of infant births and birth order. In addition, birth weights of 13 143 live births before and/or after RYGB of their mothers ( n =5819) were compared (group 3). Results: Odds ratios (ORs) for having a large-for-gestational-age (LGA) neonate were significantly less after RYGB than for non-surgical mothers: ORs for groups 1 and 2 were 0.19 (0.08–0.38) and 0.33 (0.21–0.51), respectively. In contrast, ORs in all three groups for risk of having a small for gestational age (SGA) neonate were greater for RYGB mothers compared to non-surgical mothers (ORs were 2.16 (1.00–5.04); 2.16 (1.43–3.32); and 2.25 (1.89–2.69), respectively). Neonatal complications were not different for group 1 RYGB and non-surgical women for the first pregnancy following RYGB. Pregnancy-induced hypertension and gestational diabetes were significantly lower for the first pregnancy of mothers following RYGB compared to matched pregnancies of non-surgical mothers. Conclusion: Women who had undergone RYGB not only had lower risk for having an LGA neonate compared to BMI-matched mothers, but also had significantly higher risk for delivering an SGA neonate following RYGB. RYGB women were less likely than non-operated women to have pregnancy-related hypertension and diabetes.

Purpose Endoscopic surveillance for Barrett’s oesophagus is undertaken to detect dysplasia and early cancer, and to facilitate early intervention. Evidence supporting current practice is of low quality and often influenced by opinion. This study investigated the preferences of patients for surveillance of Barrett’s oesophagus in an Australian cohort. Methods Four Barrett’s oesophagus surveillance characteristics/attributes were evaluated within a discrete choice experiment based on literature and expert opinion: (1) surveillance method (endoscopy vs a blood test vs a novel breath test), (2) risk of missing a cancer over a 10-year period, (3) screening interval, and (4) out-of-pocket cost. The data from the discrete choice experiment was analysed within the framework of random utility theory using a mixed logit regression model. Results The study sample comprised patients ( n  = 71) undergoing endoscopic surveillance for Barrett’s oesophagus of whom n  = 65 completed the discrete choice experiment. The sample was predominantly male (77%) with average age of 65 years. All attributes except surveillance method significantly influenced respondents’ preference for Barrett’s oesophagus surveillance. Policy analyses suggested that compared to the reference case (i.e. endoscopy provided annually at no upfront cost and with a 4% risk of missing cancer), increasing test sensitivity to 0.5% risk of missing cancer would increase participation by up to 50%; surveillance every 5 years would lead to 26% reduction, while every 3 to 3.5 years would result in 7% increase in participation. Respondents were highly averse to paying A$500 for the test, resulting in 48% reduction in participation. None of the other surveillance methods was preferred to endoscopy, both resulting in 11% reduction in participation. Conclusion Test sensitivity, test frequency and out-of-pocket cost were the key factors influencing surveillance uptake. Patients prefer a test with the highest sensitivity, offered frequently, that incurs no upfront costs.

Background Flexor tendon injuries are common and lead to over 3200 admissions for specialist surgical repair annually in England and Wales. Surgery to repair complete division of both flexor tendons in zone 2 of the hand is technically challenging. There is variation in surgical repair techniques with no high-quality evidence to support decision-making. In particular, the decision to repair both tendons or just one is contested. Surgery is followed by specialist rehabilitation, which takes at least 12 weeks. The resulting hand function can impact the patient’s income, life satisfaction, well-being, self-worth, and mental health. The FLARE trial aims to determine the clinical and cost-effectiveness of repairing the flexor digitorum profundus (FDP) alone (intervention) versus the repair of both FDP and flexor digitorum superficialis (FDS) (control) for the treatment of complete zone 2, single-digit flexor tendon injuries in adults. Methods A multi-centre, two-arm, blinded, non-inferiority, parallel group, randomised controlled trial with an internal pilot, economic evaluation, and nested qualitative study. Participants will be randomised 1:1 to receive either repair of FDP alone or repair of both FDP and FDS. A total of 310 adults will be recruited from NHS Trusts within the UK, randomised at surgery, and followed up within 7 days, 6 weeks, 3 months, and 6 months post-randomisation. The primary outcome measure is the patient evaluation measure (PEM) administered 6 months post-randomisation. Secondary outcomes include the PEM at other timepoints, Patient Related Wrist/Hand Evaluation (PRWHE), EuroQol 5 Dimensions Score (EQ-5D-5L), complications, total range of motion, grip strength, adherence to splint and therapy regimens, work outcomes, treatment and outcome satisfaction, and healthcare resource use. Discussion FLARE is designed with sufficient power and rigour to provide evidence on the clinical and cost-effectiveness of two surgical repair methods for single-digit, complete zone 2 flexor tendon injuries in adults. If the repair of FDP alone is as beneficial to the patient as the repair of FDP and FDS, this could save the NHS £1.8 million annually through reduced time and material costs. Furthermore, the trial findings will facilitate better shared decision-making discussions between clinicians and patients. Trial registration ISRCTN 10918157. Prospectively registered: 12.01.2023.

Background Chromothripsis, a newly discovered type of complex genomic rearrangement, has been implicated in the evolution of several types of cancers. To date, it has been described in bone cancer, SHH-medulloblastoma and acute myeloid leukemia, amongst others, however there are still no formal or automated methods for detecting or annotating it in high throughput sequencing data. As such, findings of chromothripsis are difficult to compare and many cases likely escape detection altogether. Results We introduce ShatterProof, a software tool for detecting and quantifying chromothriptic events. ShatterProof takes structural variation calls (translocations, copy-number variations, short insertions and loss of heterozygosity) produced by any algorithm and using an operational definition of chromothripsis performs robust statistical tests to accurately predict the presence and location of chromothriptic events. Validation of our tool was conducted using clinical data sets including matched normal, prostate cancer samples in addition to the colorectal cancer and SCLC data sets used in the original description of chromothripsis. Conclusions ShatterProof is computationally efficient, having low memory requirements and near linear computation time. This allows it to become a standard component of sequencing analysis pipelines, enabling researchers to routinely and accurately assess samples for chromothripsis. Source code and documentation can be found at http://search.cpan.org/~sgovind/Shatterproof .