Ancient Mitogenomes Reveal the Maternal Genetic History of East Asian Dogs.

Recent studies have suggested that dogs were domesticated during the Last Glacial Maximum (LGM) in Siberia, which contrasts with previous proposed domestication centers (e.g. Europe, the Middle East, and East Asia). Ancient DNA provides a powerful resource for the study of mammalian evolution and has been widely used to understand the genetic history of domestic animals. To understand the maternal genetic history of East Asian dogs, we have made a complete mitogenome dataset of 120 East Asian canids from 38 archaeological sites, including 102 newly sequenced from 12.9 to 1 ka BP (1,000 years before present). The majority (112/119, 94.12%) belonged to haplogroup A, and half of these (55/112, 49.11%) belonged to sub-haplogroup A1b. Most existing mitochondrial haplogroups were present in ancient East Asian dogs. However, mitochondrial lineages in ancient northern dogs (northeastern Eurasia and northern East Asia) were deeper and older than those in southern East Asian dogs. Results suggests that East Asian dogs originated from northeastern Eurasian populations after the LGM, dispersing in two possible directions after domestication. Western Eurasian (Europe and the Middle East) dog maternal ancestries genetically influenced East Asian dogs from approximately 4 ka BP, dramatically increasing after 3 ka BP, and afterwards largely replaced most primary maternal lineages in northern East Asia. Additionally, at least three major mitogenome sub-haplogroups of haplogroup A (A1a, A1b, and A3) reveal at least two major dispersal waves onto the Qinghai-Tibet Plateau in ancient times, indicating eastern (A1b and A3) and western (A1a) Eurasian origins.

Ancient genomes and the evolutionary path of modern humans.

Growing evidence from archaic and early modern human genomes brings new insights to the emergence of modern humans. We recount recent information collected from ancient DNA studies that inform us about the evolutionary pathway to modern humanity. These findings point to both individual- and population-level advantages underlying modern human expansion.

Direct-to-Consumer Advertising Survey of Psychiatrists in Massachusetts and Michigan.

PURPOSES/BACKGROUND: The goals of this preliminary study were to survey psychiatrists and to examine the impact of advertisements on their prescription of psychotropic medications. The study specifically looked at psychiatrists in Massachusetts and Michigan, as the authors were able to readily contact the members of their respective state psychiatric societies. METHODS/PROCEDURES: We used the survey software, Quatrics, to create an online survey that was sent via email link to the members of the Massachusetts Psychiatric Society (1400 estimated members), and the Michigan Psychiatric Society (700 estimated members). Details were obtained about how challenging it was for the psychiatrist to convince the patient that a medication was not indicated. Information regarding how the psychiatrist first heard about new medications and where they go to learn more about these medications was included in the survey. FINDINGS/RESULTS: We received 162 partial or full responses to our survey, representing a response rate of 8%. Those who were less than 10 years out of training were less likely to find it "easy" to change the minds of these patients, when compared with those more than 10 years out of training (Fisher exact test, P = 0.0396). The most frequent medication named as a response to "which medications do patients request" was Rexulti (brexpiprazole), followed by Vraylar (cariprazine), Caplyta (lumateperone), and aripiprazole. IMPLICATIONS/CONCLUSIONS: This survey points to the prevalence of psychiatrists getting requests for these advertised medications and illustrates that those with fewer years out of training may have a more difficult time redirecting patients from medications that are not indicated for their illness.

Genome sequences of 36,000- to 37,000-year-old modern humans at Buran-Kaya III in Crimea.

Populations genetically related to present-day Europeans first appeared in Europe at some point after 38,000-40,000 years ago, following a cold period of severe climatic disruption. These new migrants would eventually replace the pre-existing modern human ancestries in Europe, but initial interactions between these groups are unclear due to the lack of genomic evidence from the earliest periods of the migration. Here we describe the genomes of two 36,000-37,000-year-old individuals from Buran-Kaya III in Crimea as belonging to this newer migration. Both genomes share the highest similarity to Gravettian-associated individuals found several thousand years later in southwestern Europe. These genomes also revealed that the population turnover in Europe after 40,000 years ago was accompanied by admixture with pre-existing modern human populations. European ancestry before 40,000 years ago persisted not only at Buran-Kaya III but is also found in later Gravettian-associated populations of western Europe and Mesolithic Caucasus populations.

Overall survival with adjuvant atezolizumab after chemotherapy in resected stage II-IIIA non-small-cell lung cancer (IMpower010): a randomised, multicentre, open-label, phase III trial.

BACKGROUND: IMpower010 (NCT02486718) demonstrated significantly improved disease-free survival (DFS) with adjuvant atezolizumab versus best supportive care (BSC) following platinum-based chemotherapy in the programmed death-ligand 1 (PD-L1)-positive and all stage II-IIIA non-small-cell lung cancer (NSCLC) populations, at the DFS interim analysis. Results of the first interim analysis of overall survival (OS) are reported here. PATIENT AND METHODS: The design, participants, and primary-endpoint DFS outcomes have been reported for this phase III, open-label, 1 : 1 randomised study of atezolizumab (1200 mg q3w; 16 cycles) versus BSC after adjuvant platinum-based chemotherapy (1-4 cycles) in adults with completely resected stage IB (≥4 cm)-IIIA NSCLC (per the Union Internationale Contre le Cancer and American Joint Committee on Cancer staging system, 7th edition). Key secondary endpoints included OS in the stage IB-IIIA intent-to-treat (ITT) population and safety in randomised treated patients. The first pre-specified interim analysis of OS was conducted after 251 deaths in the ITT population. Exploratory analyses included OS by baseline PD-L1 expression level (SP263 assay). RESULTS: At a median of 45.3 months' follow-up on 18 April 2022, 127 of 507 patients (25%) in the atezolizumab arm and 124 of 498 (24.9%) in the BSC arm had died. The median OS in the ITT population was not estimable; the stratified hazard ratio (HR) was 0.995 [95% confidence interval (CI) 0.78-1.28]. The stratified OS HRs (95% CI) were 0.95 (0.74-1.24) in the stage II-IIIA (n = 882), 0.71 (0.49-1.03) in the stage II-IIIA PD-L1 tumour cell (TC) ≥1% (n = 476), and 0.43 (95% CI 0.24-0.78) in the stage II-IIIA PD-L1 TC ≥50% (n = 229) populations. Atezolizumab-related adverse event incidences remained unchanged since the previous analysis [grade 3/4 in 53 (10.7%) and grade 5 in 4 (0.8%) of 495 patients, respectively]. CONCLUSIONS: Although OS remains immature for the ITT population, these data indicate a positive trend favouring atezolizumab in PD-L1 subgroup analyses, primarily driven by the PD-L1 TC ≥50% stage II-IIIA subgroup. No new safety signals were observed after 13 months' additional follow-up. Together, these findings support the positive benefit-risk profile of adjuvant atezolizumab in this setting.

Proliferative Diabetic Retinopathy Requiring Vitrectomy Over Clinic Management During COVID-19: Impact of Delayed Care.

PURPOSE: This study aimed to investigate the impact of delayed retinal clinical care during the COVID-19 pandemic on the severity of proliferative diabetic retinopathy (PDR) and drivers of follow-up delay. We compared disease severity and follow-up rates of PDR patients requiring vitrectomy to those managed nonsurgically, and identified factors associated with need for vitrectomy. METHODS: The study included 739 patients diagnosed with PDR between January 1, 2018, and March 4, 2021, categorized into two groups based on outcome: vitrectomy nonvitrectomy. Statistical methods such as t-tests and chi-square tests were used to analyze differences in disease severity and follow-up rates before and after COVID-19 shutdown. A multivariate regression evaluated factors leading to vitrectomy by comparing initial ETDRS (Early Treatment of Diabetic Retinopathy Study) DR staging, disease stability, DR progression, proliferative complications, appointment intervals, follow-up variance, rescheduling rate, and no-show rate. RESULTS: Of the 739 patients, 202 required vitrectomy, 537 were managed nonsurgically. The vitrectomy group had more severe or unstable disease before shutdown. The interval between patient visits preshutdown was 29.76 ± 45.11 days in the vitrectomy group and 40.23 ± 56.73 days in the nonvitrectomy group (p < 0.001). Both groups experienced a significant increase in appointment intervals after shutdown, with the vitrectomy group having a greater increase. Both groups had significantly increased rescheduling rate and minimally increased no-show rate. Patient-directed rescheduling was the main driver of appointment delays. Disease factors, such as tractional retinal detachment and higher ETDRS DR staging, increased the odds of vitrectomy, while appointment burden and follow-up variability had a minimal impact. CONCLUSIONS: Patients with more severe PDR and greater delay in appointments due to the pandemic were more likely to require vitrectomy for proliferative complications. Patient-directed rescheduling was identified as the main driver of care delays, as opposed to clinic-directed rescheduling. This study highlights the importance of maintaining regular follow-up appointments for PDR patients during pandemics.

Returning to education after childhood acquired brain injury: Learning from lived parental experience.

BACKGROUND: Returning to education (RtE) after an acquired brain injury (ABI) can be stressful for children/young people (CYP) and families. While much can be done to support RtE, there has been limited exploration of the lived experience of parents/carers about what can both help and hinder the process. OBJECTIVE: The aim was to understand more about RtE from parents' perspectives to inform best practice and facilitate improvements in service delivery. METHODS: A service evaluation explored parent/carer views about the RtE process and the support received from healthcare professionals at a regional centre in the UK. Questionnaires (n = 59) were sent to parents of patients treated for an ABI in the last two years. RESULTS: 31 parents (response rate = 51%) completed the survey. Results highlight the many challenges of RtE. Thematic analysis of responses revealed six key themes: Parental mindset and growth; What do they need now?; Specialist support and information; Talk and share; Challenges of new and hidden needs; and Don't forget them! CONCLUSION: Parents offer crucial insight into the challenges of the RtE process. Their feedback highlights important factors for service development and reminds professionals of the key components of an effective return.

Bilateral Flexor Digitorum Accessorius Longus Precipitating Bilateral Tarsal Tunnel Syndrome: A Case Report.

CASE: A 29-year-old woman presented with bilateral tarsal tunnel syndrome caused by bilateral flexor digitorum accessorius longus, experiencing immediate relief of symptoms after surgical intervention through 1 year. CONCLUSION: Accessory muscles can cause compressive neuropathies in multiple areas of the body. In patients who have FDAL as the cause of their tarsal tunnel syndrome, surgeons should have a high index of suspicion of bilateral FDAL if the same patient develops similar contralateral symptoms.

Inhaled CpG increases survival and synergizes with checkpoint inhibition in lymphangioleiomyomatosis.

Rationale: Lymphangioleiomyomatosis (LAM) is a devastating disease primarily found in women of reproductive age that leads to cancer-like cystic destruction of the lungs. Recent work has shown that LAM causes immunosuppression and that checkpoint inhibitors can be used as LAM treatment. IN lung cancer, TLR agonist, in particular TLR9 agonist CpG has been shown to be effective. Objectives: Here we investigate the use of TLR9 agonist CpG as LAM immunotherapy in combination with checkpoint inhibitor, anti-PD1 and assess induced changes in anti-LAM immunity. Methods: We used a murine model of metastatic LAM to determine survival after intranasal treatment with TLR9 agonist CpG at two doses and in combination the checkpoint inhibitor immunotherapy, anti-PD-1. We used histology and flow cytometry to assess overall inflammation as well as changes in the immune response upon treatment. Measurements and Main Results: We found that local administration of CpG enhances survival in a murine model of LAM and that a lower dose more effectively balanced the inflammation induced by CpG with the anti-LAM therapeutic benefits. We also found that CpG reduces regulatory T cell infiltration in LAM lungs and that CD4 helper T cells are skewed toward pro-inflammatory phenotypes. We also found that CpG treatment is effective in both early stage and progressive disease and that CpG is synergistic with previously tested anti-PD1 therapy. Conclusions: We have found that TLR9 agonist CpG can be used as LAM immunotherapy and effectively synergizes with anti-PD1 therapy in LAM.

Biomechanical Efficacy of Tape Cerclage as an Augment or Stand-alone for Coracoclavicular Ligament Reconstruction.

BACKGROUND: Loss of initial reduction of the acromioclavicular joint after coracoclavicular (CC) ligament reconstruction remains a challenge for various repair techniques. Previous studies using polydioxanone suture cerclage augments for CC ligament reconstruction demonstrated poor clinical and biomechanical outcomes. Tape-style sutures have recently gained popularity because of their added stiffness and strength relative to traditional sutures. These tape cerclage systems have yet to be biomechanically studied in CC ligament reconstruction. PURPOSE: To determine the efficacy of a tape cerclage system as an augment to CC ligament reconstruction. STUDY DESIGN: Controlled laboratory study. METHODS: A total of 24 human cadaveric shoulders were utilized. These were divided into 4 repair groups: anatomic CC ligament reconstruction (ACCR), ACCR with a tape cerclage augment (ACCR + C), tendon graft sling with a cerclage augment (TGS + C), or tape cerclage sling alone (CS). The repairs underwent superior/inferior cyclic loading to evaluate for displacement. Specimens were visually inspected for cortical erosion by the tape cerclage after cyclic loading. Finally, the constructs underwent superior plane load-to-failure testing. RESULTS: Less displacement after cyclic loading was observed in the ACCR + C (mean ± SD, 0.42 ± 0.32 mm), TGS + C (0.92 ± 0.42 mm), and CS (0.93 ± 0.39 mm) groups as compared with the ACCR group (4.42 ± 3.40 mm; P = .002). ACCR + C (813.3 ± 257.5 N), TGS + C (558.0 ± 120.7 N), and CS (759.5 ± 173.7 N) demonstrated significantly greater load at failure relative to ACCR (329.2 ± 118.2 N) (P < .001). ACCR + C (60.88 ± 17.3 N/mm), TGS + C (44.97 ± 9.15 N/mm), and CS (54.52 ± 14.24 N/mm) conferred greater stiffness than ACCR (27.43 ± 6.94 N/mm) (P = .001). No cortical erosion was demonstrated in any specimen after cyclic loading. CONCLUSION: In a cadaveric model at time zero, repairs utilizing a tape cerclage system confer significantly greater load to failure and stiffness, as well as decreased displacement with cyclic loading, when compared with traditional ACCR repair. CLINICAL RELEVANCE: Tape cerclage augmentation may provide a useful augment for CC ligament reconstruction.

Analysis of Ancient Microbial DNA.

The development of next-generation sequencing has led to a breakthrough in the analysis of ancient genomes, and the subsequent genomic analyses of ancient human skeletal remains have revolutionized our understanding of human evolution. This research led to the discovery of a new hominin lineage, and demonstrated multiple admixture events with more distantly related archaic human populations such as Neandertals and Denisovans over the last 100,000 years. Moreover, it has also yielded novel insights into the evolution of ancient pathogens. The analysis of ancient microbial genomes enables the study of their recent evolution, presently covering the last several millennia. These spectacular results have been obtained despite the degradation of DNA that takes place after the death of the host and increases with time. This cumulative degradation results in very short ancient DNA molecules, low in quantity, and highly prone to contamination by modern DNA molecules, especially from human and animal DNA present in reagents used in downstream biomolecular analyses. Finally, the minute amounts of ancient molecules are further diluted in environmental DNA from the soil microorganisms that colonize bones and teeth. Thus, ancient skeletal remains can share DNA profiles with environmental samples, and the identification of ancient microbial genomes among the more recent, presently poorly characterized, environmental microbiome is particularly challenging. Here, we describe the methods developed and/or in use in our laboratory to produce reliable and reproducible paleogenomic results from ancient skeletal remains that can be used to identify the presence of ancient microbiota.

Management of scleral melt.

Scleral melting, while rare, can lead to significant ocular morbidity. Several possible risk factors for scleral melt have been identified, such as infection, autoimmune disease, trauma, and post-surgical state, and these may act in combination with each other. Treatment should be tailored according to the etiology and severity of the scleral melt. Medical management may be indicated, especially in cases of autoimmune-related melt; however, surgical procedures are often necessary due to compromised ocular integrity and limited penetration of medications into the avascular sclera. An understanding of the surgical options available and their operative outcomes is particularly important when choosing the appropriate treatment protocol for each patient.

Suture Tape Augmentation for the Repair of Index Finger Radial Collateral Ligament Injury: A Biomechanical Study.

PURPOSE: Despite their clinical importance in maintaining the stability of the pinch mechanism, injuries of the radial collateral ligament (RCL) of the index finger may be underrecognized and underreported. The purpose of this biomechanical study was to compare the repair of index finger RCL tears with either a standard suture anchor or suture tape augmentation. METHODS: The index fingers from 24 fresh-frozen human cadavers underwent repair of torn RCLs using either a standard suture anchor or suture tape augmentation. Following the repairs, the initial displacement of the repair with a 3-N ulnar deviating load was evaluated. Next, the change in displacement (cyclic deformation) of the repair after 1,000 cycles of 3 N of ulnar deviating force was calculated (displacement of the 1000th cycle - displacement of the first cycle). Finally, the amount of force required to cause clinical failure (30° ulnar deviation) of the repair was determined. RESULTS: Suture tape augmentation repairs displayed significantly less cyclic deformation (0.8 ± 0.5 mm) after cyclic loading than suture anchor repairs (1.8 ± 0.7 mm). There was no significant difference in the force required to cause the clinical failure of the repairs between the suture tape (35.1 ± 18.1 N) and suture anchor (24.5 ± 9.2 N) repairs. CONCLUSIONS: Index finger RCL repair with suture tape augmentation results in decreased deformation with repetitive motion compared with RCL repair alone. CLINICAL RELEVANCE: Suture tape augmentation may allow for early mobilization following index finger RCL repair by acting as a brace that protects the repaired ligament from deforming forces.

Evolving ancient DNA techniques and the future of human history.

Ancient DNA (aDNA) techniques applied to human genomics have significantly advanced in the past decade, enabling large-scale aDNA research, sometimes independent of human remains. This commentary reviews the major milestones of aDNA techniques and explores future directions to expand the scope of aDNA research and insights into present-day human health.

Growth performance, carcass characteristics and cost implications of supplementing Turkey poults with toasted Bambara nut by-products.

Legumes provide high quality proteins with nutritional benefits for monogastric animals. Compared to other legume pulses, Bambara nuts (Vigna subterranean) grow in marginal soils, contain 12 different proteins and 214 identifiable peptides that readily provide nutritional and health benefits to consumers. Toasted Bambara nuts are consumed by humans, while the shells are ground and included in both poultry and ruminant rations as a readily degradable protein source. The hypothesis that turkey poults supplemented with toasted Bambara nuts by-products will respond with higher daily weight gains, faster growth, superior carcass characteristics, heavier organs and higher profit margins than unsupplemented poults was tested in this study with the primary objective of evaluating the response of grower turkey poults to supplementation with graded levels of Bambara nut by-products. The feeding trial lasted for 56 days and a completely randomised experimental design was utilised to randomly allocate 60 poults to five treatments of 12 poults each, comprising the control (0%), 7.5, 15, 22.5 and 30% inclusion level of toasted Bambara nut by-products. Compared to the control group, supplemented poults achieved a significantly better (P < 0.05) feed conversion ratio, heavier carcass traits, total and eviscerated organ weights and faster average daily gains. This superior performance was highest in poults supplemented at the 30% inclusion level which returned an 85% profit margin and a 10% reduction in feed cost compared to unsupplemented poults. These findings imply that turkey farmers can break even while achieving superior growth performance, heavier carcasses and nutritional benefits accruing from supplementation with toasted Bambara nuts by-products, hence the need to accept the tested hypothesis.