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The 2022 monkeypox outbreak has affected 110 countries worldwide, outside of classic endemic areas (ie, west Africa and central Africa). On July 23, 2022, the outbreak was classified by WHO as a public health emergency of international concern. Clinical presentation varies from mild to life-changing symptoms; neurological complications are relatively uncommon and there are few therapeutic interventions for monkeypox disease. In this Grand Round, we present a case of monkeypox with encephalitis complicated by transverse myelitis in a previously healthy woman aged 35 years who made an almost complete recovery from her neurological symptoms after treatment with tecovirimat, cidofovir, steroids, and plasma exchange. We describe neurological complications associated with orthopoxvirus infections and laboratory diagnosis, the radiological features in this case, and discuss treatment options.

Recent randomised controlled trials have failed to show a benefit in mortality by using processed electroencephalography (pEEG) to guide lighter anaesthesia. We performed a meta-analysis of mortality data from randomised trials of pEEG monitoring to assess the evidence of any protective effect of pEEG-guided light anaesthesia compared with deep anaesthesia in adults aged ≥18 yr.Our study followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. In February 2022, we searched three databases (Cochrane CENTRAL, OVID Medline, EMBASE) for RCTs of pEEG monitoring that provided mortality data at 30 days, 90 days, and/or 1 yr or longer.We included 16 articles from 12 RCTs with 48 827 total participants. We observed no statistically significant mortality reduction with light anaesthesia compared with deep anaesthesia in patients aged ≥18 yr when all studies were pooled (odds ratio [OR]=0.99; 95% confidence interval (CI), 0.92-1.08). This result did not change significantly when analysing mortality at 30 days, 90 days, 1 yr or longer. We observed no mortality benefit for pEEG monitoring compared with usual care (OR=1.02; 95% CI, 0.89-1.18), targeting higher pEEG index values compared with lower values (OR=0.89; 95% CI, 0.60-1.32), or low pEEG index value alerts compared with no alerts (OR=1.02; 95% CI, 0.41-2.52).pEEG-guided lighter anaesthesia does not appear to reduce the risk of postoperative mortality. The absence of a plausible rationale for why deeper anaesthesia should increase mortality has hampered appropriate design of definitive clinical trials.CRD42022285195 (PROSPERO).

Crop genebank collections are important resources for preserving genetic diversity to face the worldwide demand for food and coping with crop diseases and climate change. However, genebanks tend to accumulate materials without systematic collection growth. Thus, tools for optimizing collections are expected to help improvement of genebanks quality. Furthermore, the genotyping efforts of genebanks would benefit from tools that can help to sample the accessions. A set of parameters to aid the optimization of genebanks are defined, in which Relative Balance is central. In this study, the foundation of our mathematical approach was Kullback-Leibler divergence, providing formulas with consistent properties. Two examples were used as proof of concept. The first one was the comparison between actual and putative optimal numbers of accessions in the Triticum set of the CIMMYT (Centro Internacional de Mejoramiento de Maíz y Trigo) Wheat Germplasm Bank, with 135,236 entries classified into ten groups. The second one was based on a set containing Triticum plus eight related genera, with 159,741 accessions classified into 217 end-groups, with the goal of illustrating the use of the analytical tools to optimize the ongoing genotyping process. The first example shows a scenario with a well-balanced allocation of accessions. The second example illustrates the optimized choice of end-groups to add 10,000 accessions to the genotyping process. The proof of concept showed the consistency and usefulness of the proposed methods for the improvement of composition in collections and their characterization.

Hearing loss has a significant impact on quality of life, and may even compromise an individual’s ability to work and their safety – we use our hearing to constantly detect and react to environmental hazards around us. Hearing loss can have a profound impact on a person’s life. This is especially true for certain patient groups. For instance, the elderly, and those with co-existing problems that affect their ability to communicate (such as dementia, cerebrovascular disease or psychiatric disorders). Even those without co-morbidities suffer the burden of disease where communication is impaired: the young who are developing their speech and language skills and adults with language barriers or other impediments to their speech. The hearing apparatus is made up of conductive and sensorineural pathways, which may be affected by pathology, leading to deafness. This article describes the aetiology of conductive and sensorineural deafness, details the relevant clinical assessment and outlines management strategies in community practice.

BackgroundAccumulating evidence supports sex differences in pharmacodynamic and pharmacokinetic drug profiles. However, recommended anaesthetic drug doses are not sex-adjusted, likely due to limited studies comparing sexes. Our objective was to systematically synthesise studies of anaesthetic key performance indicators (anaesthesia awareness), and markers of relatively lighter anaesthesia, time to emergence and dosing to achieve adequate depth of anaesthesia, for females and males.MethodsMEDLINE, Embase, and the Cochrane library databases. Studies were identified from inception of database to August 2nd, 2022. Controlled clinical trials (randomised and non-randomised) and prospective cohort studies that reported outcomes by sex for awareness with post-operative recall, connected consciousness during anaesthesia, depth of anaesthesia, and emergence from anaesthesia. Two authors undertook search, review, selection, and data abstraction. Risk of bias was assessed using the Newcastle Ottawa Scale. Results were synthesized by random effects meta-analysis where possible, or narrative form. Results were expressed as odds ratios (ORs) and mean differences (MDs) with corresponding 95% confidence intervals (CIs).ResultsOf the 19,749 studies identified from literature search, 66 citations of 64 studies (98,243 participants; 53,143 females and 45,100 males) were eligible for inclusion, of which 44 contributed to meta-analysis. Females had a higher incidence of awareness with post-operative recall (33 studies, OR 1.37, 95%CI 1.09 to 1.75) and connected consciousness during anaesthesia (3 studies, OR 2.09, 95% CI 1.04 to 4.23) than males. Time to emergence was faster in females than in males, including time to eye-opening (10 studies, MD -2.28 min, 95% CI -3.58 to -0.98), and time to response to command (6 studies, MD - 2.84 min, 95% CI -4.07 to -1.62). Data on depth of anaesthesia were heterogenous limiting synthesis to a qualitative review which did not identify differences by sex.ConclusionFemale sex was associated with a greater incidence of anaesthetic awareness, as well as faster emergence from anaesthesia. These data suggest reappraisal of anaesthetic care, including whether similar drug dosing for females and males represents best care. Equitable outcomes for females undergoing general anaesthesia warrants strategic focus in future research.Systematic review registrationPROSPERO CRD42022336087.

An increase in the efficiency of clinical trial conduct has been successfully demonstrated in the oncology field, by the use of multi-arm, multi-stage trials allowing the evaluation of multiple therapeutic candidates simultaneously, and seamless recruitment to phase 3 for those candidates passing an interim signal of efficacy. Replicating this complex innovative trial design in diseases such as Parkinson’s disease is appealing, but in addition to the challenges associated with any trial assessing a single potentially disease modifying intervention in Parkinson’s disease, a multi-arm platform trial must also specifically consider the heterogeneous nature of the disease, alongside the desire to potentially test multiple treatments with different mechanisms of action. In a multi-arm trial, there is a need to appropriately stratify treatment arms to ensure each are comparable with a shared placebo/standard of care arm; however, in Parkinson’s disease there may be a preference to enrich an arm with a subgroup of patients that may be most likely to respond to a specific treatment approach. The solution to this conundrum lies in having clearly defined criteria for inclusion in each treatment arm as well as an analysis plan that takes account of predefined subgroups of interest, alongside evaluating the impact of each treatment on the broader population of Parkinson’s disease patients. Beyond this, there must be robust processes of treatment selection, and consensus derived measures to confirm target engagement and interim assessments of efficacy, as well as consideration of the infrastructure needed to support recruitment, and the long-term funding and sustainability of the platform. This has to incorporate the diverse priorities of clinicians, triallists, regulatory authorities and above all the views of people with Parkinson’s disease.

Introduction: Previous studies have identified associations between nicotine and marijuana vaping among youth. Studies also have identified associations between vaping and both anxiety and depression among young adults. Hypothesis: We hypothesized that mental health differences would be evident across current nicotine-only vapers, current vapers of both nicotine and THC, and never vapers. Methods: A national online survey was conducted among 2,505 youth and young adults aged 13-24 during June and July 2022. The participants were recruited via an online panel and received an incentive to complete the survey. Parent consent was obtained for minors and informed consent was obtained from participants. Quotas were established for vaping and THC use. This analysis focuses on current vapers and never vapers (n=1,762). Current use was defined as having vaped in the past 30 days. Of the participants, 1,200 were current nicotine vapers (370 nicotine-only vapers and 830 dual vapers of nicotine and THC); 562 have never vaped nicotine or THC. Results: Dual vapers were significantly more likely than nicotine-only vapers to indicate addiction to nicotine, as defined as waking up at night to vape (55% vs. 45%, p Conclusions: In conclusion, our analysis shows an association between mental health symptoms with vaping nicotine and THC. Dual use may either compound the addictive nature of vaping or attract those more prone to addiction, as well as have an impact on depression. Anxiety and depression symptoms were notable among both groups, compared with never vapers, and were cited as reasons for nicotine vaping. These findings suggest the importance of addressing the use of THC and the need for building resilience skills in vaping prevention efforts.

Class II HLA loci DRB1, DQB1 and DPB1 were typed for a total of 939 Gambian participants by locus-specific amplicon sequencing. Participants were from multiple regions of The Gambia and drawn from two studies: a family study aiming to identify associations between host genotype and trachomatous scarring (N = 796) and a cohort study aiming to identify correlates of immunity to trachoma (N = 143). All loci deviated from Hardy-Weinberg equilibrium, likely due to the family-based nature of the study: 608 participants had at least one other family member included in the study population. The most common alleles for HLA-DRB1, DQB1 and DPB1 respectively were DRB1*13:04 (18.8 %), DQB1*03:19 (27.9 %) and DPB1*01:01 (25.4 %). Participants belonged to a variety of ethnicities, including the Mandinka, Fula, Wolof and Jola ethnic groups.

The International Maize and Wheat Improvement Center develops and annually distributes elite wheat lines to public and private breeders worldwide. Trials have been created in multiple sites over many years to assess the lines' performance for use in breeding and release as varieties, and to provide iterative feedback on refining breeding strategies1. The collaborator test sites are experiencing climate change, with new implications for how wheat genotypes are bred and selected2. Using a standard quantitative genetic model to analyse four International Maize and Wheat Improvement Center global spring wheat trial datasets, we examine how genotype-environment interactions have changed over recent decades. Notably, crossover interactions-a critical indicator of changes in the ranking of cultivar performance in different environments-have increased over time. Climatic factors explained over 70% of the year-to-year variability in crossover interactions for yield. Yield responses of all lines in trial environments from 1980 to 2018 revealed that climate change has increased the ranking change in breeding targeted to favourable environments by ~15%, while it has maintained or reduced the ranking change in breeding targeted to heat and drought stress by up to 13%. Genetic improvement has generally increased crossover interactions, particularly for wheat targeted to high-yielding environments. However, the latest wheat germplasm developed under heat stress was better adapted and more stable, partly offsetting the increase in ranking changes under the warmer climate.

Locus-specific amplicon sequencing was used to HLA type 336 participants of Maasai ethnicity at the HLA-A, -B, -C, -DRB1, -DQB1 and -DPB1 loci. Participants were recruited from three study villages in North Tanzania, for the purpose of investigating risk factors for trachomatous scarring in children. Other than HLA-A, all loci significantly deviated from Hardy-Weinberg equilibrium, possibly due to high relatedness between individuals: 238 individuals shared a house with at least one another participant. The most frequent allele for each locus were A*68:02 (14.3 %), B*53:01 (8.4 %), C*06:02 (19.2 %), DRB1*13:02 (17.7 %), DQB1*02:01 (16.9 %) and DPB1*01:01 (15.7 %), while the most common inferred haplotype was A*68:02 ∼ B*18:01 ∼ C*07:04 ∼ DRB1*08:04 ∼ DQB1*04:02 ∼ DPB1*04:01 (1.3 %).

Recent trials are conflicting as to whether titration of anaesthetic dose using electroencephalography monitoring reduces postoperative delirium. Titration to anaesthetic dose itself might yield clearer conclusions. We analysed our observational cohort to clarify both dose ranges for trials of anaesthetic dose and biological plausibility of anaesthetic dose influencing delirium.We analysed the use of sevoflurane in an ongoing prospective cohort of non-intracranial surgery. Of 167 participants, 118 received sevoflurane and were aged65 yr. We tested associations between age-adjusted median sevoflurane (AMS) minimum alveolar concentration fraction or area under the sevoflurane time×dose curve (AUC-S) and delirium severity (Delirium Rating Scale-98). Delirium incidence was measured with 3-minute Diagnostic Confusion Assessment Method (3D-CAM) or CAM-ICU. Associations with previously identified delirium biomarkers (interleukin-8, neurofilament light, total tau, or S100B) were tested.Delirium severity did not correlate with AMS (Spearman's ρ=-0.014, P=0.89) or AUC-S (ρ=0.093, P=0.35), nor did delirium incidence (AMS Wilcoxon P=0.86, AUC-S P=0.78). Further sensitivity analyses including propofol dose also demonstrated no relationship. Linear regression confirmed no association for AMS in unadjusted (log (IRR)=-0.06 P=0.645) or adjusted models (log (IRR)=-0.0454, P=0.735). No association was observed for AUC-S in unadjusted (log (IRR)=0.00, P=0.054) or adjusted models (log (IRR)=0.00, P=0.832). No association of anaesthetic dose with delirium biomarkers was identified (P0.05).Sevoflurane dose was not associated with delirium severity or incidence. Other biological mechanisms of delirium, such as inflammation and neuronal injury, appear more plausible than dose of sevoflurane.NCT03124303, NCT01980511.

Genetic variation in wheat is needed to address global food security challenges, particularly as climates change. Crop wild relatives are unique reservoirs of useful alleles for crop improvement and are important components of genebank collections. We analyzed how the derivatives of ‘goat grass’ (Aegilops tauschii) have been used to widen the genetic base for wheat breeding and surveyed wheat breeders to elicit adoption estimates. Synthetic hexaploid wheat (SHW) is derived by crossing goat grass with durum wheat, serving as a bridge to transfer desirable traits into modern varieties of bread wheat. Our data show that wheat scientists used 629 unique accessions from 15 countries for pre-breeding, producing 1577 primary SHWs. These derivatives represented 21% of the germplasm distributed by the genebank of the International Maize and Wheat Improvement Center between 2000 and 2018. Over the period, more than 10,000 samples of SHW were sent to 110 institutions in 40 countries, with rising numbers of synthetic hexaploid-derived lines (SHDL) included in international nurseries. Lines were screened for major diseases of wheat. At least 86 varieties have been selected from SHDL and released in 20 countries. Survey estimates indicate the highest scale of adoption in southwest China and India, with 34% and 7% of reported wheat area, respectively. These varieties demonstrate resistance to pests and pathogens, high yield potential, good quality attributes, and suitability for biofortified wheat.

Background Electronic consultations (eConsults) are an increasingly used form of telemedicine that allows a nonspecialist clinician to seek specialist advice remotely without direct patient-specialist communication. Surgical clinics may see benefits from such forms of communication but face challenges with the need for intervention planning. Objective We aimed to use the Quadruple Aim Framework to integrate published knowledge of surgical outpatient eConsults with regard to efficacy, safety, limitations, and evolving use in the era of COVID-19. Methods We systematically searched for relevant studies across four databases (Ovid MEDLINE, Embase, Scopus, and Web of Science) on November 4, 2021, with the following inclusion criteria: English language, published in the past 10 years, and data on the outcomes of outpatient surgical eConsults. Results A total of 363 studies were screened for eligibility, of which 33 (9.1%) were included. Most of the included studies were from the United States (23/33, 70%) and Canada (7/33, 21%), with a predominant multidisciplinary focus (9/33, 27%). Most were retrospective audits (16/33, 48%), with 15% (5/33) of the studies having a prospective component. Conclusions The surgical eConsult studies indicated a possible benefit for population health, promising safety results, enhanced patient and clinician experience, and cost savings compared with the traditional face-to-face surgical referral pathway. Their use appeared to be more favorable in some surgical subspecialties, and the overall efficacy was similar to that of medical subspecialties. Limited data on their long-term safety and use during the COVID-19 pandemic were identified, and this should be the focus of future research.

BACKGROUND Electronic consultations (eConsults) are an increasingly used form of telemedicine that allows a nonspecialist clinician to seek specialist advice remotely without direct patient-specialist communication. Surgical clinics may see benefits from such forms of communication but face challenges with the need for intervention planning. OBJECTIVE We aimed to use the Quadruple Aim Framework to integrate published knowledge of surgical outpatient eConsults with regard to efficacy, safety, limitations, and evolving use in the era of COVID-19. METHODS We systematically searched for relevant studies across four databases (Ovid MEDLINE, Embase, Scopus, and Web of Science) on November 4, 2021, with the following inclusion criteria: English language, published in the past 10 years, and data on the outcomes of outpatient surgical eConsults. RESULTS A total of 363 studies were screened for eligibility, of which 33 (9.1%) were included. Most of the included studies were from the United States (23/33, 70%) and Canada (7/33, 21%), with a predominant multidisciplinary focus (9/33, 27%). Most were retrospective audits (16/33, 48%), with 15% (5/33) of the studies having a prospective component. CONCLUSIONS The surgical eConsult studies indicated a possible benefit for population health, promising safety results, enhanced patient and clinician experience, and cost savings compared with the traditional face-to-face surgical referral pathway. Their use appeared to be more favorable in some surgical subspecialties, and the overall efficacy was similar to that of medical subspecialties. Limited data on their long-term safety and use during the COVID-19 pandemic were identified, and this should be the focus of future research.

SARS-CoV-2 is spreading worldwide with continuously evolving variants, some of which occur in the Spike protein and appear to increase the viral transmissibility. However, variants that cause severe COVID-19 or lead to other breakthroughs have not been well characterized. To discover such viral variants, we assembled a cohort of 683 COVID-19 patients; 388 inpatients (“cases”) and 295 outpatients (“controls”) from April to August 2020 using electronically captured COVID test request forms and sequenced their viral genomes. To improve the analytic power, we accessed 7,137 viral sequences in Washington State to filter out viral single nucleotide variants (SNVs) that did not have significant expansions over the collection period. Applying this filter led to the identification of 53 SNVs that were statistically significant, of which 13 SNVs each had 3 or more variant copies in the discovery cohort. Correlating these selected SNVs with case/control status, eight SNVs were found to significantly associate with inpatient status (q-values−11) that appeared in April 2020, peaked in June, and persisted into January 2021. This association was replicated (OR=5.46, p-value=4.71*10−12) in an independent cohort of 964 COVID-19 patients (June 1, 2020 to March 31, 2021). The haplotype included a synonymous change N73N in endoRNase, and three non-synonymous changes coding residues R203K, R203S and G204R in the nucleocapsid protein. This discovery points to the potential functional role of the nucleocapsid protein in triggering “cytokine storms” and severe COVID-19 that led to hospitalization. The study further emphasizes a need for tracking and analyzing viral sequences in correlations with clinical status.

Despite a large number of Aegilops L. species and their diversity in Azerbaijan, a majority of this genetic material has not been characterized at molecular levels. The current study has implemented DArTseq technology to evaluate genetic diversity among 150 accessions of different Aegilops species from Azerbaijan. A total of 61,574 SilicoDArTseq and 30,433 SNP markers were used to assess genetic diversity in Aegilops species. Genetic diversity was measured using Shannon’s genetic diversity index, which was equal to 0.852. Dendrograms were built to establish the relationship among Aegilops species. Both the DArTseq and SNP markers could completely segregate the U genome species from those with D genome with high confidence and allowed assigning most species to separate subclusters. The pattern of clustering within the Aegilops tauschii Coss. to certain extent was related to their geographical regions. Genetic structure among the 150 Aegilops accessions was similar with the cluster analysis. Two groups were identified in the studied population, which were exactly corresponded to two clusters in the dendrogram. Principal coordinate analysis confirmed sub-grouping obtained by cluster analysis. The first two principal coordinates explained 82.34% of the total variation. The study reported a sufficient level of genetic diversity of Aegilops from different eco-geographical regions of Azerbaijan, which can be very useful for their conservation and management, as well as for profitable diversifying the gene pool of hexaploid wheat.

Durum wheat landraces from Iran and Mexico were evaluated for important grain traits, gluten quality characteristics and ultimate baking performance. It was also characterized by SDS-PAGE for high and low molecular weight glutenins composition. Substantial phenotypic variation was observed for most traits, with promisingly useful variability identified for attributes that typically limit durum wheat from being used in industrial bread-making processes, such as gluten extensibility and actual baking performance. Promising genotypes with atypically enhanced extensibility and/or baking performance, independently, from high protein content were identified and can be considered as valuable parental stocks to be exploited in durum breeding programs targeting the widening of the end-uses of this grain. A significant number of novel glutenins subunit and/or subunit combinations were described. The Iranian group was found to be more diverse than the Mexican group, which is consistent with their respective evolution histories: The Mexican Creoles wheats represents a small sample of the variability that was present in the Iberian Peninsula when they were moved to Mexico while the Iranian landraces evolved very close to the center of Origin of durum wheat, maintained most of the variability that was developed in the region from the early days of durum wheat evolution.

The history of CGIAR and the development and implementation of the International Treaty on Plant Genetic Resources for Food and Agriculture (“Plant Treaty”) are closely intertwined. In accordance with the agreements that 11 CGIAR centers signed with the Plant Treaty’s Governing Body under Article 15 of the treaty, >730,000 accessions of crop, tree, and forage germplasm conserved in CGIAR genebanks are made available under the terms and conditions of the multilateral system of access and benefit sharing, and the CGIAR centers have transferred almost 4 million samples of plant genetic resources under the system. Many activities of CGIAR centers and their genebanks (e.g., crop enhancement, improved agronomic methods, seed system strengthening, and capacity building) are influenced by, and promote, the Plant Treaty’s objectives. The continued existence and optimal functioning of the Plant Treaty’s multilateral system of access and benefit sharing is critically important to CGIAR in the pursuit of its mission. However, the multilateral system has encountered some challenges since the Plant Treaty came into force. The successful conclusion of the ongoing process for enhancing the functioning of the multilateral system could increase monetary benefit sharing and incentives for exchanging more germplasm. In the meantime, increased efforts are necessary to promote nonmonetary benefit sharing through partnerships, technology transfer, information exchange, and capacity building. These efforts should be integrated into countries’ and organizations’ work to implement the Plant Treaty’s provisions on conservation and sustainable use of plant genetic resources, and farmers’ rights.

BackgroundSporadic Parkinson’s disease (sPD) is an aetiologically heterogeneous disorder. Identification of distinct pathogenic mechanisms causing sPD will be crucial to develop future “Precision Medicine” approaches. 31P-MRS is a non-invasive tool that can quantify key bionenergetic metabolites in individual patients.ObjectiveTo determine whether 31P-MRS can identify mitochondrial dysfunction in the midbrain/sub- stantia nigra of individual PD patients and correlates with trial-relevant clinical aspects of PD.Methods31P-MRS spectra were obtained from 35 sPD patients and 25 healthy, age-matched controls. Spectra were analysed using the jMRUI software package and AMARES spectral fitting algorithm. Clinical assessment included widely utilised clinical rating scales, genetic analysis and the calculation of predicted risk of rapid disease progression.ResultsThere was a significantly broader variance in 31P-MRS midbrain ATP with 1/3 of all PD patients having ATP levels > 2 standard deviations outside the mean control values (p=0.0030). Higher midbrain phosphocreatine was associated with greater risk of rapid disease progression (p= 0.0384).Conclusions31P-MRS may help to identify a subgroup of sPD with significant mitochondrial dysfunction or at higher risk of more rapid progression and facilitate stratification for future precision medicine neu- roprotective trials. Longitudinal studies are required to characterise if changes 31P-MRS measures mirror clinical progression.

Background The development of persistent endoplasmic reticulum (ER) stress is one of the cornerstones of prostate carcinogenesis; however, the mechanism is missing. Also, alcohol is a physiological ER stress inducer, and the link between alcoholism and progression of prostate cancer (PCa) is well documented but not well characterized. According to the canonical model, the mediator of ER stress, ATF6, is cleaved sequentially in the Golgi by S1P and S2P proteases; thereafter, the genes responsible for unfolded protein response (UPR) undergo transactivation. Methods Cell lines used were non-malignant prostate epithelial RWPE-1 cells, androgen-responsive LNCaP and 22RV1 cells, as wells as androgen-refractory PC-3 cells. We also utilized PCa tissue sections from patients with different Gleason scores and alcohol consumption backgrounds from different. Several sophisticated approaches were employed, including Structured illumination superresolution microscopy, Proximity ligation assay, Atomic force microscopy, and Nuclear magnetic resonance spectroscopy. Results Herein, we identified the trans-Golgi matrix dimeric protein GCC185 as a Golgi retention partner for both S1P and S2P, and in cells lacking GCC185, these enzymes lose intra-Golgi situation. Progression of prostate cancer (PCa) is associated with overproduction of S1P and S2P but monomerization of GCC185 and its downregulation. Utilizing different ER stress models, including ethanol administration, we found that PCa cells employ an elegant mechanism that auto-activates ER stress by fragmentation of Golgi, translocation of S1P and S2P from Golgi to ER, followed by intra-ER cleavage of ATF6, accelerated UPR, and cell proliferation. The segregation of S1P and S2P from Golgi and activation of ATF6 are positively correlated with androgen receptor signaling, different disease stages, and alcohol consumption. Finally, depletion of ATF6 significantly retarded the growth of xenograft prostate tumors and blocks production of pro-metastatic metabolites. Conclusions We found that progression of PCa associates with translocation of S1P and S2P proteases to the ER and subsequent ATF6 cleavage. This obviates the need for ATF6 transport to the Golgi and enhances UPR and cell proliferation. Thus, we provide the novel mechanistic model of ATF6 activation and ER stress implication in the progression of PCa, suggesting ATF6 is a novel promising target for prostate cancer therapy.

Surgery has a rich history, and in order to understand the various training pathways for aspiring surgeons one must have an appreciation of the evolution of surgery. This manuscript aims to deliver a brief review of the history of surgery, and explore the historical moments that have shaped the training pathway of surgeons in the United Kingdom (UK), and in doing so disseminate the latest information about surgical training in the UK. doi: https://doi.org/10.12669/pjms.37.5.4628 How to cite this:Payne T, Toms JD, Zaidi A, Thrumurthy SG. The history of surgery and surgical training in the UK. Pak J Med Sci. 2021;37(5):1532-1535. doi: https://doi.org/10.12669/pjms.37.5.4628 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Wheat grain yield (GY) improvement using genomic tools is important for achieving yield breakthroughs. To dissect the genetic architecture of wheat GY potential and stress-resilience, we have designed this large-scale genome-wide association study using 100 datasets, comprising 105,000 GY observations from 55,568 wheat lines evaluated between 2003 and 2019 by the International Maize and Wheat Improvement Center and national partners. We report 801 GY-associated genotyping-by-sequencing markers significant in more than one dataset and the highest number of them were on chromosomes 2A, 6B, 6A, 5B, 1B and 7B. We then used the linkage disequilibrium (LD) between the consistently significant markers to designate 214 GY-associated LD-blocks and observed that 84.5% of the 58 GY-associated LD-blocks in severe-drought, 100% of the 48 GY-associated LD-blocks in early-heat and 85.9% of the 71 GY-associated LD-blocks in late-heat, overlapped with the GY-associated LD-blocks in the irrigated-bed planting environment, substantiating that simultaneous improvement for GY potential and stress-resilience is feasible. Furthermore, we generated the GY-associated marker profiles and analyzed the GY favorable allele frequencies for a large panel of 73,142 wheat lines, resulting in 44.5 million datapoints. Overall, the extensive resources presented in this study provide great opportunities to accelerate breeding for high-yielding and stress-resilient wheat varieties.

The International Maize and Wheat Improvement Center develops and annually distributes elite wheat lines to public and private breeders worldwide. Trials have been created in multiple sites over many years to assess the lines' performance for use in breeding and release as varieties, and to provide iterative feedback on refining breeding strategies

Extragonadal non-gestational choriocarcinoma is a rare but well-described phenomenon occurring in patients with midline germ cell tumors. Choriocarcinoma (ChC) is an aggressive neoplasm usually developing in women as a rare complication of pregnancy. In male patients ChC occurs in the testes, usually as a component of mixed germ cell tumors. Very few patients develop extragonadal choriocarcinoma with the tumor occurring in midline locations, such as the mediastinum, retroperitoneum, and central nervous system (mostly pineal gland). Non-midline choriocarcinoma can occur in the lung, gastrointestinal tract, and breast, sometimes blended with another primary malignancy. A midline choriocarcinoma manifesting as a head and neck malignancy is exceptional. During an evaluation of multiple enlarged cervical lymph nodes suspected to be lymphoma in a 72-year-old man, a core biopsy was taken from one of the left neck lymph nodes which histologically showed a necrotic malignancy with strong diffuse pancytokeratin staining. After an initial interpretation of metastatic carcinoma, further samples were taken from both tonsils and from a right level 5 neck lymph node. Histologically, all samples contained the same tumor, showing profound pleomorphism and multinucleated syncytial-type giant cells. A panel of immunohistochemistry studies were performed, including β-human chorionic gonadotropin, with positive findings leading to a diagnosis of extragonadal non-gestational choriocarcinoma.

Breeding for grain yield (GY) in bread wheat at the International Maize and Wheat Improvement Center (CIMMYT) involves three-stage testing at Obregon, Mexico in different selection environments (SEs). To understand the efficiency of selection in the SEs, we performed a large retrospective quantitative genetics study using CIMMYT’s yield trials evaluated in the SEs (2013-2014 to 2017-2018), the South Asia Bread Wheat Genomic Prediction Yield Trials (SABWGPYTs) evaluated in five target sites in India, Pakistan and Bangladesh (2014-2015 to 2017-2018) and the Elite Spring Wheat Yield Trials (ESWYTs) evaluated in several sites globally (2003-2004 to 2016-2017). First, we compared the narrow-sense heritabilities in the Obregon SEs and target sites and observed that the mean heritability in the SEs was 44.2% and 92.3% higher than the mean heritabilities in the SABWGPYT and ESWYT sites, respectively. Second, we observed significant GCs between a SE in Obregon and all the five SABWGPYT sites and 65.1% of the ESWYT sites, demonstrating the efficiency of indirect selection in the Obregon SEs. Third, we observed high ratios of response to indirect selection in the SEs of Obregon with a mean of 0.80 + 0.21 and 2.6 + 5.4 in the SABWGPYT and ESWYT sites, respectively. Furthermore, our results also indicated that for all the SABWGPYT sites and 82% of the ESWYT sites, a response greater than 0.5 can be achieved by indirect selection in Obregon. We also performed genomic prediction for GY in the target sites using the performance of the same lines in the SEs of Obregon and observed moderate mean prediction accuracies of 0.24 + 0.08 and 0.28 + 0.08 in the SABWGPYT and ESWYT sites, respectively using the genotype x environment (GxE) model. However, we observed similar accuracies using the baseline model with environment and line effects and no advantage of modeling GxE interactions. Overall, this study provides important insights into the suitability of the Obregon SEs in breeding for GY, while the variable genomic predictabilities of GY and the high year-to-year GY fluctuations reported, highlight the importance of multi-environment testing across time and space to stave off GxE induced uncertainties in varietal yields.

IntroductionSialorrhoea is a debilitating symptom in neurological disease and there is a growing literature for the use of intrasalivary gland Botulinum Toxin (botox) injections in its management. However, provision of intrasalivary gland botox remains inconsistent and sialorrhoea is often poorly controlled in motor neuron disease (MND).Sialorrhoea in association with bulbar dysfunction can cause intolerance of non-invasive ventilation (NIV) and respiratory infection, so its treatment is critical within a home ventilation service (HVS).This treatment can also be used to enable tracheostomy cuff deflation to facilitate weaning from ventilation. We report on the outcomes of intrasalivary gland botox in our HVS.MethodsIn 2015, we set up an intrasalivary gland botox service for patients under our HVS. Under ultrasound guidance, we injected submandibular gland(SMG), parotid gland (PG) or both.Results109 intrasalivary gland botox procedures were performed in 72 patients. Diagnostic groups included MND 32Cerebral Palsy 8 and Weaning 14. Glands injected were, SMG (6%), PG (47%) and both (47%). The majority (84%) received the Dysport preparation with mean dose 273 units. 94% were ultrasound guided. 81% of injections resulted in a positive treatment effect, with 47% patients requesting repeat injections. Complications were angioedema (0.9%) and worsening dysphagia (3.7% following SMG injection). Mean survival following treatment was 40 months with 53% patients still alive.ConclusionsIntrasalivary gland botox appears effective across a range of neurological conditions requiring long-term NIV with few complications. Dysphagia may be an important complication of SMG injection. A randomised controlled trial may help establish the evidence base.

A one-pot protocol for the dearomatizing spirocyclization/cross-coupling of alkyne-tethered indoles/pyrroles is described. Mechanistic studies support a process by which palladium complexes generated in situ act as both π-acid and cross-coupling catalysts. Overall, this facilitates an efficient cascade process that enables the simultaneous preparation of synthetically challenging quaternary spirocyclic carbons and tetrasubstituted alkenes in a single operation.

A comprehensive understanding of the population structure and genetic diversity of potential germplasm is necessary for making breeding decisions and to fully interpret marker-trait associations. The purpose of this study was to examine the genetic diversity and population structure of a panel of 194 synthetic hexaploid-derived wheat (SHW; Triticum aestivum L.) accessions using 6904 polymorphic single nucleotide polymorphism (SNP) markers. Ancestry-based dissimilarity indices and marker-based genetic distances were positively correlated (r = 0.67). The variation in the primary synthetic parent in the pedigrees accounted for 4.52%, while the degree of the synthetic contribution accounted for only 1.06% of variation in the genetic distance. In addition, variation in the Aegilops tauschii Coss. (syn. Aegilops squarrosa auct. non L.) accession and T. turgidum accession used in the initial cross accounted for 3.48% and 2.75% of the variation in genetic distance, respectively. Using a model-based population structure approach, seven sub-populations were identified in the panel. Results of the model-based population structure analysis was for the most part in agreement with the distance-based clustering using unweighted pair group method with arithmetic mean (UPGMA) of the genetic distance or ancestry data and the principle component analysis of relatedness. We conclude that using a model-based approach provides a more statistically robust estimation of population structure. Results of this study, while highlighting the potential contribution of introgressed genome in the panel, provide the foundation for employing this panel in genome-wide association studies.

Development of winter wheat (Triticum aestivum) synthetics started at CIMMYT-Mexico in 2004, when winter durum wheat (Triticum turgidum) germplasm from Ukraine and Romania was crossed with Aegilops tauschii accessions from the Caspian Sea region. Chromosomes were doubled after pollination and embryo rescue, but chromosome number and cytological validation was not performed. F2 populations were grown in Mexico and were shipped to Turkey in 2008. During 2009–2015, these populations were subjected to rigorous pedigree selection under dry, cold, disease-affected environments of the Central Anatolian Plateau. The wide segregation and partial sterility observed in 2009 gradually decreased and, by 2016, most of the F8 single spike progenies demonstrated good fertility and agronomic performance. Since 2013, lines have been selected from synthetic populations and evaluated at multiple sites. Superior lines were characterized for resistance to leaf, stripe and stem rust, plant height, and reaction to common bunt and soil-borne pathogens. Thousand kernel weight of many lines exceeded 50 g, compared with the check varieties that barely reached 40 g. Threshability of synthetic lines varied from 0 to 95%, demonstrating genetic variation for this important domestication trait. Screening against Hessian fly, sunny pest and Russian wheat aphid identified several resistant genotypes. Both durum and Aegilops parents affected synthetic wheat traits. Several studies are underway to reveal the genetic diversity of synthetic lines and the basis of resistance to diseases and insects. This synthetic germplasm represents a new winter bread wheat parental pool. It is available upon request to interested breeding/research programmes.

Mechanistic disease stratification will be crucial to develop a precision medicine approach for future disease modifying therapy in sporadic Parkinson’s disease (sPD). Mitochondrial and lysosomal dysfunction are key mechanisms in the pathogenesis of sPD and therefore promising targets for therapeutic intervention. We investigated mitochondrial and lysosomal function in skin fibroblasts of 100 sPD patients and 50 age-matched controls. A combination of cellular assays, RNA-seq based pathway analysis and genotyping was applied. Distinct subgroups with mitochondrial (mito-sPD) or lysosomal (lyso-sPD) dysfunction were identified. Mitochondrial dysfunction correlated with reduction in complex I and IV protein levels. RNA-seq based pathway analysis revealed marked activation of the lysosomal pathway with enrichment for lysosomal disease gene variants in lyso-sPD. Conversion of fibroblasts to induced neuronal progenitor cells and subsequent differentiation into tyrosine hydroxylase positive neurons confirmed and further enhanced both mitochondrial and lysosomal abnormalities. Treatment with ursodeoxycholic acid improved mitochondrial membrane potential and intracellular ATP levels even in sPD patient fibroblast lines with comparatively mild mitochondrial dysfunction. The results of our study suggest that in-depth phenotyping and focussed assessment of putative neuroprotective compounds in peripheral tissue are a promising approach towards disease stratification and precision medicine in sPD.

Introduction PDAC is increasing in incidence and has the worst survival of any malignancy. Lifestyle choices to reduce risk, based on robust evidence, are required. There are plausible biological mechanisms for how a moderate intake of alcohol (UK recommendations of ≤14 units/week) could prevent PDAC. These are alcohol: mitigating against pathological effects of KRAS genetic mutations, decreasing excess mitogenic insulin secretion, and the effects of antioxidants in alcoholic drinks. These mechanisms must be supported by robust epidemiological data to infer causality. The aim of this work is to systematically review prospective cohort studies, selected according to predefined criteria, to assess if a moderate alcohol consumption is inversely associated with PDAC risk. Cohort studies minimise biases inherent in other observational methodologies. Methods Medline, PubMed and EMBASE electronic databases were searched for prospective cohort studies investigating a moderate alcohol consumption and PDAC up to January 2019. The inclusion criteria were: >100 PDAC cases, definition of moderate consumption within UK guidelines, clear description of the comparator group, reporting effect sizes as risk/hazard ratios (RR/HR) and adjustment for covariates including: age, sex, smoking, body mass index and diabetes mellitus. Pooled effect sizes were calculated using an inverse variance random-effects model. Results Four prospective cohort studies meeting inclusion criteria were identified (9,090 PDAC cases, 57.5% female, mean age at diagnosis was 61.1 years). The cohorts were in the Netherlands, UK, pan-European and the US. The pooled effect size showed no association between a moderate alcohol consumption and PDAC risk (HR = 0.97, 95% CI; 0.91–1.03, I2 for heterogeneity 0.0%). There was no evidence of publication bias (Egger’s p = 0.404). Three cohorts investigated moderate intake of different beverages, reporting no association with either: wine (HR = 0.95, 95% CI; 0.83–1.09, I2 = 0.0%) beer (HR = 0.96, 95% CI; 0.79–1.17, I2 = 0.0%) or liquor (HR = 1.18, 95% CI, 0.89–1.57, I2 = 71.7%). There was no biological gradient within the moderate range. Conclusions The plausible biological mechanisms for a protective effect of alcohol are not supported by the epidemiological work. Drinking alcohol moderately cannot be recommended to decrease PDAC risk in the general population. Further research in a large prospective cohort which investigates risk in specific groups such as smokers and according to body mass index is required to see if alcohol may be beneficial in high risk groups for PDAC.

Matthew Thomas Payne’s chapter considers the role of franchise management through video games. He uses the case study of Nintendo’s NES and SNES micro-consoles. His essay posits that franchises can refer to both software and hardware, as the built-in games on Nintendo’s mini-consoles function as a form of franchise management and corporate canonizing by privileging certain video game texts over others.