Heterotopic ossification, osteolysis and implant failure following cervical total disc replacement with the M6-C™ artificial disc.

INTRODUCTION: A recent study reported a 34% mid-term revision rate after M6-C™ cervical total disc replacement (CTDR) for wear-related osteolysis. Here, we aim to investigate the prevalence, risk factors, and radiographic characteristics of periprosthetic bony changes and implant failure of the M6-C™ artificial disc. METHODS: We retrospectively analysed radiographic (conventional X-ray, CT scan) and clinical outcomes (EQ-5D-5L, Neck Disability Index (NDI), and Visual Analog Scale (VAS) for neck and arm pain) data collected during routine follow-up of patients who underwent CTDR with the M6-C™ between 2011 and 2015. RESULTS: In total, 85 patients underwent CTDR with the M6-C™. Follow-up data were available for 43 patients (54% female, mean age 44 years) with 50 implants and a mean follow-up of 8.1 years (6.5-11 years). Implant failure with the presence of severe osteolysis was identified in 5 (12%) patients who were all male (p = 0.016) and implanted at the C5/6 level (p = 0.11). All failed implants required revision surgery. The overall prevalence of osteolysis was 44% (22/50 implants) and 34% (17/50 implants) for significant heterotopic ossification. Patients with high-grade osteolysis showed higher VAS arm pain (p = 0.05) and lower EQ-5D-VAS health VAS (p = 0.03). CONCLUSION: We report a lower reoperation rate for failed M6-C™ implants than previously published, but confirmed that osteolysis and heterotopic ossification are common following CTDR with the M6-C™ and may be asymptomatic. Therefore, we strongly recommend ongoing clinical and radiographic monitoring after CTDR with the M6-C™, particularly for male patients implanted at the C5/6 level.

Modern medical schools curricula: Necessary innovations and priorities for change.

Medical schools' curricula have expanded over the decades to incorporate important new medical breakthroughs and discoveries. Their current focus and overall structures remain, however, stubbornly captive of early 20th-century thinking, with changes having been undertaken in a piecemeal fashion. Indeed, since the notable Flexner reform in 1910, medical schools' study plans have suffered successive and typically always partial adjustments which have failed to keep up with scientific, technological and sociological change. This difficulty may be attributable to the well-known conservatism of medical schools, where updating study plans is a process that invariably encounters numerous barriers to change. These observations were afforded detailed attention some 15 years ago when de Oliveira wrote: 'it is now perfectly demonstrated that public medical schools have not been able to adapt their operation in depth and in due time to the new demands of teaching dictated by an explosive scientific and technological development'. Recent advances in communication and information technologies, as well as the introduction of new pedagogical techniques, have the potential to bring significant benefits to medical practice and healthcare systems, but these have not in the main become properly taught and utilized. The proposition that healthcare is evolving from reactive disease care to care that is predictive, preventive, personalized and participatory was initially regarded as highly speculative, yet systems approaches to biology and medicine are now beginning to provide experience of both health and disease at the molecular, cellular and organ levels. Medicine is a broad scientific field. In contrast to the 19th century, current medical 'sectarianism' is a positive by-product of rapid and gratifying medical progress, and the multiplicity of new models means that the lines of evidence legitimately bearing on practice and health policymaking are already highly diverse and likely to become ever more variegated over time. Put simply, most sound decisions, by definition, will be evidence-informed and not evidence-based, where divergence may be as informative as convergence. Here, the most enduring lesson of history is, perhaps, that clinical medicine is constantly rediscovering its humanistic core. Complexities create opportunities for innovation. In innovative environments, high-performing organizations are finding ways to create a culture that supports a diverse workforce preparing to deliver different models of care, with direct implications for excellence of patient experience and strong repercussions for medical education. The COVID-19 crisis saw major increases in the use of telemedicine, virtual office visits and other forms of online contact, and these are likely to increase considerably. This particular transformation will not be easy or comfortable to make. But reconfiguration of medical education seems inevitable, fuelled by online educational technology and the need to transform clinical training to more outpatient settings with promotion based on competency and person-centeredness, not simply time. As we prepare to enter 2024, this is an exciting time to be working in healthcare. We have more evidence than ever about how to provide high quality, person-centered care, and to keep patients safe. Shame on us if there is any hesitation about applying this knowledge to make the healthcare experience better for patients and providers. Embracing change and making continuous improvements are essential and urgent priorities for medicine and healthcare and, as we describe in the current article, will become more and more indispensably important in our rapidly changing world.

DichroIDP: a method for analyses of intrinsically disordered proteins using circular dichroism spectroscopy.

Intrinsically disordered proteins (IDPs) are comprised of significant numbers of residues that form neither helix, sheet, nor any other canonical type of secondary structure. They play important roles in a broad range of biological processes, such as molecular recognition and signalling, largely due to their chameleon-like ability to change structure from unordered when free in solution to ordered when bound to partner molecules. Circular dichroism (CD) spectroscopy is a widely-used method for characterising protein secondary structures, but analyses of IDPs using CD spectroscopy have suffered because the methods and reference datasets used for the empirical determination of secondary structures do not contain adequate representations of unordered structures. This work describes the creation, validation and testing of a standalone Windows-based application, DichroIDP, and a new reference dataset, IDP175, which is suitable for analyses of proteins containing significant amounts of disordered structure. DichroIDP enables secondary structure determinations of IDPs and proteins containing intrinsically disordered regions.

Methods of crop improvement and applications towards fortifying food security.

Agriculture has supported human life from the beginning of civilization, despite a plethora of biotic (pests, pathogens) and abiotic (drought, cold) stressors being exerted on the global food demand. In the past 50 years, the enhanced understanding of cellular and molecular mechanisms in plants has led to novel innovations in biotechnology, resulting in the introduction of desired genes/traits through plant genetic engineering. Targeted genome editing technologies such as Zinc-Finger Nucleases (ZFNs), Transcription Activator-Like Effector Nucleases (TALENs), and Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) have emerged as powerful tools for crop improvement. This new CRISPR technology is proving to be an efficient and straightforward process with low cost. It possesses applicability across most plant species, targets multiple genes, and is being used to engineer plant metabolic pathways to create resistance to pathogens and abiotic stressors. These novel genome editing (GE) technologies are poised to meet the UN's sustainable development goals of "zero hunger" and "good human health and wellbeing." These technologies could be more efficient in developing transgenic crops and aid in speeding up the regulatory approvals and risk assessments conducted by the US Departments of Agriculture (USDA), Food and Drug Administration (FDA), and Environmental Protection Agency (EPA).

Beyond prosociality: Recalling many types of moral behavior produces positive emotion.

Prosocial acts can increase positive emotions and contribute to emotional well-being, but it is unclear whether other types of moral behavior have similar effects. Respondents from a large online sample (N = 1783) were randomly assigned to recall recent instances when they had performed moral, self-indulgent, or routine acts. Those who recalled self-indulgent behaviors or acts associated with care, fairness, loyalty, authority, and sanctity-based morality increased in positive emotions relative to routine acts controls. Initial evidence suggests that effects for recalling moral acts occurred in part because individuals who recalled these behaviors generated positive moral self-appraisals and satisfied a basic psychological need for relatedness. Study results are consistent with the recent claim that morality is a basic psychological need.

Using prosocial behavior to safeguard mental health and foster emotional well-being during the COVID-19 pandemic: A registered report of a randomized trial.

BACKGROUND: The COVID-19 pandemic, the accompanying lockdown measures, and their possible long-term effects have made mental health a pressing public health concern. Acts that focus on benefiting others-known as prosocial behaviors-offer one promising intervention that is both flexible and low cost. However, neither the range of emotional states prosocial acts impact nor the size of those effects is currently clear-both of which directly influence its attractiveness as a treatment option. OBJECTIVE: To assess the effect of prosocial activity on emotional well-being (happiness, belief that one's life is valuable) and mental health (anxiety, depression). METHODS: 1,234 respondents from the United States and Canada were recruited from Amazon's Mechanical Turk and randomly assigned (by computer software) to perform prosocial (N = 411), self-focused (N = 423), or neutral (N = 400) behaviors three times a week for three weeks. A follow-up assessment was given two weeks after the intervention. Participants were blind to alternative conditions. Analyses were based on 1052 participants (Nprosocial = 347, Nself = 365, Nneutral = 340). FINDINGS: Those in the prosocial condition did not differ on any outcome from those in the self-focused or neutral acts conditions during the intervention or at follow-up, nor did prosocial effects differ for those who had been negatively affected socially or economically by the pandemic (all p's > 0.05). Exploratory analyses that more tightly controlled for study compliance found that prosocial acts reduced anxiety relative to neutral acts control (ß = -0.12 [95% CI: -0.22 to -0.02]) and increased the belief that one's life is valuable (ß = 0.11 [95% CI: 0.03 to 0.19]). These effects persisted throughout the intervention and at follow-up. CONCLUSION: Prosocial acts may provide small, lasting benefits to emotional well-being and mental health. Future work should replicate these results using tighter, pre-registered controls on study compliance.

Discerning the global phylogeographic distribution of Phyllosticta citricarpa by means of whole genome sequencing.

Phyllosticta citricarpa is a fungal pathogen causing citrus black spot (CBS). As a regulated pest in some countries, the presence of the pathogen limits the export of fruit and is therefore of agricultural and economic importance. In this study, we used high throughput sequencing data to infer the global phylogeographic distribution of this pathogen, including 71 isolates from eight countries, Argentina, Australia, Brazil, China, Cuba, Eswatini, South Africa and the United States of America. We assembled draft genomes and used a pairwise read mapping approach for the detection and enumeration of variants between isolates. We performed SSR marker discovery based on the assembled genome with the best assembly statistics, and generated genotype profiles for all isolates with 1987 SSR markers in silico. Furthermore, we identified 32,560 SNPs relative to a reference sequence followed by population genetic analyses based on the three datasets; pairwise variant counts, SSR genotypes and SNP genotypes. All three analysis approaches gave similar overall results. Possible pathways of dissemination among the populations from China, Australia, southern Africa and the Americas are postulated. The Chinese population is the most diverse, and is genetically the furthest removed from all other populations, and is therefore considered the closest to the origin of the pathogen. Isolates from Australia, Eswatini and the South African province Mpumalanga are closely associated and clustered together with those from Argentina and Brazil. The Eastern Cape, North West, and KwaZulu-Natal populations in South Africa grouped in another cluster, while isolates from Limpopo are distributed between the two aforementioned clusters. Southern African populations showed a close relationship to populations in North America, and could be a possible source of P. citricarpa populations that are now found in North America. This study represents the largest whole genome sequencing survey of P. citricarpa to date and provides a more comprehensive assessment of the population genetic diversity and connectivity of P. citricarpa from different geographic origins. This information could further assist in a better understanding of the epidemiology of the CBS pathogen, its long-distance dispersal and dissemination pathways, and can be used to refine phytosanitary regulations and management programmes for the disease.

The T1-tetramerisation domain of Kv1.2 rescues expression and preserves function of a truncated NaChBac sodium channel.

Cytoplasmic domains frequently promote functional assembly of multimeric ion channels. To investigate structural determinants of this process, we generated the 'T1-chimera' construct of the NaChBac sodium channel by truncating its C-terminal domain and splicing the T1-tetramerisation domain of the Kv1.2 channel to the N terminus. Purified T1-chimera channels were tetrameric, conducted Na+ when reconstituted into proteoliposomes, and were functionally blocked by the drug mibefradil. Both the T1-chimera and full-length NaChBac had comparable expression levels in the membrane, whereas a NaChBac mutant lacking a cytoplasmic domain had greatly reduced membrane expression. Our findings support a model whereby bringing the transmembrane regions into close proximity enables their tetramerisation. This phenomenon is found with other channels, and thus, our findings substantiate this as a common assembly mechanism.

The PCDDB (Protein Circular Dichroism Data Bank): A Bioinformatics Resource for Protein Characterisations and Methods Development.

The Protein Circular Dichroism Data Bank (PCDDB) [https://pcddb.cryst.bbk.ac.uk] is an established resource for the biological, biophysical, chemical, bioinformatics, and molecular biology communities. It is a freely-accessible repository of validated protein circular dichroism (CD) spectra and associated sample and metadata, with entries having links to other bioinformatics resources including, amongst others, structure (PDB), AlphaFold, and sequence (UniProt) databases, as well as to published papers which produced the data and cite the database entries. It includes primary (unprocessed) and final (processed) spectral data, which are available in both text and pictorial formats, as well as detailed sample and validation information produced for each of the entries. Recently the metadata content associated with each of the entries, as well as the number and structural breadth of the protein components included, have been expanded. The PCDDB includes data on both wild-type and mutant proteins, and because CD studies primarily examine proteins in solution, it also contains examples of the effects of different environments on their structures, plus thermal unfolding/folding series. Methods for both sequence and spectral comparisons are included. The data included in the PCDDB complement results from crystal, cryo-electron microscopy, NMR spectroscopy, bioinformatics characterisations and classifications, and other structural information available for the proteins via links to other databases. The entries in the PCDDB have been used for the development of new analytical methodologies, for interpreting spectral and other biophysical data, and for providing insight into structures and functions of individual soluble and membrane proteins and protein complexes.

DichroWeb, a website for calculating protein secondary structure from circular dichroism spectroscopic data.

Circular dichroism (CD) spectroscopy is a widely-used method for characterizing the secondary structures of proteins. The well-established and highly used analysis website, DichroWeb (located at: http://dichroweb.cryst.bbk.ac.uk/html/home.shtml) enables the facile quantitative determination of helix, sheet, and other secondary structure contents of proteins based on their CD spectra. DichroWeb includes a range of reference datasets and algorithms, plus graphical and quantitative methods for determining the quality of the analyses produced. This article describes the current website content, usage and accessibility, as well as the many upgraded features now present in this highly popular tool that was originally created nearly two decades ago.

College and the "Culture War": Assessing Higher Education's Influence on Moral Attitudes.

Moral differences contribute to social and political conflicts. Against this backdrop, colleges and universities have been criticized for promoting liberal moral attitudes. However, direct evidence for these claims is sparse, and suggestive evidence from studies of political attitudes is inconclusive. Using four waves of data from the National Study of Youth and Religion, we examine the effects of higher education on attitudes related to three dimensions of morality that have been identified as central to conflict: moral relativism, concern for others, and concern for social order. Our results indicate that higher education liberalizes moral concerns for most students, but it also departs from the standard liberal profile by promoting moral absolutism rather than relativism. These effects are strongest for individuals majoring in the humanities, arts, or social sciences, and for students pursuing graduate studies. We conclude with a discussion of the implications of our results for work on political conflict and moral socialization.

Effect of parachute delivery on red blood cell (RBC) and plasma quality measures of blood for transfusion.

BACKGROUND: Parachute airdrop offers a rapid transfusion supply option for humanitarian aid and military support. However, its impact on longer-term RBC survival is undocumented. This study aimed to determine post-drop quality of RBCs in concentrates (RCC), and both RBCs and plasma in whole blood (WB) during subsequent storage. STUDY DESIGN AND METHODS: Twenty-two units of leucodepleted RCC in saline, adenine, glucose, mannitol (SAGM) and 22 units of nonclinical issue WB were randomly allocated for air transportation, parachute drop, and subsequent storage (parachute), or simply storage under identical conventional conditions (4 ± 2°C) (control). All blood products were 6-8 days post-donation. Parachute units were packed into Credo Cubes, (Series 4, 16 L) inside a PeliCase (Peli 0350) and rigged as parachute delivery packs. Packs underwent a 4-h tactical flight (C130 aircraft), then parachuted from 250 to 400 ft before ground recovery. The units were sampled aseptically before and after airdrop at weekly intervals. A range of assays quantified the RBC storage lesion and coagulation parameters. RESULTS: Blood units were maintained at 2-6°C and recovered intact after recorded ground impacts of 341-1038 m s-2 . All units showed a classical RBC storage lesion and increased RBC microparticles during 42 days of storage. Fibrinogen and clotting factors decreased in WB during storage. Nevertheless, no significant difference was observed between Control and Parachute groups. Air transportation and parachute delivery onto land did not adversely affect, or shorten, the shelf life of fresh RBCs or WB. DISCUSSION: Appropriately packaged aerial delivery by parachute can be successfully used for blood supply.

Using prosocial behavior to safeguard mental health and foster emotional well-being during the COVID-19 pandemic: A registered report protocol for a randomized trial.

The COVID-19 pandemic, the accompanying lockdown measures, and their possible long-term effects have made mental health a pressing public health concern. Acts that focus on benefiting others-known as prosocial behaviors-offer one promising intervention that is both flexible and low cost. However, neither the range of emotional states prosocial acts impact nor the size of those effects is currently clear, both of which directly influence its attractiveness as a treatment option. Using a large online sample from Canada and the United States, we will examine the effect of a three-week prosocial intervention on two indicators of emotional well-being (happiness and the belief that one's life is valuable) and mental health (anxiety and depression). Respondents will be randomly assigned to perform prosocial, self-focused, or neutral behaviors each week. Two weeks after the intervention, a final survey will assess whether the intervention has a lasting effect on mental health and emotional well-being. Our results will illuminate whether prosocial interventions are a viable approach to addressing mental health needs during the current COVID-19 pandemic, as well for those who face emotional challenges during normal times.

Inoculum Dynamics and Infection of Citrus Fruit by Phyllosticta citricarpa.

Citrus black spot, caused by Phyllosticta citricarpa, is characterized by fruit blemishes and premature fruit drop, resulting in significant economic losses in summer rainfall areas. The pathogen forms both conidia and ascospores during its life cycle. However, the occurrence of these spores and their contributions to infection of fruit in field conditions are not well understood. Our research using direct leaf litter monitoring and volumetric spore trapping in Queensland orchards revealed that pseudothecia and ascospores in leaf litter as well as trapped ascospores had low abundance, while pycnidia and conidia were highly abundant. Both P. citricarpa and endophytic Phyllosticta spp. were identified, with P. citricarpa being dominant. In replicated field trials, we determined that infection of Imperial mandarin fruit by P. citricarpa occurred from fruit set until week 20 of fruit development, with the key infection events taking place between weeks 4 and 16 in Queensland subtropical conditions. These results demonstrate that protecting fruit during weeks 4 to 16 significantly reduced P. citricarpa infection. We found no significant correlation between the disease incidence in fruit and P. citricarpa conidial abundance in leaf litter or ascospore abundance measured by volumetric spore trapping. Therefore, it is suggested that inoculum sources in the tree canopy other than those detected by spore trapping and direct leaf litter monitoring may play a major role in the epidemiology of citrus black spot. Improved knowledge regarding epidemiology of P. citricarpa and an understanding of propagules causing infection may aid in development of more effective disease management strategies.

Valproic acid interactions with the NavMs voltage-gated sodium channel.

Valproic acid (VPA) is an anticonvulsant drug that is also used to treat migraines and bipolar disorder. Its proposed biological targets include human voltage-gated sodium channels, among other membrane proteins. We used the prokaryotic NavMs sodium channel, which has been shown to be a good exemplar for drug binding to human sodium channels, to examine the structural and functional interactions of VPA. Thermal melt synchrotron radiation circular dichroism spectroscopic binding studies of the full-length NavMs channel (which includes both pore and voltage sensor domains), and a pore-only construct, undertaken in the presence and absence of VPA, indicated that the drug binds to and destabilizes the channel, but not the pore-only construct. This is in contrast to other antiepileptic compounds that have previously been shown to bind in the central hydrophobic core of the pore region of the channel, and that tend to increase the thermal stability of both pore-only constructs and full-length channels. Molecular docking studies also indicated that the VPA binding site is associated with the voltage sensor, rather than the hydrophobic cavity of the pore domain. Electrophysiological studies show that VPA influences the block and inactivation rates of the NavMs channel, although with lower efficacy than classical channel-blocking compounds. It thus appears that, while VPA is capable of binding to these voltage-gated sodium channels, it has a very different mode and site of action than other anticonvulsant compounds.

A service evaluation of specialist nurse telephone follow-up of bowel cancer patients after surgery.

INTRODUCTION: the NHS Long Term Plan has called for a reduction in the number of outpatient appointments to reduce pressure on hospital services and increase ease of access for patients. This article presents a service evaluation of an innovative, nurse-led telephone follow-up service for a group of elective bowel cancer patients following surgery. METHODS: the records of patients who underwent surgery over a 2-year period were accessed to determine the number of telephone follow-ups and other investigations. This was used to model the potential cost saving for commissioners against traditional clinic follow-up. Patient satisfaction was assessed by the European Organisation for Research and Treatment of Cancer questionnaire on Outpatient Satisfaction in 30 patients. RESULTS: feedback on the service was overwhelmingly positive, with patients praising the care received from the specialist nurses, but also commenting on increased continuity of care, ease of access and convenience. The service also potentially creates significant savings for commissioners as the agreed tariff for nurse telephone follow-up is significantly less than the outpatient tariff. DISCUSSION: this innovative follow-up system is well liked by patients and should provide savings for commissioners. The hospital also benefits from an increase in capacity to see new or more unwell patients, and a reduction in carbon emissions. Such a service, however, is dependent on people, and although it has functioned effectively in this department for approximately 20 years, it would only be generalisable to other units if staff had appropriate expertise.