Midfoot Fusion Using Superconstructs for the Charcot Foot: Current Techniques and Complications.

Neuroarthropathy of the foot and ankle presents a series of challenges. The treating physician faces a perfect storm of pathomechanics, deformity, and medical comorbidities. Successful treatment requires a systematic approach in diagnosis, nonsurgical management, surgical management, and long-term maintenance of the affected extremity. Nonsurgical care of the Charcot foot remains the mainstay of treatment and is successful in most cases. Surgery has become more accepted for patients with severe deformity. The concept of a superconstruct has been introduced to describe modern surgical techniques and implants that have been developed since the early 2000s where stability and durability are maximized. A superconstruct is defined by four factors: (1) fusion is extended beyond the zone of injury to bridge the area of bony dissolution; (2) aggressive bone resection is performed to allow for adequate reduction of deformity without undue tension on the soft-tissue envelope; (3) stronger implants are used than for nonneuropathic fusion procedures, including some specifically developed for fixation of the Charcot foot; and (4) the devices are applied in a position that maximizes mechanical stability to allow the implants to become load sharing. It is important to review the current techniques and implants used in fusion of the neuropathic midfoot and discuss the expected outcomes and complications based on the authors' experience.

Management of Acute Ankle Fractures in Patients With Diabetes.

Ankle fractures in patients with diabetes can be difficult to manage, especially when patients present with hyperglycemia. Treatment often requires a combination of both medical and surgical care, especially in patients with poorly controlled diabetes. The goal of any treatment is to obtain a well-aligned ankle fracture that heals without any further displacement and to avoid the development of a Charcot joint. Nonsurgical treatment is usually reserved for nondisplaced fractures. Displaced fractures often require surgical treatment, and there are different options available, including standard fixation, fixation with multiple syndesmotic screw placement, external (thin wire) fixation alone, hybrid or combined internal and external fixation techniques, and primary arthrodesis. It is important to discuss the approach to the evaluation and treatment of these patients.

COVID-19 and the Motorcycle Taxi Sector in Sub-Saharan African Cities: A Key Stakeholders' Perspective.

This article assesses the impact of the COVID-19 outbreak on the urban motorcycle taxi (MCT) sector in Sub-Saharan Africa (SSA). MCT operators in SSA provide essential transport services and have shown ingenuity and an ability to adapt and innovate when responding to different challenges, including health challenges. However, policymakers and regulators often remain somewhat hostile toward the sector. The article discusses the measures and restrictions put in place to reduce the spread of COVID-19 and key stakeholders' perspectives on these and on the sector's level of compliance. Primary data were collected in six SSA countries during the last quarter of 2020. Between 10 and 15 qualitative interviews with key stakeholders relevant to the urban MCT sector were conducted in each country. These interviews were conducted with stakeholders based in the capital city and a secondary city, to ensure a geographically broader understanding of the measures, restrictions, and perspectives. The impact of COVID-19 measures on the MCT and motor-tricycle taxi sector was significant and overwhelmingly negative. Lockdowns, restrictions on the maximum number of passengers allowed to be carried at once, and more generally, a COVID-19-induced reduction in demand, resulted in a drop in income for operators, according to the key stakeholders. However, some key stakeholders indicated an increase in MCT activity and income because of the motorcycles' ability to bypass police and army controls. In most study countries measures were formulated in a non-consultative manner. This, we argue, is symptomatic of governments' unwillingness to seriously engage with the sector.

Conducting evaluations of evidence that are transparent, timely and can lead to health-protective actions.

BACKGROUND: In February 2021, over one hundred scientists and policy experts participated in a web-based Workshop to discuss the ways that divergent evaluations of evidence and scientific uncertainties are used to delay timely protection of human health and the environment from exposures to hazardous agents. The Workshop arose from a previous workshop organized by the European Environment Agency (EEA) in 2008 and which also drew on case studies from the EEA reports on 'Late Lessons from Early Warnings' (2001, 2013). These reports documented dozens of hazardous agents including many chemicals, for which risk reduction measures were delayed for decades after scientists and others had issued early and later warnings about the harm likely to be caused by those agents. RESULTS: Workshop participants used recent case studies including Perfluorooctanoic acid (PFOA), Extremely Low Frequency - Electrical Magnetic Fields (ELF-EMF fields), glyphosate, and Bisphenol A (BPA) to explore myriad reasons for divergent outcomes of evaluations, which has led to delayed and inadequate protection of the public's health. Strategies to overcome these barriers must, therefore, at a minimum include approaches that 1) Make better use of existing data and information, 2) Ensure timeliness, 3) Increase transparency, consistency and minimize bias in evidence evaluations, and 4) Minimize the influence of financial conflicts of interest. CONCLUSION: The recommendations should enhance the production of "actionable evidence," that is, reliable evaluations of the scientific evidence to support timely actions to protect health and environments from exposures to hazardous agents. The recommendations are applicable to policy and regulatory settings at the local, state, federal and international levels.

An in silico proteomics screen to predict and prioritize protein-protein interactions dependent on post-translationally modified motifs.

Motivation: The development of proteomic methods for the characterization of domain/motif interactions has greatly expanded our understanding of signal transduction. However, proteomics-based binding screens have limitations including that the queried tissue or cell type may not harbor all potential interacting partners or post-translational modifications (PTMs) required for the interaction. Therefore, we sought a generalizable, complementary in silico approach to identify potentially novel motif and PTM-dependent binding partners of high priority. Results: We used as an initial example the interaction between the Src homology 2 (SH2) domains of the adaptor proteins CT10 regulator of kinase (CRK) and CRK-like (CRKL) and phosphorylated-YXXP motifs. Employing well-curated, publicly-available resources, we scored and prioritized potential CRK/CRKL-SH2 interactors possessing signature characteristics of known interacting partners. Our approach gave high priority scores to 102 of the >9000 YXXP motif-containing proteins. Within this 102 were 21 of the 25 curated CRK/CRKL-SH2-binding partners showing a more than 80-fold enrichment. Several predicted interactors were validated biochemically. To demonstrate generalized applicability, we used our workflow to predict protein-protein interactions dependent upon motif-specific arginine methylation. Our data demonstrate the applicability of our approach to, conceivably, any modular binding domain that recognizes a specific post-translationally modified motif. Supplementary information: Supplementary data are available at Bioinformatics online.

Thermal reactionomes reveal divergent responses to thermal extremes in warm and cool-climate ant species.

BACKGROUND: The distributions of species and their responses to climate change are in part determined by their thermal tolerances. However, little is known about how thermal tolerance evolves. To test whether evolutionary extension of thermal limits is accomplished through enhanced cellular stress response (enhanced response), constitutively elevated expression of protective genes (genetic assimilation) or a shift from damage resistance to passive mechanisms of thermal stability (tolerance), we conducted an analysis of the reactionome: the reaction norm for all genes in an organism's transcriptome measured across an experimental gradient. We characterized thermal reactionomes of two common ant species in the eastern U.S, the northern cool-climate Aphaenogaster picea and the southern warm-climate Aphaenogaster carolinensis, across 12 temperatures that spanned their entire thermal breadth. RESULTS: We found that at least 2 % of all genes changed expression with temperature. The majority of upregulation was specific to exposure to low temperatures. The cool-adapted A. picea induced expression of more genes in response to extreme temperatures than did A. carolinensis, consistent with the enhanced response hypothesis. In contrast, under high temperatures the warm-adapted A. carolinensis downregulated many of the genes upregulated in A. picea, and required more extreme temperatures to induce down-regulation in gene expression, consistent with the tolerance hypothesis. We found no evidence for a trade-off between constitutive and inducible gene expression as predicted by the genetic assimilation hypothesis. CONCLUSIONS: These results suggest that increases in upper thermal limits may require an evolutionary shift in response mechanism away from damage repair toward tolerance and prevention.

The chemistry of ynol and thioynol ethers.

Alkynyl ethers and alkynyl thioethers ('ynol ethers' and 'thioynol ethers') are appealing building-blocks in synthetic chemistry due to their ease of manipulation and predictable reactivity. Until recently however, their potential has remained underexploited due to difficulties in preparation and isolation. Although recent advances in synthetic chemistry have highlighted various applications for ynol ethers, the equivalent thioynol examples have been rather less exploited despite a unique and fascinating reactivity profile. Although superficially the chemistry of alkynyl ethers and their sulfide counterparts are similar, close examination of their chemistry reveals important differences which can be exploited by the synthetic chemist. This review will examine the preparation of both classes of compound and examine their reactivity to highlight their powerful synthetic applications. Particular focus will be made of thiynol ethers whose chemistry exhibits some fascinating differences compared to their oxygen counterparts and have immense untapped potential for synthetic chemistry.

Transition-metal-free synthesis of ynol ethers and thioynol ethers via displacement at sp centers: a revised mechanistic pathway.

We present here valuable extensions to our previous work in preparing highly functionalized, heteroatom-substituted alkynes via displacement at an sp center. Our results show that a wide range of ynol ethers can be prepared by the same methodology and that the same protocol can be applied to the synthesis of synthetically useful thioynol ethers. We also present new observations that have led us to revise our original hypothesis in favor of a pathway involving radical intermediates.

Introduction of the Capsules environment to support further growth of the SBGrid structural biology software collection.

The expansive scientific software ecosystem, characterized by millions of titles across various platforms and formats, poses significant challenges in maintaining reproducibility and provenance in scientific research. The diversity of independently developed applications, evolving versions and heterogeneous components highlights the need for rigorous methodologies to navigate these complexities. In response to these challenges, the SBGrid team builds, installs and configures over 530 specialized software applications for use in the on-premises and cloud-based computing environments of SBGrid Consortium members. To address the intricacies of supporting this diverse application collection, the team has developed the Capsule Software Execution Environment, generally referred to as Capsules. Capsules rely on a collection of programmatically generated bash scripts that work together to isolate the runtime environment of one application from all other applications, thereby providing a transparent cross-platform solution without requiring specialized tools or elevated account privileges for researchers. Capsules facilitate modular, secure software distribution while maintaining a centralized, conflict-free environment. The SBGrid platform, which combines Capsules with the SBGrid collection of structural biology applications, aligns with FAIR goals by enhancing the findability, accessibility, interoperability and reusability of scientific software, ensuring seamless functionality across diverse computing environments. Its adaptability enables application beyond structural biology into other scientific fields.

Clinical and research markers of oxidative stress in chronic kidney disease.

CONTEXT: Kidney-related pathologies have increasing prevalence rates, produce a considerable financial burden, and are characterized by elevated levels of oxidative stress (OS). OBJECTIVE: This review examines relationships between chronic kidney disease (CKD) and markers of OS and antioxidant status (AS). METHODS: A systematic review of MEDLINE-indexed clinical trials, randomized controlled trials and comparative studies that examined OS and AS was performed. RESULTS AND CONCLUSION: Several markers emerged as well-suited indicators of OS and AS in CKD: malondialdehyde, F2-isoprostanes, lipid hydroperoxides, asymmetric dimethylarginine, 8-oxo-7,8-dihydro-2'-deoxyguanosine, protein carbonyls, advanced oxidation protein products and glutathione-related activity.

Comparative phosphoproteomic analysis of neonatal and adult murine brain.

Developmental processes are governed by diverse regulatory mechanisms including a suite of signaling pathways employing reversible phosphorylation. With the advent of large-scale phosphoproteomics, it is now possible to identify thousands of phosphorylation sites from tissues at distinct developmental stages. We describe here the identification of over 6000 nonredundant phosphorylation sites from neonatal murine brain. When compared to nearly three times the number of phosphorylation sites identified from 3-week-old murine brain, remarkably one-third of the neonatal sites were unique. This fraction only dropped to one-quarter when allowing the site to stray plus or minus 15 residues. This provides evidence for considerable change in the profiles of developmentally regulated phosphoproteomes. Using quantitative MS we characterized a novel phosphorylation site (Ser265) identified uniquely in the neonatal brain on doublecortin (Dcx), a protein essential for proper mammalian brain development. While the relative levels of Dcx and phospho-Ser265 Dcx between embryonic and neonatal brain were similar, their levels fell precipitously by postnatal day 21, as did phospho-Ser297, a site required for proper neuronal migration. Both sites lie near the microtubule-binding domain and may provide functionally similar regulation via different kinases.

Performance study of personal inhalable aerosol samplers at ultra-low wind speeds.

The assessment of personal inhalable aerosol samplers in a controlled laboratory setting has not previously been carried out at the ultra-low wind speed conditions that represent most modern workplaces. There is currently some concern about whether the existing inhalable aerosol convention is appropriate at these low wind speeds and an alternative has been suggested. It was therefore important to assess the performance of the most common personal samplers used to collect the inhalable aerosol fraction, especially those that were designed to match the original curve. The experimental set-up involved use of a hybrid ultra-low speed wind tunnel/calm air chamber and a rotating, heating breathing mannequin to measure the inhalable fraction of aerosol exposure. The samplers that were tested included the Institute of Occupational Medicine (IOM), Button, and GSP inhalable samplers as well as the closed-face cassette sampler that has been (and still is) widely used by occupational hygienists in many countries. The results showed that, down to ∼0.2 m s(-1), the samplers matched the current inhalability criterion relatively well but were significantly greater than this at the lowest wind speed tested. Overall, there was a significant effect of wind speed on sampling efficiency, with lower wind speeds clearly associated with an increase in sampling efficiency.

Charcot foot: a surgical algorithm.

The historic treatment of Charcot foot has entailed non-weight-bearing immobilization during the acute active phase, followed by longitudinal management with accommodative bracing. This treatment plan yields poor outcomes, even in cases classified as successful. An appreciation of poor outcomes convinced experts to attempt correction of the resultant deformities. Early attempts at surgical correction of the acquired deformities in patients with medical comorbidities were complicated by infection, wound failure, and mechanical loss of correction. New surgical techniques have been designed to obtain and maintain correction and minimize the risks for complications and poor outcomes in this complex patient population.

Occupational and environmental aerosol exposure assessment: a scientific journey from the past, through the present and into the future.

This paper reviews how aerosol exposure assessment, for people in both working and living environments, has evolved over the years. It charts the main scientific developments that led to progressively improved ways of thinking and methods to assess exposure to airborne particulate matter in a manner more relevant to human health. It has been a long scientific journey as one generation of pioneering contributors has handed off to the next. In the process a consistent rationale has emerged, producing aerosol sampling criteria--and in turn exposure standards--which have been increasingly relevant to actual human exposures. The journey continues as a new generation of scientists steps up to deal with the new challenges that are emerging. An appreciation of the history of what went before is essential to charting the most effective path looking forward.

Proposed modification to the inhalable aerosol convention applicable to realistic workplace wind speeds.

The current convention for sampling inhalable aerosols was based on several mannequin studies performed in wind tunnels at wind speeds between 0.5 and 4 m s(-1). In reality, as we now know, the wind speed in most modern indoor working environments is generally at or below ∼0.2 m s(-1). Inhalability studies performed in calm air aerosol chambers have shown that human aspiration efficiency at essentially zero wind speed is not consistent with the existing inhalable aerosol convention, calling into question the universal applicability of the current standard. More recently, experiments were carried out in a new hybrid wind tunnel-calm air chamber at more representative workplace wind speeds, between ∼0.1 and 0.5 m s(-1), to fill in this knowledge gap. Comparing these new data to both the existing inhalable aerosol convention and a recently proposed alternative for low wind movement suggests that, while the existing inhalable aerosol convention remains appropriate for wind speeds above ∼0.2 m s(-1), the modified version is more appropriate for the range below ∼0.2 m s(-1).

Sampling conventions for estimating ultrafine and fine aerosol particle deposition in the human respiratory tract.

OBJECTIVES: To provide targets for personal samplers designed for estimating particle deposition at distinct locations in the body, accounting if necessary for inter- and intra-person variation. PROPOSAL: Ultrafine and fine aerosol sampling conventions are proposed for approximating the deposition efficiency for five distinct loci of the respiratory tract. The 2 × 5 = 10 conventions represent averages over variation in physical activity level, posture, sex, and breathing mode. Recognizing three approximate relationships among the 10 deposition efficiencies, the number of independent conventions is reduced to only seven, namely three ultrafine and four fine aerosol conventions. The ultrafine and fine conventions are defined as ideal sampling efficiencies in terms of thermodynamic (independent of particle density) and aerodynamic diameter, respectively. APPLICATION: Addition of measured mass, surface area, or particle count from aerosol collected by sampler pairs in agreement with convention can be used to estimate dose (prior to clearance) at a particular locus in the mean over breathing conditions ranging from sitting, to light, or to heavy exercise, normal or mouth breathing, and male or female, with aerosol density effects partially corrected automatically by the separate aerodynamic and thermodynamic sampling. Linear combinations of the conventions can be used for yet simpler sampling, though with limited distinctness as to deposition locus. Alternatively to estimating simply a mean, the large inter- and intra-person variation (relative standard deviation of the order of 100%) corresponding to the wide range of breathing conditions can be approximately corrected by using 'arrays' of samplers in agreement with convention, given suitable profiling of the individual whose dose is to be assessed. OUTCOME: The intent behind the proposed conventions is not to eliminate the current aerosol penetration conventions, which have found international application in exposure assessment particularly for determining compliance with standards on acceptable aerosol levels. The aim is to promote personal sampler design leading to more sharply defined health research than can be done at present.

Implementation of the International Academy of Cytology Yokohama standardized reporting for breast cytopathology: An 8-year retrospective study.

BACKGROUND: The International Academy of Cytology (IAC) Yokohama reporting system was recently proposed to serve as a standardized diagnostic platform for the cytological interpretation of breast fine needle aspiration biopsy (FNAB). Five cytological categories were suggested, linked to a certain risk of malignancy (ROM). The aim of this study was to assess the potency of this newly proposed reporting guideline, with a review of literatures. METHODS: This is a retrospective study over 8-year duration in which all the breast FNABs performed in our institution were recategorized in accordance to the IAC Yokohama reporting system. Kappa coefficient was used to evaluate the agreement between the proposed cytological category and corresponding histological diagnosis, with the level of significance set at 5%. Cyto-histopathological correlation and its diagnostic performance were also assessed. RESULTS: A total of 1136 breast FNABs were analyzed, including 31 repeat FNABs. Of these, 521 (47.1%) cases had matched histopathological results. Respective ROM for each category was: "insufficient" 13.6%, "benign" 0.4%, "atypical" 25.0%, "suspicious" 85.7%, and "malignant" 100%. There was substantial agreement (κ=0.757) between cytology and histopathological results. Our data revealed a high-diagnostic specificity, sensitivity, positive and negative predictive value of 99.3% (95% CI: 97.6%-99.9%), 94.2% (95% CI: 87.9%-97.9%), 98.0% (95% CI: 92.5%-99.5%), 98.0% (95% CI: 96.1%-99.1%) respectively when both the "suspicious" and "malignant" cases were considered as positive tests, with area under the curve of 0.993. CONCLUSIONS: The IAC Yokohama system is a reliable, evidence-based, and standardized reporting system that helps to facilitate communication among cytopathologists, radiologists, and surgeons toward individualized patient management.

Lasso stitch with peroneal retinaculoplasty for repair of fractured os peroneum: a report of two cases.

UNLABELLED: Fracture of the os peroneus with retraction of the peroneus longus tendon can lead to weakness, instability, and progressive foot deformity. Treatment recommendations vary and include simple immobilization, repair of the fractured ossicle, excision of part or all of the fractured ossicle with repair of the tendon and tenodesis with the peroneus brevis tendon. We present two patients treated with excision of the proximal fragment and repair of the tendon to the distal fragment with relief of pain and restoration of function. The distal fragment was captured with a looped suture which allowed avoidance of a plantar exposure while still achieving an adequate repair. We also describe a technique for retinaculoplasty of the inferior peroneal retinaculum which we believe important to prevent postoperative adhesions to the tendon. LEVEL OF EVIDENCE: Level V, expert opinion. See Guidelines for Authors for a complete description of levels of evidence.

SE: an algorithm for deriving sequence alignment from a pair of superimposed structures.

BACKGROUND: Generating sequence alignments from superimposed structures is an important part of many structure comparison programs. The accuracy of the alignment affects structure recognition, classification and possibly function prediction. Many programs use a dynamic programming algorithm to generate the sequence alignment from superimposed structures. However, this procedure requires using a gap penalty and, depending on the value of the penalty used, can introduce spurious gaps and misalignments. Here we present a new algorithm, Seed Extension (SE), for generating the sequence alignment from a pair of superimposed structures. The SE algorithm first finds "seeds", which are the pairs of residues, one from each structure, that meet certain stringent criteria for being structurally equivalent. Three consecutive seeds form a seed segment, which is extended along the diagonal of the alignment matrix in both directions. Distance and the amino acid type similarity between the residues are used to resolve conflicts that arise during extension of more than one diagonal. The manually curated alignments in the Conserved Domain Database were used as the standard to assess the quality of the sequence alignments. RESULTS: SE gave an average accuracy of 95.9% over 582 pairs of superimposed proteins tested, while CHIMERA, LSQMAN, and DP extracted from SHEBA, which all use a dynamic programming algorithm, yielded 89.9%, 90.2% and 91.0%, respectively. For pairs of proteins with low sequence or structural similarity, SE produced alignments up to 18% more accurate on average than the next best scoring program. Improvement was most pronounced when the two superimposed structures contained equivalent helices or beta-strands that crossed at an angle. When the SE algorithm was implemented in SHEBA to replace the dynamic programming routine, the alignment accuracy improved by 10% on average for structure pairs with RMSD between 2 and 4 A. SE also used considerably less CPU time than DP. CONCLUSION: The Seed Extension algorithm is fast and, without using a gap penalty, produces more accurate sequence alignments from superimposed structures than three other programs tested that use dynamic programming algorithm.

Meeting report: moving upstream-evaluating adverse upstream end points for improved risk assessment and decision-making.

BACKGROUND: Assessing adverse effects from environmental chemical exposure is integral to public health policies. Toxicology assays identifying early biological changes from chemical exposure are increasing our ability to evaluate links between early biological disturbances and subsequent overt downstream effects. A workshop was held to consider how the resulting data inform consideration of an "adverse effect" in the context of hazard identification and risk assessment. OBJECTIVES: Our objective here is to review what is known about the relationships between chemical exposure, early biological effects (upstream events), and later overt effects (downstream events) through three case studies (thyroid hormone disruption, antiandrogen effects, immune system disruption) and to consider how to evaluate hazard and risk when early biological effect data are available. DISCUSSION: Each case study presents data on the toxicity pathways linking early biological perturbations with downstream overt effects. Case studies also emphasize several factors that can influence risk of overt disease as a result from early biological perturbations, including background chemical exposures, underlying individual biological processes, and disease susceptibility. Certain effects resulting from exposure during periods of sensitivity may be irreversible. A chemical can act through multiple modes of action, resulting in similar or different overt effects. CONCLUSIONS: For certain classes of early perturbations, sufficient information on the disease process is known, so hazard and quantitative risk assessment can proceed using information on upstream biological perturbations. Upstream data will support improved approaches for considering developmental stage, background exposures, disease status, and other factors important to assessing hazard and risk for the whole population.