Advanced 3D Printing of Polyetherketoneketone Hydroxyapatite Composites via Fused Filament Fabrication with Increased Interlayer Connection.

Additively manufactured implants, surgical guides, and medical devices that would have direct contact with the human body require predictable behaviour when stress is applied during their standard operation. Products built with Fused Filament Fabrication (FFF) possess orthotropic characteristics, thus, it is necessary to determine the properties that can be achieved in the XY- and Z-directions of printing. A concentration of 10 wt% of hydroxyapatite (HA) in polyetherketoneketone (PEKK) matrix was selected as the most promising biomaterial supporting cell attachment for medical applications and was characterized with an Ultimate Tensile Strength (UTS) of 78.3 MPa and 43.9 MPa in the XY- and Z-directions of 3D printing, respectively. The effect of the filler on the crystallization kinetics, which is a key parameter for the selection of semicrystalline materials suitable for 3D printing, was explained. This work clearly shows that only in situ crystallization provides the ability to build parts with a more thermodynamically stable primary form of crystallites.

Gcn2 rescues reprogramming in the absence of Hog1/p38 signaling in C. neoformans during thermal stress.

The fungus Cryptococcus neoformans is an opportunistic pathogen of people that reprograms its translatome to facilitate adaptation and virulence within the host. We studied the role of Hog1/p38 in reprogramming translation during thermal stress adaptation, and found that this pathway acts on translation via crosstalk with the Gcn2 pathway, a well-studied regulator of general translation control. Using a combination of molecular assays and phenotypic analysis, we show that increased output from the Gcn2 pathway in a Hog1 deletion mutant is associated with rescue of thermal stress adaptation at both molecular and phenotypic scales. We characterize known outputs of the Hog1 pathway during thermal stress as either Gcn2-dependent or Gcn2-independent, and demonstrate that Hog1 activation regulates the Gcn2 pathway even in the absence of thermal stress. Finally, we implicate this phenomenon in another Hog1-regulated process, morphogenesis, and recapitulate Hog1-Gcn2 crosstalk in the distantly related fungal pathogen, Candida albicans. Our results point to an important link between the stress response machinery and translation control, and clarify the etiology of phenotypes associated with Hog1 deletion. More broadly, this study highlights complex interplay between core conserved signal transduction pathways and the utility of molecular assays to better understand how these pathways are connected.

SARS-CoV-2 ORF7a Mutation Found in BF.5 and BF.7 Sublineages Impacts Its Functions.

A feature of the SARS-CoV-2 Omicron subvariants BF.5 and BF.7 that recently circulated mainly in China and Japan was the high prevalence of the ORF7a: H47Y mutation, in which the 47th residue of ORF7a has been mutated from a histidine (H) to a tyrosine (Y). Here, we evaluated the effect of this mutation on the three main functions ascribed to the SARS-CoV-2 ORF7a protein. Our findings show that H47Y mutation impairs the ability of SARS-CoV-2 ORF7a to antagonize the type I interferon (IFN-I) response and to downregulate major histocompatibility complex I (MHC-I) cell surface levels, but had no effect in its anti-SERINC5 function. Overall, our results suggest that the H47Y mutation of ORF7a affects important functions of this protein, resulting in changes in virus pathogenesis.

Paediatric femoral shaft fractures: an instructional review for the FRCS examination.

This review presents the principal features of paediatric femoral shaft fractures including the contemporary management strategies and relevant supporting evidence. The article is an overview of information relevant to clinical practice, in addition to preparation for the FRCS (Orth) examination.

Long-term patient-centred outcomes of periacetabular osteotomy in a large consecutive series.

Aims: We assessed the long-term outcomes of a large cohort of patients who have undergone a periacetabular osteotomy (PAO), and sought to validate a patient satisfaction questionnaire for use in a PAO cohort. Methods: All patients who had undergone a PAO from July 1998 to February 2013 were surveyed, with several patient-reported outcome measures (PROMs) and radiological measurements of preoperative acetabular dysplasia and postoperative correction also recorded. Patients were asked to rate their level of satisfaction with their operation in achieving pain relief, restoration of activities of daily living, ability to perform recreational activity, and their overall level of satisfaction with the procedure. Results: A total of 143 PAOs were performed between 1998 and 2013. Of those, 90 postoperative surveys were returned. Only 65 patients (73 hips) had both pre- and postoperative radiographs available for measurement. The mean time to follow-up was 15 years (6.5 to 20). Most patients were female (91%), with a mean age of 26.4 years (14.9 to 48.3) at the time of their surgery. A statistically significant improvement in radiological correction was detected in all hips (p < 0.001). A total of 67 patients (92.3%) remained either very satisfied or satisfied with their PAO. The internal consistency of the patient satisfaction questionnaire, measured using Cronbach's α, ranged from 0.89 to 0.94 indicating 'good' to 'excellent' reliability. Conclusion: Outcomes of importance to patients undergoing a PAO include several key domains: pain relief, improve activities of daily living, and improve recreational ability. Our study demonstrates high rates of long-term patient satisfaction in all domains, and found the patient satisfaction questionnaire to be a valid and reliable instrument for use in this cohort.

Indigenous Women's Perspectives on Contraception in Rural Guatemala.

In rural, Indigenous Guatemala, women's healthcare is fragmented and inadequate. Our interdisciplinary, multinational research team aimed to 1) describe reproductive health in one rural Indigenous community; 2) explore contraceptive use; and 3) learn about and prioritize Indigenous Maya women's reproductive health beliefs and needs. Our study team conducted mixed-methods surveys with 62 women, led focus groups with 20 community health workers, and analyzed data using concurrent mixed methods analysis. We found that 51% of women surveyed reported current family planning, with 33% using a biomedical method. We found high mean fertility, 6.9 live births per woman aged 40-49 (national average 4.7), with significant socioeconomic variation. We also found that poverty correlated with total fertility, while education inversely correlated. Our research found that contraceptive use had a strong association with access to healthcare and with women's reported sexual autonomy (which we instrumentalized based on women's answers to the question "can you refuse to have sex with your husband?"). Many women we spoke to feared contraception, specifically concerned it could cause cancer. Overall, Guatemalan Indigenous women expressed unease seeking reproductive healthcare within health systems that have historically and currently excluded and mistreated Indigenous communities. Our research documented unexplored influences on contraceptive use, including the relationship between sexual autonomy and contraception and widespread concern of cancer with contraceptive use. We conclude, moving forward, that we and other researchers should continue to collaborate with communities to improve Indigenous women's reproductive healthcare.

Morphological transformation from fibers to sheets in embiopteran silk.

Embioptera (webspinners) are insects that construct domiciles using silk produced from their front feet. This silk is the finest known with measured single fiber diameters in the 30-140 nm range. In the wild, some webspinner silk on trees is observed to have a clothlike or shiny sheetlike appearance. Both forms of silk shield the occupants from rain water effectively: presumably valuable in tropical environments. In this article we elucidate the mechanism by which silk fibers are transformed into these structures through interaction with water. We quantify the evaporation rates of single water droplets which have been suspended on unmodified as-spun silk for two Trinidadian arboreal species: Antipaluria urichi (Clothodidae) and Pararhagadochir trinitatis (Scelembiidae). These rates are compared to those of droplets suspended on rose petals due to similar wetting properties (both hydrophobicity and pinning). We observe that on sufficiently thick silk, droplet evaporation rates decrease with time. This behavior is a result of a thin soluble film developing on the drop surface that later becomes a solid residual film. Experimentally verified theoretical models are invoked to support the results.

On Bayesian integration in sensorimotor learning: Another look at Kording and Wolpert (2004).

Kording and Wolpert (2004), hereafter referred to as KW, describe an experiment where subjects strove for accuracy in a stochastic environment and, on some trials, received mid-trial and post-trial feedback. KW claims that subjects learned the underlying stochastic distribution from the post-trial feedback of previous trials. KW also claims that subjects regarded mid-trial feedback that had a smaller visual size as more precise and they were therefore more sensitive to such mid-trial feedback. KW concludes that the observations are consistent with optimal Bayesian learning. KW has become an extremely influential paper in the large literature arguing that subjects are optimal Bayesian learners in stochastic environments. It is therefore crucial that the KW conclusions follow from their dataset. We note that KW analyzes data that have been both averaged across trials and averaged across other important trial-specific details. We also note that KW mischaracterizes the accuracy of the mid-trial feedback and the relative sizes of the mid-trial feedback. When we analyze the trial-level KW data, we do not find that subjects were more sensitive to mid-trial feedback when it had a smaller visual size. Our trial-level analysis also suggests a recency bias, rather than evidence that the subjects learned the stochastic distribution. In other words, we do not find that the observations are consistent with optimal Bayesian learning. In the KW dataset, it seems that evidence for optimal Bayesian learning is a statistical artifact of analyzing averaged data. Our results from the KW dataset would seem to have important implications for the literature on Bayesian judgments.

Development and validation of multivariable machine learning algorithms to predict risk of cancer in symptomatic patients referred urgently from primary care: a diagnostic accuracy study.

OBJECTIVES: To develop and validate tests to assess the risk of any cancer for patients referred to the NHS Urgent Suspected Cancer (2-week wait, 2WW) clinical pathways. SETTING: Primary and secondary care, one participating regional centre. PARTICIPANTS: Retrospective analysis of data from 371 799 consecutive 2WW referrals in the Leeds region from 2011 to 2019. The development cohort was composed of 224 669 consecutive patients with an urgent suspected cancer referral in Leeds between January 2011 and December 2016. The diagnostic algorithms developed were then externally validated on a similar consecutive sample of 147 130 patients (between January 2017 and December 2019). All such patients over the age of 18 with a minimum set of blood counts and biochemistry measurements available were included in the cohort. PRIMARY AND SECONDARY OUTCOME MEASURES: sensitivity, specificity, negative predictive value, positive predictive value, Receiver Operating Characteristic (ROC) curve Area Under Curve (AUC), calibration curves RESULTS: We present results for two clinical use-cases. In use-case 1, the algorithms identify 20% of patients who do not have cancer and may not need an urgent 2WW referral. In use-case 2, they identify 90% of cancer cases with a high probability of cancer that could be prioritised for review. CONCLUSIONS: Combining a panel of widely available blood markers produces effective blood tests for cancer for NHS 2WW patients. The tests are affordable, and can be deployed rapidly to any NHS pathology laboratory with no additional hardware requirements.

Characterization of a Cleavable Fusion of Human CYP24A1 with Adrenodoxin Reveals the Variable Role of Hydrophobics in Redox Partner Binding.

The improper maintenance of the bioactivated form of vitamin-D (1α,25(OH)2D) may result in vitamin-D insufficiency and therefore compromise the absorption of dietary calcium. A significant regulator of vitamin-D metabolism is the inactivating function of the mitochondrial enzyme cytochrome P450 24A1 (CYP24A1). In humans, CYP24A1 carries out hydroxylation of carbon-23 (C23) or carbon-24 (C24) of the 1α,25(OH)2D side chain, eventually resulting in production of either an antagonist of the vitamin-D receptor (C23 pathway) or calcitroic acid (C24 pathway). Despite its importance to human health, the human isoform (hCYP24A1) remains largely uncharacterized due in part to the difficulty in producing the enzyme using recombinant means. In this study, we utilize a cleavable fusion with the cognate redox partner, human Adx (hAdx), to stabilize hCYP24A1 during production. The subsequent cleavage and isolation of active hCYP24A1 allowed for an investigation of substrate and analog binding, enzymatic activity, and redox partner recognition. We demonstrate involvement of a nonpolar contact involving Leu-80 of hAdx and a nonconserved proximal surface of hCYP24A1. Interestingly, shortening the length of this residue (L80V) results in enhanced binding between the CYP-Adx complex and 1α,25(OH)2D yet unexpectedly results in decreased catalysis. The same mutation has a negligible effect on rat CYP24A1 (a C24-hydroxylase), indicating the presence of a species-specific requirement that may correlate with differences in regioselectivity of the reaction. Taken together, this work presents an example of production of a challenging human CYP as well as providing details regarding hydrophobic modulation of a CYP-Adx complex that is critical to human vitamin-D metabolism.

Orthopaedic and trauma care in low-resource settings: the burden and its challenges.

BACKGROUND AND BURDEN: Trauma with its early and late consequences disproportionately effects those from poor countries. The availability of effective orthopaedic and trauma care varies significantly across the globe. CHALLENGES: The balancing out of quality care is required to reach the health-related UN development goal set out in 2015. A multifactorial approach addressing local, national and international aspects is key to improving the discrepancy seen between high- and low-income countries.

A One Health Approach to Compare Self-Prescribed Antibiotic Use across Rural and Semi-urban Populations in San Lucas Tolimán, Guatemala.

Antimicrobial resistance resulting from antibiotic overuse represents an increasing public health challenge. The purpose of this study was to investigate antibiotic self-medication practices in a rural, indigenous Guatemalan population, and to compare self-prescribing patterns in rural and semi-urban populations using a One Health integrated approach, a framework acknowledging that health arises at the interface of humans, animals, and the environment. We conducted a mixed methods study using semi-structured interviews in and around San Lucas Tolimán, Guatemala. Antibiotic self-medication was common in both rural and semi-urban populations, regardless of demographic characteristics. Antibiotic usage in animals, while less common, almost always occurred without a veterinary consult. Although subjects recognized that self-medication could be harmful to health, they face significant barriers to accessing appropriate care. These patterns of use have impacts on the rise of antimicrobial resistance locally, and have the potential to contribute to the spread of such resistance globally.

Trainee Perspectives Regarding Advanced Clinical Global Health Fellowships in North America.

Postgraduate clinical global health (GH) training is a rapidly evolving field. To understand and improve training opportunities, we sought the perspectives of current and former trainees related to their advanced clinical training or global health fellowships and the anticipated impact on their careers. Clinical GH fellowships across North America were identified through websites and previous studies. An e-mail was sent to program directors to invite all current and former GH fellows to complete a web-based questionnaire. We contacted 100 GH fellowship programs. Fifty-two fellows from 10 different specialties completed the survey. The median fellowship length was 23.3 months, with an annual median of 4.8 months spent in low-income and middle-income countries, which was less than their reported ideal of 6 months. The majority reported satisfaction, the anticipation of career benefits, and that they would recommend fellowship training to others. Challenges included insufficient funding, mentorship, and formal curricula. Conducting research in high-income countries was a significant negative predictor of fellowship satisfaction. Most fellows (73.1%) were not at all or only a little concerned about the absence of fellowship accreditation, with only 17.3% desiring accreditation. Survey respondents were largely satisfied with their training and valued program flexibility and educational opportunities, including advanced tropical medicine certificates or diplomas. However, to improve fellowship training, improvements are needed in mentorship, standardized curricula, institutional support, and funding. For GH fellowship training to be effective and sustainable, institutions will need to balance the needs of fellows, training programs, and the communities (low-, middle-, and high-income countries) where the fellows serve.

The clinical features, management options and complications of paediatric femoral fractures.

This article discusses the incidence, applied anatomy and classification of paediatric femoral fractures based on critical appraisal of the available evidence. The aim is to identify techniques that are relevant to contemporary practice whilst excluding the technical details of individual procedures that are beyond the scope of this review. Injuries of the proximal, diaphyseal and distal segments are considered individually as there are considerations that are specific to each anatomical site. Femoral neck fractures are rare injuries and require prompt anatomical reduction and stable fixation to minimise the potentially devastating consequences of avascular necrosis. Diaphyseal fractures are relatively common, and there is a spectrum of management options that depend on patient age and size. Distal femoral fractures often involve the physis, which contributes up to 70% of femoral length. Growth arrest is common consequence of fractures in this region, resulting in angular and length-related deformity. Long-term surveillance is recommended to identify deformity in evolution and provide an opportunity for early intervention. Deliberate injury should be considered in all fractures, particularly distal femoral physeal injuries and fractures in the non-walking child.

Overview of the contemporary management of supracondylar humeral fractures in children.

PURPOSE: Supracondylar fractures are common injuries accounting for approximately 15% of all fractures in children with a large body of literature on this subject. METHODS:  This article critically appraises the available evidence to provide an overview of the treatment options including the role and timing of surgery, the geometry of wire fixation and the management of nerve and arterial injury. CONCLUSION:  Management decisions are based on a number of considerations particularly fracture stability. Closed reduction and percutaneous K-wire stabilisation are commonly recommended for an unstable displaced fracture. These techniques are however associated with the potential for iatrogenic neurological injury. Vascular injury is also rare but must be recognised and treated promptly to avoid significant permanent morbidity.

Reducing and managing chronic obstructive pulmonary disease exacerbations with tiotropium + olodaterol.

OBJECTIVE: The aim of this study was to review clinical evidence supporting the use of fixed-dose combination of tiotropium and olodaterol, a long-acting muscarinic antagonist (LAMA) and a long-acting ß2-agonist (LABA), respectively, as the initial and follow-up treatment choice in patients with chronic obstructive pulmonary disease (COPD) as per Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2020 recommendations-the impact of this treatment strategy on the reduction in the risk of exacerbations-and the importance of early therapeutic interventions. METHODS: For this narrative review, the available literature was searched to identify studies including patients with COPD receiving tiotropium and olodaterol as either monotherapy or combination therapy and studies including patients with COPD receiving inhaled corticosteroids (ICS) in addition to long-acting bronchodilators. Relevant studies were included in the review. RESULTS: Patients with COPD are often prescribed ICS therapy, which, when used over a long term, can be associated with local and systemic adverse effects. The GOLD 2020 report recommends dual bronchodilator therapy as both an initial and follow-up treatment option. A LABA + LAMA combination is mechanistically synergistic, and cumulative evidence surrounding the efficacy and safety of fixed-dose combination of tiotropium and olodaterol supports therapeutic advantages over monotherapy in most patients with COPD. CONCLUSIONS: The early stages of COPD may represent a "window of therapeutic opportunity" during which initiation of tiotropium and olodaterol dual bronchodilator therapy may improve lung function and quality of life and reduce exacerbations in patients with COPD.

Using Community Health Workers and a Smartphone Application to Improve Diabetes Control in Rural Guatemala.

BACKGROUND: The global prevalence of diabetes has nearly doubled since 1980. Seventy-five percent of patients with diabetes live in low- and middle-income countries, such as Guatemala, where health care systems are often poorly equipped for chronic disease management. Community health workers (CHWs) and mobile health technology have increasingly been applied to the diabetes epidemic in these settings, although mostly in supportive rather than primary roles in diabetes management. We sought to improve diabetes care in rural Guatemala through the development of a CHW-led diabetes program and a smartphone application to provide CHWs with clinical decision support. METHODS: We worked with our local partners to develop a program model and the smartphone application (using the CommCare platform) and to train CHWs. We recruited patients with type 2 diabetes living in rural communities. Program evaluation used a single-group, pre-post design. Primary outcomes were hemoglobin A1c and the percentage of patients meeting A1c goals compared with baseline. We also followed a variety of process metrics, including application reliability. RESULTS: Eighty-nine patients enrolled during the study period. The hemoglobin A1c percentage decreased significantly at 3 months (-1.0; 95% CI=-1.7, -0.6), 6 months (-1.5; 95% CI=-2.2, -0.8), 9 months (-1.3; 95% CI=-2.0, -0.6), and 12 months (-1.0; 95% CI=-1.7, -0.4). The percentage of patients with A1c ≤ 8% increased significantly at 3 months (23.6% to 44.4%, P=.007), 6 months (22.0% to 44.0%, P=.015), and 9 months (23.9% to 45.7%, P=.03). CHWs and supervising physicians agreed with application medication recommendations >90% of the time. CONCLUSION: Our results suggest that CHWs can safely and effectively manage diabetes with the assistance of a smartphone application and remote physician supervision. This model should be evaluated versus other standards of care and could be adapted to other low-resource settings and chronic diseases.

A Single Centre Randomised Control Study to Assess the Impact of Pre-Operative Carbohydrate Loading on Women Undergoing Major Surgery for Epithelial Ovarian Cancer.

Objective Historically, patients have fasted before elective surgery to ensure an empty stomach to avoid aspiration. A fasting-induced catabolic state however may adversely influence recovery after surgery. Our study was designed to test the effect of oral carbohydrate loading on clinical parameters in patients undergoing major surgery for advanced-stage ovarian cancer. Methods A double-blinded single-centre randomised trial was designed to recruit 110 patients with advanced-stage epithelial ovarian cancer undergoing either primary surgery, or neoadjuvant chemotherapy prior to debulking surgery. Following written informed consent, the patients were randomised into two groups. Group 1 received the carbohydrate drink (intervention) and group 2 received flavoured water (placebo). The quantity of fluid in both groups was 800ml the night before the surgery and 400ml two hours before the induction of anaesthesia. The primary endpoint of the study was the Length of Hospital Stay (LoHS); the secondary parameters assessed were pain scores, nausea and vomiting scores, bowel function, and postoperative complication rate. Results Between March 2009 and December 2011, 80 patients were randomised and 75 completed the study. A decision was made to close the trial early as a change in routine clinical practice meant that patients were admitted on the day of surgery rather than a day before. Analysis of the data revealed that there were no significant differences between the study groups in terms of LoHS and other clinical parameters. Conclusion In this single-center study, which failed to recruit the planned number of patients, we were unable to demonstrate that oral carbohydrate intake pre-operatively has significant impact on the recovery process or the length of hospitalisation postoperatively. Future studies should examine all aspects of an Enhanced Recovery Program after Surgery as a package as compared to a single element to enhance patient outcome.

Interventional Bronchoscopic Therapies for Chronic Obstructive Pulmonary Disease.

Patients with severe chronic obstructive pulmonary disease who fail maximal medical therapy have bronchoscopic options that can improve lung function, quality of life, and exercise performance. Those with upper lobe predominant emphysema can consider bronchoscopic lung volume reduction with endobronchial valves. Select patients with diffuse emphysema and severe hyperinflation can also be considered for endobronchial valves. Bronchoscopic techniques targeting cholinergic pathways and mucus hypersecretion are under development. Ultimately, patients with advanced chronic obstructive pulmonary disease who are not eligible for or have failed bronchoscopic interventions can consider lung volume reduction surgery or even lung transplantation, if free from major comorbidities.