Biologic Therapies in Stress Fractures: Current Concepts.

Stress fractures, a common overuse injury in physically active individuals, present a significant challenge for athletes and military personnel. Patients who sustain stress fractures have demanding training regimes, where periods of rest and immobilisation have unacceptable negative consequences on sport goals and finances. Aside from being an overuse injury, there are various contributing risk factors that put certain individuals at risk of a stress fracture. The main two being nutritional deficiencies and hormonal variations which have significant effects on bone metabolism and turnover. Historically, treatment of stress fractures focused on conservative strategies such as rest and immobilisation. Calcium and vitamin D deficiencies have been closely linked to stress fractures and so over time supplementation has also played a role in treatment. With the introduction of biologics into orthopaedics, newer treatment strategies have been applied accelerate fracture healing and perhaps improve fracture callus quality. If such therapies can reduce, time spent away from sport and activity, it would be ideal for treating stress fractures. This article aims to offers insights into the evolving landscape of stress fracture management. It investigates the pre-clinical evidence and available published clinical applications. Though fracture healing is well understood, the role of biologics for fracture healing is still indeterminate. Available literature for the use of biologics therapies in stress fractures is restricted and most reports have used biologics as a supplement to surgical fixation in subjects in studies that lack control groups. Randomised control trials have been proposed and registered by a few groups with results awaited. Assessing individuals for risk factors, addressing hormonal imbalances and nutritional deficiencies seem an effective approach to addressing the burden of stress fractures. We await better designed trials and studies to accurately determine the clinical benefit of adding biologics to management of these injuries.

No Child's Play: Under-five Child Feces Management in a Rural Area of Bengaluru Urban District, India.

Background: Inappropriate feces disposal leads to environmental contamination, and increases the risk of exposure to children. We aimed to estimate the proportion of rural households with knowledge and practice of safe management of feces (SMoF) among under-five children and to identify associated factors. Materials and Methods: A cross-sectional study was conducted in eight villages in Bengaluru Urban district over 2 months, using a face-validated semi-structured interview schedule. SMoF was defined based on five criteria - defecation site, transport tool, feces disposal, cleaning of transport tool, and hand washing. Results: Out of 320 under-five children surveyed, 15.7% were pre-ambulatory and 84.3% were ambulatory. The majority of the caregivers (92.5%) felt that children should defecate in the latrine and only 23.7% were aware that child feces were more infectious than adult feces. SMoF was only practiced by caregivers of ambulatory children (52.6%). Households with older caregivers (P = 0.01) and those living in a pucca house (P = 0.02) with a latrine inside (P = 0.04) were found to practice SMoF. Children of households that practiced unsafe disposal of child feces experienced more diarrheal episodes (P = 0.04). Caregivers >20 years were found to have better odds of SMoF [20-25 years (adjusted odds ratio, aOR: 9.02), 26-30 years (aOR: 12.17), >30 years (aOR: 8.93)] compared to those <20 years. Conclusion: The proportion of households with knowledge and practice of SMoF was low. Awareness of SMoF is essential to reduce the incidence of diarrheal diseases and improve sanitation. Our findings also call for awareness building at schools and colleges.

Comparative evaluation of efficacy of physics forcep and conventional forceps for extraction of maxillary molars.

BACKGROUND: Tooth extraction is one of the most commonly performed procedures in dentistry. It is usually a traumatic procedure often resulting in immediate destruction and loss of alveolar bone and surrounding soft tissues. It is the only dental procedure which was carried out by dentists in the previous centuries and various instruments have evolved for this procedure over time. Atraumatic extraction is one of the essential dental procedures, as atraumatic extraction leads to proper wound healing and appropriate bone healing. Physics forceps have got a new role in extraction technique, that it makes just one contact point with the tooth as a unique benefit. Physics forceps depends on the physics of rotational power, lever and torque much like a bottle top removal. A study was conducted to evaluate the efficacy of physics forceps and conventional forces in the extraction of maxillary molar. METHODS: Eligible participants were adults aged 18-50 diagnosed with grossly decayed maxillary molars with poor endodontic prognosis and willing to participate in the study. Exclusion criteria were as follows: patients with dilacerate roots; patients with systemic diseases like hypertension, diabetes mellitus, thyroid, tuberculosis, epilepsy seizures, COVID-19 positive; patients' non-acceptance to voluntarily participate in research a refusal to sign the informed consent. Parameters such as a crown fracture or root fracture; buccal bone fracture; time taken for extraction and operator ease on the VAS scale are assessed. RESULTS: Results showed that with the use of physics forces, there was very less incidence of crown fracture and no incidence of buccal bone fracture, whereas with the conventional forceps the result showed that in almost all the time taken for extraction was much more in conventional forcep and the operator ease rating was more with conventional forceps. CONCLUSIONS: Hence, oral surgeons as well as general practitioner should adapt the use of physics forceps in routine extractions.

Acetabular cup positioning in primary routine total hip arthroplasty-a review of current concepts and technologies.

INTRODUCTION: Total hip arthroplasty (THA) has revolutionized the treatment of hip joint arthritis. With the increased popularity and success of the procedure, research has focused on improving implant survival and reducing surgical complications. Optimal component orientation has been a constant focus with various philosophies proposed. Regardless of the philosophy, achieving an accurate acetabular position for each clinical scenario is crucial. In this paper, we review the recent developments in improving the accuracy and ideal positioning of the acetabular cup in routine primary THA. METHODOLOGY: A review of the recent scientific literature for acetabular cup placement in primary THA was performed, with available evidence for safe zones, spinopelvic relationship, preoperative planning, patient-specific instrumentation, navigation THA and robotic THA. CONCLUSION: Though the applicability of Lewinnek safe zones has been questioned with an improved understanding of spinopelvic relationships, its role remains in positioning the acetabular cup in a patient with normal spinopelvic alignment and mobility. Evaluation of spinopelvic relationships and accordingly adjusting acetabular anteversion and inclination can significantly reduce the incidence of dislocation in patients with a rigid spine. In using preoperative radiography, the acetabular inclination, anteversion and intraoperative pelvic position should be evaluated. With improving technology and the advent of artificial intelligence, superior and more accurate preoperative planning is possible. Patient-specific instrumentation, navigated and robotic THA have been reported to improve accuracy in acetabular cup positioning as decided preoperatively but any significant clinical advantage over conventional THA is yet to be elucidated.

Repair of osteochondral defects: efficacy of a tissue-engineered hybrid implant containing both human MSC and human iPSC-cartilaginous particles.

Both mesenchymal stromal cells (MSC) and induced pluripotent stem cells (iPSC) offer the potential for repair of damaged connective tissues. The use of hybrid implants containing both human MSC and iPSC was investigated to assess their combined potential to yield enhanced repair of osteochondral defects. Human iPSC-CP wrapped with tissue engineered constructs (TEC) containing human MSC attained secure defect filling with good integration to adjacent tissue in a rat osteochondral injury model. The presence of living MSC in the hybrid implants was required for effective biphasic osteochondral repair. Thus, the TEC component of such hybrid implants serves several critical functions including, adhesion to the defect site via the matrix and facilitation of the repair via live MSC, as well as enhanced angiogenesis and neovascularization. Based on these encouraging studies, such hybrid implants may offer an effective future intervention for repair of complex osteochondral defects.

Total Knee Arthroplasty in Paget's Disease using 3D-Printed Patient-Specific Femoral Jig - A Case Report.

Introduction: Patients with Paget's disease develop abnormal bony anatomy which can result in significantly altered lower limb alignment predisposing them to early secondary osteoarthritis. Due to the severe extra-articular deformity, total knee arthroplasty (TKA) in these patients is challenging. Conventional knee arthroplasty using intramedullary guides is not an option and can lead to erroneous limb alignment postoperatively. Patient-specific instrumentation (PSI) is a simple solution in such complex primary knee arthroplasty. Case Report: A 70-year-old male patient presented with a severe left femur deformity and left knee pain. He was diagnosed to have monostotic Paget's disease of the left femur with tricompartmental osteoarthritis of the left knee. After reduction in pathological bone turnover, the patient was planned for a total knee replacement. As a standard intramedullary femoral jig was not applicable due to the femoral deformity, a computed topography-based 3D-printed patient-specific instrument was used. This custom jig was used to define and perform the distal femur cut at 90 degrees to the mechanical axis of the femur in the coronal and sagittal plane. Postoperatively, the patient did well and achieved good function and pain relief. Conclusion: The use of a 3D-printed PSI for complex primary knee arthroplasty is an excellent option with no additional operative time than a conventional knee arthroplasty. Although a robotic or computer-navigated TKA would be an excellent option in this case, we restored the limb alignment using a cost-effective patient-specific femoral jig. This could be a viable option in centers without navigation or robotic arthroplasty.

Small extracellular vesicles derived from human adipose-derived mesenchymal stromal cells cultured in a new chemically-defined contaminate-free media exhibit enhanced biological and therapeutic effects on human chondrocytes in vitro and in a mouse osteoarthritis model.

Human small extracellular vesicles (sEVs) derived from adipose-derived mesenchymal stromal cells (ASC) have been reported to suppress the progression of osteoarthritis (OA) in animal studies and subsequently, translation of this potential to assess their clinical efficacy is anticipated. However, fabrication protocols for sEVs to eliminate potential contamination by culture medium-derived components need to be established prior to their clinical use. The purpose of the present studies was to elucidate the influence of medium-derived contaminants on the biological effects of sEVs, and to establish isolation methods for sEVs using a new clinical grade chemically-defined media (CDM). The quantity and purity of ASC-derived sEVs cultured in four different CDMs (CDM1, 2, 3 and 4) were evaluated. The concentrates of the four media incubated without cells were used as the background (BG) control for each set of sEVs. The biological effect of sEVs fabricated in the four different CDMs on normal human articular chondrocytes (hACs) were evaluated in vitro using a variety of methodological assessments. Finally, the sEVs with the highest purity were tested for their ability to suppress the progression of knee OA mouse model. Analysis of the BG controls revealed that CDM1-3 contained detectable particles, while there was no visible contamination of culture media-derived components detected with CDM4. Accordingly, the sEVs fabricated with CDM4 (CDM4-sEVs) exhibited the highest purity and yield. Notably, the CDM4-sEVs were the most efficient in promoting the cellular proliferation, migration, chondrogenic differentiation, and anti-apoptotic activity of hACs. Furthermore, CDM4-sEVs significantly suppressed the osteochondral degeneration in vivo model. Small EVs derived from ASCs cultured in a CDM without detectable contaminants demonstrated enhanced biological effects on hACs and the progression of OA. Thus, sEVs isolated with CDM4 most optimally meet the requirements of efficacy and safety for assessment in their future clinical applications.

Nutrition claims influence expectations about food attributes, attenuate activity in reward-associated brain regions during tasting, but do not impact pleasantness.

INTRODUCTION: Nutrition claims are one of the most common tools used to improve food decisions. Previous research has shown that nutrition claims impact expectations; however, their effects on perceived pleasantness, valuation, and their neural correlates are not well understood. These claims may have both intended and unintended effects on food perception and valuation, which may compromise their effect on food decisions. METHODS: We investigated the effects of nutrition claims on expectations, perceptions, and valuation of milk-mix drinks in a behavioral (n = 110) and an fMRI (n = 39) study. In the behavioral study, we assessed the effects of a "fat-reduced" and a "protein-rich" nutrition claim on expected and perceived food attributes of otherwise equal food products. In the fMRI study, we investigated the effect of a "protein-rich" claim on taste pleasantness perception and valuation, and on their neural correlates during tasting and swallowing. RESULTS: We found that both nutrition claims increased expected and perceived healthiness and decreased expected but not perceived taste pleasantness. The "protein-rich" claim increased expected but not perceived satiating quality ratings, while the "fat-reduced" claim decreased both expected and perceived satiating quality ratings. In the absence vs. presence of the "protein-rich" claim, we observed an increased activity in a cluster extending to the left nucleus accumbens during tasting and an increased functional connectivity between this cluster and a cluster in right middle frontal gyrus during swallowing. CONCLUSION: Altogether, we found that nutrition claims impacted expectations and attenuated reward-related responses during tasting but did not negatively affect perceived pleasantness. Our findings support highlighting the presence of nutrients with positive associations and exposure to foods with nutrition claims to increase their acceptance. Our study offers insights that may be valuable in designing and optimizing the use of nutrition claims.

Hepatocyte apoptosis fragment product cytokeratin-18 M30 level and non-alcoholic steatohepatitis risk diagnosis: an international registry study / 中华医学杂志(英文版)

BACKGROUND@#Liver biopsy for the diagnosis of non-alcoholic steatohepatitis (NASH) is limited by its inherent invasiveness and possible sampling errors. Some studies have shown that cytokeratin-18 (CK-18) concentrations may be useful in diagnosing NASH, but results across studies have been inconsistent. We aimed to identify the utility of CK-18 M30 concentrations as an alternative to liver biopsy for non-invasive identification of NASH.@*METHODS@#Individual data were collected from 14 registry centers on patients with biopsy-proven non-alcoholic fatty liver disease (NAFLD), and in all patients, circulating CK-18 M30 levels were measured. Individuals with a NAFLD activity score (NAS) ≥5 with a score of ≥1 for each of steatosis, ballooning, and lobular inflammation were diagnosed as having definite NASH; individuals with a NAS ≤2 and no fibrosis were diagnosed as having non-alcoholic fatty liver (NAFL).@*RESULTS@#A total of 2571 participants were screened, and 1008 (153 with NAFL and 855 with NASH) were finally enrolled. Median CK-18 M30 levels were higher in patients with NASH than in those with NAFL (mean difference 177 U/L; standardized mean difference [SMD]: 0.87 [0.69-1.04]). There was an interaction between CK-18 M30 levels and serum alanine aminotransferase, body mass index (BMI), and hypertension ( P  < 0.001, P  = 0.026 and P  = 0.049, respectively). CK-18 M30 levels were positively associated with histological NAS in most centers. The area under the receiver operating characteristics (AUROC) for NASH was 0.750 (95% confidence intervals: 0.714-0.787), and CK-18 M30 at Youden's index maximum was 275.7 U/L. Both sensitivity (55% [52%-59%]) and positive predictive value (59%) were not ideal.@*CONCLUSION@#This large multicenter registry study shows that CK-18 M30 measurement in isolation is of limited value for non-invasively diagnosing NASH.

MAFLD: How is it different from NAFLD?

“Metabolic dysfunction-associated fatty liver disease (MAFLD)” is the term suggested in 2020 to refer to fatty liver disease related to systemic metabolic dysregulation. The name change from nonalcoholic fatty liver disease (NAFLD) to MAFLD comes with a simple set of criteria to enable easy diagnosis at the bedside for the general medical community, including primary care physicians. Since the introduction of the term, there have been key areas in which the superiority of MAFLD over the traditional NAFLD terminology has been demonstrated, including for the risk of liver and extrahepatic mortality, disease associations, and for identifying high-risk individuals. Additionally, MAFLD has been adopted by a number of leading pan-national and national societies due to its concise diagnostic criterion, removal of the requirement to exclude concomitant liver diseases, and reduction in the stigma associated with this condition. The current article explores the differences between MAFLD and NAFLD diagnosis, areas of benefit, some potential limitations, and how the MAFLD terminology has opened up new fields of research.

Comparison of the Length of Styloid Process in Panoramic Radiographs to Computed Tomography as the Gold Standard.

Aims: To compare the length of styloid process assessed using computed tomography (CT) and panoramic radiographs (PAN). Materials and Methods: PAN were taken for 15 patients requiring CT reporting to PMS Dental College or metro scans, after obtaining informed consent and fulfilling all the inclusion and exclusion criteria. CT images were taken in metro scans. The apparent lengths of styloid process were measured in both CT and PAN using software provided with the respective machines. Ethical committee approval was obtained from PMS Dental College, Trivandrum. Results: The length of left styloid process in CT was observed 20-30 mm in 4 (27%) patients and same in PAN was observed in 5 (33%) patients. Out of 15 patients, abnormal styloid process (length >30 mm) was observed in 11 (73%) patients when measured with CT and 10 (67%) patients in PAN. In CT, the length of the styloid process on the right side was observed between 20 and 30 mm, in 3 (20%) patients. PAN of 2 (13%) patients were found between 20 and 30 mm. On the right side, abnormal styloid process (length >30 mm) was noted in 12 (80%) patients using CT and 13 (87%) patients in PAN. The length of styloid process in the combined sample (both right and left side) was found to be between 20 and 30 mm in 3 (10%) patients and styloid process >30 mm long (in both CT and PAN) was observed in 12 (40%) patients. Conclusions: This study demonstrated positive correlation between CT and panoramic measurements. "P" values were statistically significant on both sides with values of right side (P = 0.01) and left side (P = 0.002), respectively. Hence, PAN, which are routinely taken, cost-effective and involving relatively low radiation dose, may be used as substitute for CT for the purpose of diagnosis of elongated styloid process. However, for precise measurement of the length of styloid process, CT is still the imaging modality of choice.

The Influence of Stress in Modulating the Relationship between Coronavirus Disease-2019 Disease and Sleep Quality.

Introduction: The emotional well-being of health-care employees is critical to the quality of patient care and the efficient operation of health services. Not only has the coronavirus disease-2019 (COVID-19) virus caused significant rates of morbidity and mortality around the world but it has also caused sleep disruption, stress, and pandemic-related anxiety among health-care workers. The current study examines associations among COVID-related fear, stress, and sleep quality in health professionals. Methods: From January to June 2021, a cross-sectional survey was done in Kerala among doctors, nurses, paramedical workers, and housekeeping employees. About 822 health-care providers from various districts took part in the study by completing a Google forms-based semi-structured, self-administered questionnaire. The data were coded, entered, and analyzed using SPSS 20.0. Descriptive statistical analysis, percentages, and ratios were employed to summarize the data. Results: The majority of participants were between the ages of 46 and 55 (35%). Forty-four percent and 46% of respondents, respectively, were concerned about contracting COVID-19 and spreading the virus to others. COVID-19 restrictions were the primary concern of psychological distress among respondents (90%). Approximately one-fourth of the subjects reported using sleep medication, 42% took 30 min or longer to fall asleep, and 39% slept for 6 h or less. Poor sleep quality was reported to be prevalent in 62% of the population. Conclusion: The COVID-19 pandemic has the potential to cause significant levels of fear, stress, and sleep disruption in health-care professionals. As a result, the COVID-19 pandemic represented a significant threat to their psychological health, and public health strategies should focus on improving it.

Development of Cu3N electrocatalyst for hydrogen evolution reaction in alkaline medium.

A wide variety of electrocatalysts has been evolved for hydrogen evolution reaction (HER) and it is reasonable to carry out HER with low cost electrocatalyst and a good efficiency. In this study, Cu3N was synthesized by nitridation of Cu2O and further utilized as an electrocatalyst towards HER. The developed Cu3N electrocatalyst was tested and results showed a low overpotential and moderate Tafel slope value (overpotential: 149.18 mV and Tafel slope 63.28 mV/dec at 10 mA/cm2) in alkaline medium with a charge transfer resistance value as calculated from electrochemical impendence spectroscopy being 1.44 Ω. Further from the experimental results, it was observed that the reaction kinetics was governed by Volmer-Heyrovsky mechanism. Moreover, Cu3N has shown an improved rate of electron transfer and enhanced accessible active sites, due to its structural properties and electrical conductivity. Thus the overall results show an excellent electrochemical performance, leading to a new pathway for the synthesis of low cost electrocatalyst for energy conversion and storage.

Novel strategy to personalise use of ibuprofen for closure of patent ductus arteriosus in preterm neonates.

OBJECTIVE: Exploration of a novel therapeutic drug monitoring (TDM) strategy to personalise use of ibuprofen for closure of patent ductus arteriosus (PDA) in preterm neonates. DESIGN: Prospective, single-centre, open-label, pharmacokinetics study in preterm neonates. SETTING: Neonatal intensive care unit at McMaster Children's Hospital. PATIENTS: Neonates with a gestational age ≤28+6 weeks treated with oral ibuprofen for closure of a PDA. METHODS: Population pharmacokinetic parameters, concentration-time profiles and exposure metrics were obtained using pharmacometric modelling and simulation. MAIN OUTCOME MEASURE: Association between ibuprofen plasma concentrations measured at various sampling time points on the first day of treatment and attainment of the target exposure over the first 3 days of treatment (AUC0-72h >900 mg·hour/L). RESULTS: Twenty-three preterm neonates (median birth weight 780 g and gestational age 25.9 weeks) were included, yielding 155 plasma ibuprofen plasma samples. Starting from 8 hours' postdose on the first day, a strong correlation between ibuprofen concentrations and AUC0-72h was observed. At 8 hours after the first dose, an ibuprofen concentration >20.5 mg/L was associated with a 90% probability of reaching the target exposure. CONCLUSION: We designed a novel and practical TDM strategy and have shown that the chance of reaching the target exposure (AUC0-72h >900 mg·hour/L) can be predicted with a single sample collection on the first day of treatment. This newly acquired knowledge can be leveraged to personalise ibuprofen dosing regimens and improve the efficacy of ibuprofen use for pharmacological closure of a PDA.

Pseudomonas syringae addresses distinct environmental challenges during plant infection through the coordinated deployment of polysaccharides.

Prior to infection, phytopathogenic bacteria face a challenging environment on the plant surface, where they are exposed to nutrient starvation and abiotic stresses. Pathways enabling surface adhesion, stress tolerance, and epiphytic survival are important for successful plant pathogenesis. Understanding the roles and regulation of these pathways is therefore crucial to fully understand bacterial plant infections. The phytopathogen Pseudomonas syringae pv. tomato (Pst) encodes multiple polysaccharides that are implicated in biofilm formation, stress survival, and virulence in other microbes. To examine how these polysaccharides impact Pst epiphytic survival and pathogenesis, we analysed mutants in multiple polysaccharide loci to determine their intersecting contributions to epiphytic survival and infection. In parallel, we used qRT-PCR to analyse the regulation of each pathway. Pst polysaccharides are tightly coordinated by multiple environmental signals. Nutrient availability, temperature, and surface association strongly affect the expression of different polysaccharides under the control of the signalling protein genes ladS and cbrB and the second messenger cyclic-di-GMP. Furthermore, functionally redundant, combinatorial phenotypes were observed for several polysaccharides. Exopolysaccharides play a role in mediating leaf adhesion, while α-glucan and alginate together confer desiccation tolerance. Our results suggest that polysaccharides play important roles in overcoming environmental challenges to Pst during plant infection.

From MAFLD to hepatocellular carcinoma and everything in between / 中华医学杂志(英文版)

Metabolic (dysfunction) associated fatty liver disease (MAFLD), previously known as non-alcoholic fatty liver disease, is the most common cause of chronic liver disease worldwide. Many risk factors contribute to the pathogenesis of MAFLD with metabolic dysregulation being the final arbiter of its development and progression. MAFLD poses a substantial economic burden to societies, which based on current trends is expected to increase over time. Numerous studies have addressed various aspects of MAFLD from its risk associations to its economic and social burden and clinical diagnosis and management, as well as the molecular mechanisms linking MAFLD to end-stage liver disease and hepatocellular carcinoma. This review summarizes current understanding of the pathogenesis of MAFLD and related diseases, particularly liver cancer. Potential therapeutic agents for MAFLD and diagnostic biomarkers are discussed.

MAFLD enhances clinical practice for liver disease in the Asia-Pacific region

Fatty liver is now a major cause of liver disease in the Asia-Pacific region. Liver diseases in this region have distinctive characteristics. First, fatty liver is frequently observed in leanormal-weight individuals. However, there is no standard definition of this unique phenotype. Second, fatty liver is often observed in patients with concomitant viral hepatitis. The exclusion of viral hepatitis from non-alcoholic fatty liver disease limits its value and detracts from the investigation and holistic management of coexisting fatty liver in patients with viral hepatitis. Third, fatty liver-associated hepatocellular carcinoma (HCC) is generally categorized as non-B non-C HCC. Fourth, the population is aging rapidly, and it is imperative to develop a practicable, low-intensity exercise program for elderly patients. Fifth, most patients and nonspecialized healthcare professionals still lack an awareness of the significance of fatty liver both in terms of intrahepatic and extrahepatic disease and cancer. Recently, an international expert panel proposed a new definition of fatty liver: metabolic dysfunction-associated fatty liver disease (MAFLD). One feature of MAFLD is that metabolic dysfunction is a prerequisite for diagnosis. Pertinent to regional issues, MAFLD also provides its diagnostic criteria in leanormal-weight individuals. Furthermore, MAFLD is independent of any concomitant liver disease, including viral hepatitis. Therefore, MAFLD may be a more suitable definition for fatty liver in the Asia-Pacific region. In this review, we introduce the regional characteristics of fatty liver and discuss the advantages of MAFLD for improving clinical practice for liver disease in the region.