Characteristics, trends, and management of Penile cancer in the United States: A population-based study.

BACKGROUND: Penile cancer (PeCa) is a rare disease. HPV infection, smoking, phimosis, and lichen sclerosus represent well-known associated risk factors. OBJECTIVES: Primary aim of our study is to evaluate the incidence and risk factors of PeCa and to outline the adopted diagnostic and therapeutic approaches. Secondary aim is to investigate risk factors associated with aggressive disease and to identify the complications arising from its surgical treatment. MATERIALS AND METHODS: We conducted a retrospective analysis using the PearlDiver™ Mariner database, from January 1, 2011, to December 31, 2021, identifying all patients diagnosed with PeCa and PeIN, evaluating comorbidities, risk factors, and social and economic conditions. We evaluated the imaging modalities employed for staging as well as the treatment strategies. Finally, we evaluated the most frequent complications associated with inguinal lymphadenectomy (ILND). RESULTS: During the study period, 17,494 patients were diagnosed with PeCa and 5,965 with penile intraepithelial neoplasia (PeIN). US was the most frequently utilized imaging modality, followed by PET and PET/CT. Use of CT and MRI was around 5%. Surgical treatment was the predominant strategy, utilized in 31.3% of PeCa and 22.9% of PeIN. Wide Local Excision/Glansectomy emerged as the most common surgical procedures. MLR analysis identified smoking as a risk factor for metastatic PeCa (OR; 95% CI = 1.49; 1.379-1.609), HPV infections were associated with a 35% decrease in risk (OR; 95% CI = 0.65; 0.562-0.744) (all P < 0.001). Lichen sclerosus and phimosis were associated with a doubled risk of demolitive surgery. Approximately 40% of patients experienced complications associated with ILND. CONCLUSION: Despite advances in PeCa management, there's no significant move toward more conservative treatments. Surgical treatments are still marked by high rates of complications, potentially affect the sexual and psychosocial health of patients. These issues may foster a tendency toward avoidance behaviors, contributing to a delayed clinical presentation and treatment.

Conservative treatment of 3- and 4-part proximal humeral fractures: Can poor outcomes be predicted?

PURPOSE: 3- and 4-part proximal humeral fractures are frequently treated conservatively. This study aims to combine radiographic, and patient reported outcome data to identify factors leading to poor outcomes following conservative treatment. METHODS: A retrospective local database analysis identified 3- and 4-part fractures. Radiographic and functional outcomes including Oxford Shoulder Score (OSS), QuickDash (QD), Subjective Shoulder Score (SSV) and VAS pain scores were collected. RESULTS: 104 patients were included at mean follow-up of 55 months. Analysis highlighted significant OSS differences in 3- versus 4-part (p = 0.027), dominant arm injury (p = 0.046), age > 65 (p = 0.006), varus coronal neck-shaft angle < 115 versus 115-155 degrees (p = 0.008), posterior head tilt > 155 degrees (p = 0.005), greater tuberosity (GT) displacement > 5 mm (p = 0.001), GT comminution (p = 0.01), medial calcar hinge displacement > 2 mm (p = 0.032). According to QD scores; age > 65 (p = 0.012), varus neck-shaft angle (p = 0.01), GT displacement > 5 mm (p = 0.001), GT comminution (p = 0.01), medial calcar hinge displacement > 2 mm (p = 0.006). SSV varied significantly with 3- versus 4-part fractures (p = 0.005), age > 65 (p = 0.04), varus neck-shaft angle (p = 0.001), posterior head tilt (p = 0.005), GT displacement > 5 mm (p = 0.001), GT comminution (p = 0.003), and medial calcar hinge displacement > 2 mm (p = 0.001). CONCLUSION: We highlight risk factors for unfavourable outcomes following conservative management, aiding surgeons in shared decision-making and patient expectation management.

Assessment of bone regeneration after maxillary radicular cyst enucleation with or without bone grafting materials: a retrospective cohort study.

OBJECTIVE: The limitations of spontaneous bone healing underscore the necessity for exploring alternative strategies to enhance bone regeneration in maxillary radicular cyst cases. This retrospective study aimed to assess the impact of a bone substitute material (i.e., Bio-Oss) on bone volume regeneration following maxillary radicular cyst enucleation using cone-beam computed tomography (CBCT). MATERIALS AND METHODS: Seventy-three patients with maxillary radicular cysts were divided into two groups: one undergoing guided bone regeneration (GBR) with Bio-Oss and absorbable collagen membrane (n = 35), and the other receiving cyst excision alone (n = 38). Volumetric measurements using Amira software on CBCT scans evaluated bone regeneration, with cystic lesion shrinkage rates calculated. Intergroup comparisons utilized independent sample t-tests (P < 0.05), and linear regression analysis assessed the influence of preoperative cyst volume and group on bone healing. RESULTS: Both groups showed similar success rates in bone formation at the 12-month follow-up, with no significant differences between them (mean (SD), control: 75.16 (19.17) vs. GBR: 82 (20.22), P > 0.05). Linear regression analysis revealed a negative correlation between preoperative cyst volume and bone regeneration in both groups (P < 0.05). CONCLUSION: Bio-Oss may not significantly enhance bone augmentation in maxillary radicular cysts. In addition, preoperative cyst volume negatively affected the shrinkage rate of cystic lesions. CLINICAL RELEVANCE: Clinicians should consider patient-specific factors such as anatomy and lesion size when determining the need for bone substitute materials. Future research could focus on optimizing treatment protocols and alternative regenerative strategies to improve patient outcomes in maxillary cyst cases.

Exploring the structural assembly of rice ADP-glucose pyrophosphorylase subunits using MD simulation.

ADP-glucose pyrophosphorylase plays a pivotal role as an allosteric enzyme, essential for starch biosynthesis in plants. The higher plant AGPase comparises of a pair of large and a pair of small subunits to form a heterotetrameric complex. Growing evidence indicates that each subunit plays a distinct role in regulating the underlying mechanism of starch biosynthesis. In the rice genome, there are four large subunit genes (OsL1-L4) and three small subunit genes (OsS1, OsS2a, and OsS2b). While the structural assembly of cytosolic rice AGPase subunits (OsL2:OsS2b) has been elucidated, there is currently no such documented research available for plastidial rice AGPases (OsL1:OsS1). In this study, we employed protein modeling and MD simulation approaches to gain insights into the structural association of plastidial rice AGPase subunits. Our results demonstrate that the heterotetrameric association of OsL1:OsS1 is very similar to that of cytosolic OsL2:OsS2b and potato AGPase heterotetramer (StLS:StSS). Moreover, the yeast-two-hybrid results on OsL1:OsS1, which resemble StLS:StSS, suggest a differential protein assembly for OsL2:OsS2b. Thus, the regulatory and catalytic mechanisms for plastidial AGPases (OsL1:OsS1) could be different in rice culm and developing endosperm compared to those of OsL2:OsS2b, which are predominantly found in rice endosperm.

The development of non-resorbable bone allografts: Biological background and clinical perspectives.

Bone grafts are typically categorized into four categories: autografts, allografts, xenografts, and synthetic alloplasts. While it was originally thought that all bone grafts should be slowly resorbed and replaced with native bone over time, accumulating evidence has in fact suggested that the use of nonresorbable xenografts is favored for certain clinical indications. Thus, many clinicians take advantage of the nonresorbable properties/features of xenografts for various clinical indications, such as contour augmentation, sinus grafting, and guided bone regeneration, which are often combined with allografts (e.g., human freeze-dried bone allografts [FDBAs] and human demineralized freeze-dried bone allografts [DFDBAs]). Thus, many clinicians have advocated different 50/50 or 70/30 ratios of allograft/xenograft combination approaches for various grafting procedures. Interestingly, many clinicians believe that one of the main reasons for the nonresorbability or low substitution rates of xenografts has to do with their foreign animal origin. Recent research has indicated that the sintering technique and heating conducted during their processing changes the dissolution rate of hydroxyapatite, leading to a state in which osteoclasts are no longer able to resorb (dissolve) the sintered bone. While many clinicians often combine nonresorbable xenografts with the bone-inducing properties of allografts for a variety of bone augmentation procedures, clinicians are forced to use two separate products owing to their origins (the FDA/CE does not allow the mixture of allografts with xenografts within the same dish/bottle). This has led to significant progress in understanding the dissolution rates of xenografts at various sintering temperature changes, which has since led to the breakthrough development of nonresorbable bone allografts sintered at similar temperatures to nonresorbable xenografts. The advantage of the nonresorbable bone allograft is that they can now be combined with standard allografts to create a single mixture combining the advantages of both allografts and xenografts while allowing the purchase and use of a single product. This review article presents the concept with evidence derived from a 52-week monkey study that demonstrated little to no resorption along with in vitro data supporting this novel technology as a "next-generation" biomaterial with optimized bone grafting material properties.

Clinical and radiographic evaluation of Bio-Oss granules and Bio-Oss Collagen in the treatment of periodontal intrabony defects: a retrospective cohort study

Abstract Objective This retrospective study aimed to analyze the clinical efficacy of two regenerative surgical methods — Bio-Oss granules combined with barrier membranes and Bio-Oss Collagen alone — and to help clinicians achieve better periodontal regeneration outcomes in the specific periodontal condition. Methodology Patients who underwent periodontal regeneration surgery from January 2018 to April 2022 were retrospectively screened, and their clinical and radiographic outcomes at 6 months postoperatively were analyzed. The probing depth (PD), clinical attachment level (CAL), bleeding on probing (BOP), gingival recession (GR), distance from the cemento-enamel junction to the bottom of the bone defect (CEJ-BD), and depth of intrabony defects (INFRA) were recorded before the operation (T0) and 6 months after it (T1), and subsequently compared. Results In total, 143 patients were included — 77 were placed in the Bio-Oss group and 66 were placed in the Bio-Oss Collagen group. All indicators, including PD and CAL at T1, showed significant differences compared to baseline, for both groups (P<0.001). PD reduction was greater in the group receiving the Bio-Oss Collagen treatment (P=0.042). Furthermore, in cases when the baseline PD range was 7-11 mm and the age range was 35-50 years, PD reduction was more significant for patients receiving the Bio-Oss Collagen treatment (P=0.031, 0.023). A linear regression analysis indicated that postoperative PD and CAL were positively correlated with baseline values, and that the efficacy tended to decrease with increasing age. Conclusion Both the use of Bio-Oss Collagen alone and the use of Bio-Oss granules combined with barrier membranes resulted in significant effects in the treatment of periodontal intrabony defects. The Bio-Oss Collagen treatment generated more improvements in PD than the Bio-Oss granules combined with barrier membranes, particularly within the baseline PD range of 7-11 mm and the 35-50 years age group. Additionally, age was the main factor influencing the effectiveness of regenerative surgery for intrabony defects: older individuals exhibited fewer improvements.

Histomorphometric Comparison of Bio-Oss vs. Osteodens in Maxillary Sinus Floor Elevation Procedures / Comparación histomorfométrica de Bio-Oss frente a Osteodens en procedimientos de elevación del suelo del seno maxilar

Introduction: The loss of dental elements can lead to excessive bone loss in the posterior maxillary segments, which can limit the placement of dental implants in that area, the pneumatization of the maxillary sinus and the absence of dental elements to keep the bone active are some of the main causes. Among the wide range of available grafting materials, bovine hydroxyapatite has been extensively studied and has shown excellent clinical and histological results. Materials and methods: A total of 17 maxillary sinus floor elevations were performed (n = 8 Osteodens, n = 9 Bio-Oss). After a healing period of 6 to 8 months, a block of the grafted area was obtained using trephines and analyzed by histomorphometry. Results: The percentage of neoformed bone tissue was higher for Bio-Oss (39.0% ± 11.1) compared to Osteodens (33.4% ± 8.3), while the remaining graft values were slightly lower in Bio-Oss compared to Osteodens (16.3% ± 11.2 and 20.8% ± 12.1, respectively). The proportion of connective tissue was similar in both groups (44.7% Bio-Oss and 45.8% Osteodens). Age, gender, and residual height of the sinus floor did not show statistically significant differences. Conclusions: In this study, both graft materials (Bio-Oss and Osteodens) showed no statistically significant differences in their ability to regenerate suitable bone tissue for implant placement after 6 months of healing. Further studies with a larger sample size are needed to validate these results.

Introducción: La pérdida de elementos dentarios puede provocar una excesiva pérdida ósea en los segmentos maxilares posteriores, lo que puede limitar la colocación de implantes dentarios en esa zona, la neumatización del seno maxilar y la ausencia de elementos dentarios que mantengan el hueso activo son algunas de las principales causas. Entre la amplia gama de materiales de injerto disponibles, la hidroxiapatita bovina ha sido ampliamente estudiada y ha mostrado excelentes resultados clínicos e histológicos. Materiales y métodos: Se realizaron un total de 17 elevaciones del suelo del seno maxilar (n = 8 Osteodens, n = 9 Bio-Oss). Tras un periodo de cicatrización de 6 a 8 meses, se obtuvo un bloque de la zona injertada mediante trépanos y se analizó mediante histomorfometría. Resultados: El porcentaje de tejido óseo neoformado fue mayor en Bio-Oss (39,0% ± 11,1) en comparación con Osteodens (33,4% ± 8,3), mientras que los valores del injerto remanente fueron ligeramente inferiores en Bio-Oss en comparación con Osteodens (16,3% ± 11,2 y 20,8% ± 12,1, respectivamente). La proporción de tejido conjuntivo fue similar en ambos grupos (44,7% Bio-Oss y 45,8% Osteodens). La edad, el sexo y la altura residual del piso sinusal no mostraron diferencias estadísticamente significativas. Conclusiones: En este estudio, ambos materiales de injerto (Bio-Oss y Osteodens) no mostraron diferencias estadísticamente significativas en su capacidad para regenerar tejido óseo adecuado para la colocación de implantes tras 6 meses de cicatrización. Se necesitan más estudios con un tamaño de muestra mayor para validar estos resultados.

A New Concept of Horizontal Bone Augmentation Using Collagen Bovine Bone Blocks Without Membrane at Implant Placement: A Preliminary Study.

Purpose: A buccal bone thickness (BBT) of at least 1.8-2 mm is necessary to ensure long-term implant stability, and a bone grafting procedure is commonly needed to restore this BBT. This study aims to prove the effectiveness of a novel bone augmentation technique in which minero-organic bone substitutes are solely used to restore adequate BBT, excluding the need for coverage membranes. Methods: Fifty partially edentulous patients having a residual bone width ranging between 5 and 6 mm were enrolled in this study. The horizontal buccal defects were grafted simultaneously at implant placement. Minero-organic collagen bovine bone blocks (CBBB) were placed on the outer side of the buccal bone wall, and adapted to the defect morphology through slow compressive movements. The grafted sites were not covered with any type of membrane nor stabilized with fixation pins. Cone-beam computed tomography scans were obtained pre-operatively, immediately post-surgery, and four months later. Scans were superimposed on the ITK-Snap software to measure the amount of bone gain and assess the percentage of CBBB resorption. Measurements were effectuated at four different levels apically to crestal level. Results: Radiographic findings showed BBT increase and CBBB resorption in all cases, four months post-grafting. A mean horizontal bone gain of 1.39 mm was calculated at a crestal level. Conclusion: Based on these findings, it appears that this novel and user-friendly bone grafting technique can achieve positive outcomes from both clinical and radiographic perspectives.

The impact of deproteinized bovine bone particle size on histological outcomes in sinus floor elevation: a systematic review and meta-analysis.

OBJECTIVES: The main purpose of this study was to evaluate whether large granular bovine bone can be as effective as small granular bovine bone in maxillary sinus floor elevation. METHODS: A comprehensive online search of eligible articles was conducted using PubMed, EMBASE, Cochrane Library, Scopus, and Web of Science, and a systematic review and meta-analysis was performed from establishment to February, 2023. The outcome indicators were the percentage of connective tissue, the percentage of newly formed bone and the percentage of residual xenograft respectively. The meta-analysis was conducted by using the Stata 15.1 (Stata Conpernarn, USA) and Review Manager software5.4.1. RESULTS: After careful screening and review, a total of 4 studies were included for systematic review and meta-analysis. The data were extracted to compare the histological performance of bovine bones with different particle sizes after maxillary sinus elevation. No significant differences were found in the percentage of connective tissue, the percentage of newly formed bone, and the percentage of residual xenograft. CONCLUSION: In this study, a systematically review of the previous literature showed that similar histological results were obtained for both large-particle bovine bone and small-particle bovine bone. Therefore, the large granular bovine bone and the small granular bovine bone were equally effective in maxillary sinus elevation. It is difficult to make conclusion from limited evidence from four studies. More clinical evidence was needed.

The Interplay of Raloxifene and Sonochemical Bio-Oss in Early Maxillary Sinus Bone Regeneration: A Histological and Immunohistochemical Analysis in Rabbits.

The study aimed to assess the efficacy of using Raloxifene with ultrasonic processing to enhance Bio-Oss®, a bone graft substitute, for maxillary sinus bone height reconstruction. A total of 24 rabbit maxillary sinuses were distributed into three groups, each receiving different treatments: Bio-Oss® only, sonicated Bio-Oss, and sonicated Bio-Oss® with Raloxifene. Surgical procedures and subsequent histomorphometric and immunohistochemistry analyses were conducted to evaluate the bone formation, connective tissue, and remaining biomaterial, as well as the osteoblastic differentiation and maturation of collagen fibers. Results indicated that the sonicated Bio-Oss® and Bio-Oss® groups showed similar histological behavior and bone formation, but the Raloxifene group displayed inflammatory infiltrate, low bone formation, and disorganized connective tissue. The statistical analysis confirmed significant differences between the groups in terms of bone formation, connective tissue, and remaining biomaterial. In conclusion, the study found that while sonicated Bio-Oss® performed comparably to Bio-Oss® alone, the addition of Raloxifene led to an unexpected delay in bone repair. The findings stress the importance of histological evaluation for accurate bone repair assessment and the necessity for further investigation into the local application of Raloxifene. Future research may focus on optimizing bone substitutes with growth factors to improve bone repair.

Stabilization of Bio-Oss® particulates using photocurable hydrogel to enhance bone regeneration by regulating macrophage polarization.

Bone substitutes are widely used in maxillofacial and oral surgeries. However, in clinical practice, bone substitutes with various forms, including separated particulates, powders, and blocks, have exhibited poor handling properties and space maintenance characteristics, resulting in long surgery procedures and unstable volume of the newly formed bone. Movable separated particulates with high stiffness have induced local inflammatory responses that hinder bone regeneration. The present study aimed to develop a new method to enhance the stability and operability of bone substitutes commonly used in dentistry by premixing with photocurable hydrogel GelMA. The GelMA-encapsulated particulate had a strong capacity to aggregate separated particulates and firmly attach to the host bone defect after photocuring compared to particulates alone. Additionally, macrophages at the surface of the GelMA-stabilized particulates tended to present a more M2-like phenotype than those at the surface of Bio-Oss®, leading to more MMR+ multinucleated giant cell formation and the induction of blood vessel invasion and new bone formation. In conclusion, this hydrogel-coated bone substitute strategy facilitates bone regeneration with increased operability, a stable volume of osteogenic space, and a favorable osteogenic microenvironment, indicating its potential value in the field of maxillofacial and oral surgeries when bone substitutes are needed.

The Synthetic Collagen-Binding Peptide NIPEP-OSS Delays Mouse Myeloma Progression.

Multiple myeloma (MM) is the second most common hematological malignancy. It is a clonal B-cell disorder characterized by the proliferation of malignant plasma cells in the bone marrow, the presence of monoclonal serum immunoglobulin, and osteolytic lesions. An increasing amount of evidence shows that the interactions of MM cells and the bone microenvironment play a significant role, suggesting that these interactions may be good targets for therapy. The osteopontin-derived collagen-binding motif-bearing peptide NIPEP-OSS stimulates biomineralization and enhances bone remodeling dynamics. Due to its unique targeted osteogenic activity with a broad safety margin, we evaluated the potential of NIPEP-OSS for anti-myeloma activity using MM bone disease (MMBD) animal models. In a 5TGM1-engrafted NSG model, the survival rates of the control and treated groups were significantly different (p = 0.0014), with median survival times of 45 and 57 days, respectively. The bioluminescence analyses showed that myeloma slowly developed in the treated mice compared to the control mice in both models. NIPEP-OSS enhanced bone formation by increasing biomineralization in the bone. We also tested NIPEP-OSS in a well-established 5TGM1-engrafted C57BL/KaLwRij model. Similar to the previous model, the median survival times of the control and treated groups were significantly different (p = 0.0057), with 46 and 63 days, respectively. In comparison with the control, an increase in p1NP was found in the treated mice. We concluded that NIPEP-OSS delays mouse myeloma progression via bone formation in MMBD mouse models.

SIRT6 ameliorates LPS-induced apoptosis and tight junction injury in ARDS through the ERK1/2 pathway and autophagy.

Sirtuin6 (SIRT6) has been demonstrated to be involved in a range of physiological processes and diseases, while its role in acute respiratory distress syndrome (ARDS) remains unclear. Therefore, this study focused on the role and underlying mechanism of SIRT6 in ARDS with the aim of identifying potential therapeutic targets. In this study, we found that SIRT6 was significantly decreased in lipopolysaccharide (LPS)-induced A549 cells and a murine model. In vitro overexpression of SIRT6 restored the expression of tight junction proteins (ZO-1 and occludin) and alleviated cell apoptosis and inflammation, while knockdown of SIRT6 aggravated the loss of tight junction proteins (ZO-1 and occludin) and promoted cell apoptosis and inflammation in LPS-induced A549 cells. Furthermore, the overexpression of SIRT6 enhanced autophagy and inhibited the ERK1/2 pathway, while the knockdown of SIRT6 inhibited autophagy and activated the ERK1/2 pathway. The autophagy activator rapamycin and the ERK1/2 inhibitor PD98059 rescued the effects of SIRT6 knockdown on tight junction proteins, apoptosis, and inflammation. Mechanistically, SIRT6 deacetylated histone 3 at Lys9 to negatively regulate the ERK1/2 pathway. In vivo, the SIRT6-specific inhibitor OSS_128167 also significantly accelerated LPS-induced loss of tight junction proteins, lung inflammation, and apoptosis. Meanwhile, the SIRT6-specific inhibitor OSS_128167 also activated the ERK1/2 pathway and inhibited lung autophagy. These results suggested that SIRT6 could ameliorate the loss of tight junction proteins, inflammation, and apoptosis in LPS-induced ARDS by inhibiting the ERK1/ 2 pathway and enhancing autophagy, indicating that SIRT6 plays a beneficial role in ARDS and might be a potential therapeutic target for ARDS.

Retinal Structure and Function in a Knock-in Mouse Model for the FAM161A-p.Arg523∗ Human Nonsense Pathogenic Variant.

Purpose: Pathogenic variants in FAM161A are the most common cause of retinitis pigmentosa in Israel. Two founder pathogenic variants explain the vast majority of cases of Jewish origin, 1 being a nonsense variant (p.Arg523∗). The aim of this study was to generate a knock-in (KI) mouse model harboring the corresponding p.Arg512∗ pathogenic variant and characterize the course of retinal disease. Design: Experimental study of a mouse animal model. Subjects/Participants/Controls: A total of 106 Fam161a knock-in mice and 29 wild-type mice with C57BL/6J background particiapted in this study. Methods: Homozygous Fam161a p.Arg512∗ KI mice were generated by Cyagen Biosciences. Visual acuity (VA) was evaluated using optomotor tracking response and retinal function was assessed by electroretinography (ERG). Retinal structure was examined in vivo using OCT and fundus autofluorescence imaging. Retinal morphometry was evaluated by histologic and immunohistochemical (IHC) analyses. Main Outcome Measures: Visual and retinal function assessments, clinical imaging examinations, quantitative histology, and IHC studies of KI as compared with wild-type (WT) mice retinas. Results: The KI model was generated by replacing 3 bp, resulting in p.Arg512∗. Homozygous KI mice that had progressive loss of VA and ERG responses until the age of 18 months, with no detectable response at 21 months. OCT showed complete loss of the outer nuclear layer at 21 months. Fundus autofluorescence imaging revealed progressive narrowing of blood vessels and formation of patchy hyper-autofluorescent and hypo-autofluorescent spots. Histologic analysis showed progressive loss of photoreceptor nuclei. Immunohistochemistry staining showed Fam161a expression mainly in photoreceptors cilia and the outer plexiform layer (OPL) in WT mice retinas, whereas faint expression was evident mainly in the cilia and OPL of KI mice. Conclusions: The Fam161a - p.Arg512∗ KI mouse model is characterized by widespread retinal degeneration with relatively slow progression. Surprisingly, disease onset is delayed and progression is slower compared with the previously reported knock-out model. The common human null mutation in the KI mouse model is potentially amenable for correction by translational read-through-inducing drugs and by gene augmentation therapy and RNA editing, and can serve to test these treatments as a first step toward possible application in patients. Financial Disclosures: The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Situational assessment for fecal sludge management in major cities of Pakistan.

With enhanced focus on global sanitation, access to toilets at the household level is increasing in developing countries although the provision of sewer networks is not expanding at the same pace. This is resulting in the adaptation of on-site sanitation facilities to contain the fecal sludge. The fecal sludge generated by the on-site sanitation facilities requires emptying, treatment, and safe end-use or disposal. In this study, the sanitation situation and need for fecal sludge management was evaluated in major cities of Pakistan including Karachi (provincial capital), Lahore (provincial capital), and Islamabad (national capital). Primary and secondary data were collected from key informant interviews of the stakeholders, national and international reports, research, and review articles. Infographics on wastewater and fecal sludge from origin to disposal were developed using a shit flow diagram tool and enabling environment was evaluated with a modified service delivery assessment tool. The results indicate that sewerage network coverage exists for 60%, 63%, and 50% of the areas in Karachi, Lahore, and Islamabad respectively. The sewerage network in major cities is old, leaking, and insufficient, thus a limited amount of wastewater reaches the treatment plants. Total wastewater treatment in Karachi and Islamabad is 10% and 9% respectively whereas, in Lahore, there is no infrastructure for the same. The safe sanitation in Lahore (8%) and Islamabad (25%) is coming from on-site sanitation systems with fecal sludge buried safely onsite. National level sanitation programs exist in the country but are limited to reducing open defecation and containments of fecal sludge only. The inclusion of complete fecal sludge management related framework, guidelines, and policies can help achieve the goal of safe sanitation for all.

Agreement between the American Shoulder and Elbow Surgeons Society Standardized Shoulder Assessment score (ASES) and the Oxford Shoulder Score (OSS) in patients presenting with shoulder pathology: A cohort analysis of the Clinical Quality Registry for Outcomes in Shoulder and Elbow Pathology (CROSEP) registry.

Background: The choice of patient-reported outcome measure (PROM) used in shoulder studies varies based on clinician's preference and location. This creates difficulties when attempting to compare studies which have used different PROMs as their outcome measure. This study aims to assess the agreement between the American Shoulder and Elbow Surgeons score (ASES) and the Oxford Shoulder Score (OSS), and identify factors associated with agreement. Methods: Patients with shoulder pathology were identified from a multi-cohort observational practice registry. 1050 paired ASES and OSS pre-treatment scores were prospectively collected. Linear regression was performed to assess the agreement between the PROMs. Mixed-effects analysis of variance was performed to assess the influence of factors associated with agreement. Results: Regression for mean total and mean function ASES and OSS demonstrated good fit (adjusted R2 57.7%, P < 0.001; and 63.9%, P < 0.001). Mean pain subscore demonstrated a poorer fit (adjusted R2 39.4%, P < 0.001). Crosswalks to convert between mean scores were produced with reasonable precision. Veterans RAND 12-Item Health Survey score, age and diagnosis cohort influenced agreement. Conclusion: Mean total and mean function ASES and OSS scores agree well with each other. This allows for a more informed comparison of studies using either PROMs as their outcome measure.

CGF-HLC-I repaired the bone defect repair of the rabbits mandible through tight junction pathway.

Background: The human-like collagen I (HLC-I) combined concentrated growth factors was used to construct CGF-HLC-I composite biomaterials to repair the critical bone defect disease model of rabbit mandible. This study aimed to research the repair mechanism of CGF-HLC-I/Bio-Oss in rabbit mandibular critical bone defect, to provide a new treatment direction for clinical bone defect repair. Methods: The optimal concentration of HLC-I (0.75%) was selected in this study. Nine New Zealand white rabbits were randomly divided into 3 groups, normal control group, Bio-Gide/Bio-Oss and CGF-0.75%HLC-I/Bio-Oss group (n = 3, each group). CGF-0.75%HLC-I/Bio-Oss and Bio-Gide/Bio-Oss were implanted into rabbit mandibles, then X-ray, Micro-CT, HE and Masson staining, immunohistochemical staining and biomechanical testing were performed with the bone continuity or maturity at 4, 8 and 12 weeks after surgery. The repair mechanism was studied by bioinformatics experiments. Results: As the material degraded, the rate of new bone formation in the CGF-0.75% HLC-I/Bio-Oss group was better than that the control group by micro-CT. The biomechanical test showed that the compressive strength and elastic modulus of the CGF-0.75%HLC-I/Bio-Oss group were higher than those of the control group. HE and Masson staining showed that the bone continuity or maturity of the CGF-0.75%HLC-I/Bio-Oss group was better than that of the control group. Immunohistochemical staining showed significantly higher bone morphogenetic protein 2 (BMP2) and Runt-related transcription factor 2 (RUNX2) in the CGF-0.75%HLC-I/Bio-Oss group than the control group at 8 and 12 W and the difference gradually decreased with time. There were 131 differentially expressed proteins (DEPs) in the Bio-Gide/Bio-Oss and CGF-0.75%HLC-I/Bio-Oss groups, containing 95 up-regulated proteins and 36 down-regulated proteins. KEGG database enrichment analysis showed actinin alpha 1 (ACTN1) and myosin heavy-Chain 9 (MYH9) are the main potential differential proteins related to osteogenesis, and they are enriched in the TJs pathway. Conclusion: CGF-0.75%HLC-I/Bio-Oss materials are good biomaterials for bone regeneration which have strong osteoinductive activity. CGF-0.75%HLC-I/Bio-Oss materials can promote new bone formation, providing new ideas for the application of bone tissue engineering scaffold materials in oral clinics.

Definition of chemical markers for Hancornia speciosa Gomes by chemometric analysis based on the chemical composition of extracts, their vasorelaxant effect and α-glucosidase inhibition.

ETHNOPHARMACOLOGICAL RELEVANCE: Hancornia speciosa Gomes (Apocynaceae) is a tree found in the Brazilian savannah, traditionally used to treat several diseases, including diabetes and hypertension. The anti-hypertensive activity of H. speciosa leaves (HSL) has been demonstrated in different models and is credited to the vasodilator effect and ACE (angiotensin-converting enzyme) inhibition. The hypoglycemic effect of HSL has been also reported. AIM OF THE STUDY: To establish correlations between the biological activities elicited by H. speciosa extracts and the contents of their major compounds, aiming to define chemical markers related to the potential antihypertensive and antidiabetic effects of the species. Additionally, it aimed to isolate and characterize the chemical structure of a marker related to the α-glucosidase inhibitory effect. MATERIALS AND METHODS: Extracts of a single batch of H. speciosa leaves were prepared by extraction with distinct solvents (ethanol/water in different proportions; methanol/ethyl acetate), employing percolation or static maceration as extraction techniques, at different time intervals. The contents of chlorogenic acid, rutin and FlavHS (a tri-O-glycoside of quercetin) were quantified by a developed and validated HPLC-PDA method. Bornesitol was determined by HPLC-PDA after derivatization with tosyl chloride, whereas total flavonoids were measured spectrophotometrically. Identification of other constituents in the extracts was performed by UPLC-DAD-ESI-MS/MS analysis. The vasorelaxant activity was assayed in rat aortic rings precontracted with phenylephrine, and α-glucosidase inhibition was tested in vitro. Principal component analysis (PCA) was employed to evaluate the contribution of each marker to the biological responses. Isolation of compound 1 was carried out by column chromatography and structure characterization was accomplished by NMR and UPLC-DAD-ESI-MS/MS analyses. RESULTS: The contents of the chemical markers (mean ± s.d. % w/w) varied significantly among the extracts, including total flavonoids (2.68 ± 0.14 to 5.28 ± 0.29), bornesitol (5.11 ± 0.26 to 7.75 ± 0.78), rutin (1.46 ± 0.06 to 1.97 ± 0.02), FlavHS (0.72 ± 0.05 to 0.94 ± 0.14) and chlorogenic acid (0.67 ± 0.09 to 0.91 ± 0.02). All extracts elicited vasorelaxant effect (pIC50 between 4.97 ± 0.22 to 6.48 ± 0.10) and α-glucosidase inhibition (pIC50 between 3.49 ± 0.21 to 4.03 ± 0.10). PCA disclosed positive correlations between the vasorelaxant effect and the contents of chlorogenic acid, rutin, total flavonoids, and FlavHS, whereas a negative correlation was found with bornesitol concentration. No significant correlation between α-glucosidase inhibition and the contents of the above-mentioned compounds was found. On the other hand, PCA carried out with the areas of the ten major peaks from the chromatograms disclosed positive correlations between a peak ascribed to co-eluted triterpenes and α-glucosidase inhibition. A triterpene was isolated and identified as 3-O-ß-(3'-R-hydroxy)-hexadecanoil-lupeol. CONCLUSION: According to PCA results, the vasorelaxant activity of H. speciosa extracts is related to flavonoids and chlorogenic acid, whereas the α-glucosidase inhibition is associated with lipophilic compounds, including esters of lupeol like 3-O-ß-(3'-R-hydroxy)-hexadecanoil-lupeol, described for the first time for the species. These compounds can be selected as chemical markers for the quality control of H. speciosa plant drug and derived extracts.

G3BP2 regulates oscillatory shear stress-induced endothelial dysfunction.

GTPase-activating SH3 domain-binding protein 2 (G3BP2) is a mediator that responds to environmental stresses through stress granule formation and is involved in the progression of chronic diseases. However, no studies have examined the contribution of G3BP2 in the oscillatory shear stress (OSS)-induced endothelial dysfunction. Here we assessed the effects of G3BP2 in endothelial cells (ECs) function and investigated the underlying mechanism. Using shear stress apparatus and partial ligation model, we identified that stress granule-related genes in ECs could be induced by OSS with RNA-seq, and then confirmed that G3BP2 was highly and specifically expressed in athero-susceptible endothelia in the OSS regions. G3bp2 -/- Apoe -/- mice had significantly decreased atherosclerotic lesions associated with deficiency of G3BP2 in protecting endothelial barrier function, decreasing monocyte adhesion to ECs and inhibiting the proinflammatory cytokine levels. Furthermore, loss of G3BP2 diminished OSS-induced inflammation in ECs by increasing YAP nucleocytoplasmic shuttling and phosphorylation. These data demonstrate that G3BP2 is a critical OSS regulated gene in regulating ECs function and that G3BP2 inhibition in ECs is a promising atheroprotective therapeutic strategy.

Irrigated Crop Types Mapping in Tashkent Province of Uzbekistan with Remote Sensing-Based Classification Methods.

Appropriate crop type mapping to monitor and control land management is very important in developing countries. It can be very useful where digital cadaster maps are not available or usage of Remote Sensing (RS) data is not utilized in the process of monitoring and inventory. The main goal of the present research is to compare and assess the importance of optical RS data in crop type classification using medium and high spatial resolution RS imagery in 2018. With this goal, Landsat 8 (L8) and Sentinel-2 (S2) data were acquired over the Tashkent Province between the crop growth period of May and October. In addition, this period is the only possible time for having cloud-free satellite images. The following four indices "Normalized Difference Vegetation Index" (NDVI), "Enhanced Vegetation Index" (EVI), and "Normalized Difference Water Index" (NDWI1 and NDWI2) were calculated using blue, red, near-infrared, shortwave infrared 1, and shortwave infrared 2 bands. Support-Vector-Machine (SVM) and Random Forest (RF) classification methods were used to generate the main crop type maps. As a result, the Overall Accuracy (OA) of all indices was above 84% and the highest OA of 92% was achieved together with EVI-NDVI and the RF method of L8 sensor data. The highest Kappa Accuracy (KA) was found with the RF method of L8 data when EVI (KA of 88%) and EVI-NDVI (KA of 87%) indices were used. A comparison of the classified crop type area with Official State Statistics (OSS) data about sown crops area demonstrated that the smallest absolute weighted average (WA) value difference (0.2 thousand ha) was obtained using EVI-NDVI with RF method and NDVI with SVM method of L8 sensor data. For S2-sensor data, the smallest absolute value difference result (0.1 thousand ha) was obtained using EVI with RF method and 0.4 thousand ha using NDVI with SVM method. Therefore, it can be concluded that the results demonstrate new opportunities in the joint use of Landsat and Sentinel data in the future to capture high temporal resolution during the vegetation growth period for crop type mapping. We believe that the joint use of S2 and L8 data enables the separation of crop types and increases the classification accuracy.