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Lactate elevation is a well-characterized biomarker of mitochondrial dysfunction, but its role in diabetic kidney disease (DKD) is not well defined. Urine lactate was measured in patients with type 2 diabetes (T2D) in 3 cohorts (HUNT3, SMART2D, CRIC). Urine and plasma lactate were measured during euglycemic and hyperglycemic clamps in participants with type 1 diabetes (T1D). Patients in the HUNT3 cohort with DKD had elevated urine lactate levels compared with age- and sex-matched controls. In patients in the SMART2D and CRIC cohorts, the third tertile of urine lactate/creatinine was associated with more rapid estimated glomerular filtration rate decline, relative to first tertile. Patients with T1D demonstrated a strong association between glucose and lactate in both plasma and urine. Glucose-stimulated lactate likely derives in part from proximal tubular cells, since lactate production was attenuated with sodium-glucose cotransporter-2 (SGLT2) inhibition in kidney sections and in SGLT2-deficient mice. Several glycolytic genes were elevated in human diabetic proximal tubules. Lactate levels above 2.5 mM potently inhibited mitochondrial oxidative phosphorylation in human proximal tubule (HK2) cells. We conclude that increased lactate production under diabetic conditions can contribute to mitochondrial dysfunction and become a feed-forward component to DKD pathogenesis.

Maleic acid (MA) induces renal tubular cell dysfunction directed to acute kidney injury (AKI). AKI is an increasing global health burden due to its association with mortality and morbidity. However, targeted therapy for AKI is lacking. Previously, we determined mitochondrial-associated proteins are MA-induced AKI affinity proteins. We hypothesized that mitochondrial dysfunction in tubular epithelial cells plays a critical role in AKI. In vivo and in vitro systems have been used to test this hypothesis. For the in vivo model, C57BL/6 mice were intraperitoneally injected with 400 mg/kg body weight MA. For the in vitro model, HK-2 human proximal tubular epithelial cells were treated with 2 mM or 5 mM MA for 24 h. AKI can be induced by administration of MA. In the mice injected with MA, the levels of blood urea nitrogen (BUN) and creatinine in the sera were significantly increased (p

There is a need to define regions of gene activation or repression that control human kidney cells in states of health, injury, and repair to understand the molecular pathogenesis of kidney disease and design therapeutic strategies. Comprehensive integration of gene expression with epigenetic features that define regulatory elements remains a significant challenge. We measure dual single nucleus RNA expression and chromatin accessibility, DNA methylation, and H3K27ac, H3K4me1, H3K4me3, and H3K27me3 histone modifications to decipher the chromatin landscape and gene regulation of the kidney in reference and adaptive injury states. We establish a spatially-anchored epigenomic atlas to define the kidneys active, silent, and regulatory accessible chromatin regions across the genome. Using this atlas, we note distinct control of adaptive injury in different epithelial cell types. A proximal tubule cell transcription factor network of ELF3, KLF6, and KLF10 regulates the transition between health and injury, while in thick ascending limb cells this transition is regulated by NR2F1. Further, combined perturbation of ELF3, KLF6, and KLF10 distinguishes two adaptive proximal tubular cell subtypes, one of which manifested a repair trajectory after knockout. This atlas will serve as a foundation to facilitate targeted cell-specific therapeutics by reprogramming gene regulatory networks.

Aims: This study aimed to compare outcomes of internal fixation and non-operative management in younger adults. Methods: A retrospective cohort study was undertaken in patients aged 18–55 with 2-part or 3-part proximal humerus fractures at a Level 1 trauma centre from January 2010 to December 2018. Outcome measures were the Oxford shoulder score (OSS), EQ-5D-5L, and radiological outcomes. Complications recorded included further surgery, loss of position/fixation, and non-union/malunion. Statistical analysis included univariable analysis and multivariable analysis performed using binary logistic regression and linear regression. Results: A total of 184 eligible patients were included; 99 underwent operative fixation and 85 were managed with sling immobilisation. The mean (SD) age in the operative group was 39.3 ± 10.6 and in the non-operative group was 43.2 ± 10.8 (p = 0.02). Seventy-seven percent completed a minimum 12-month follow-up (median 3.2 years, IQR 2–6.5 years). Most 3-part fractures were treated surgically (78%), as opposed to 44% of 2-part fractures. All open fractures, all segmental fractures, eight head split fractures (89%), and 12 fracture-dislocations (80%) were treated surgically. There was no difference in mean OSS (43.7 operative vs 42.1 non-operative, p = 0.27), mean EQ-5D-5L utility score (0.81 vs 0.78, p = 0.32) or proportion returned to work (83% vs 75%, p = 0.34). Adjusted for case-mix, there was no difference in OSS (adjusted mean difference 0.24, 95%CI −2.73 to 3.22, p = 0.87) or EQ-5D-5L utility score (adjusted mean difference 0.00, 95%CI −0.06 to 0.07, p = 0.96). The complication rate was high (36% non-operative, 27% operative, p = 0.24). A higher rate of varus malunion was observed in the non-operative group (24.0% vs 41.4%, p < 0.001). Following operative management, 23% underwent subsequent surgery compared with 7% of the non-operative group (p = 0.002). Conclusion: In younger adults with proximal humerus fractures no differences in patient reported outcome measures were observed between groups. Operative management was associated with improved radiological outcomes, but a higher rate of subsequent surgery. [ABSTRACT FROM AUTHOR]

The promotion of food from underutilized plants can help combat biodiversity loss, foster cultural preservation, and empower farmers in the face of market pressures and sustainable production conditions. The nutritional and aromatic characterization of two undervalued types of Sorbus domestica fruits, differentiated by their apple and pear shapes, has been carried out. Official Association of Analytical Communities methods have been used for proximate composition and mineral analysis determinations, and gas chromatography was used for the analysis of volatile components in three states of ripeness and compared with the aromas of fresh apple and quince jam. S. domestica fruits are a good source of K, Ca, Fe, and fiber and are an important source of antioxidants in the human diet. S. domestica fruits have proven to be very distinctive in the aromatic fraction. 1-hexanol, hexyl 1,3-octanediol, phenylacetaldehyde, nonanal, hexanal, and α-farnesene are the most potent odor compounds in the overripening stage of the fruits. The aroma profiles of immature S. domestica fruits were dominated by aldehydes, while in the overripe stage, the fruit accumulated abundant esters, alcohols, and sesquiterpenoids. S. domestica fruits could be introduced as an alternative to seasonal fruit consumption and could generate sustainable production and consumption alternatives while recovering cultural and food heritage. [ABSTRACT FROM AUTHOR]

Objective: This study aimed to determine if patients with chronic ankle instability (CAI) exhibit biomechanical changes associated with the increased risk of anterior cruciate ligament (ACL) injury during landing tasks. Study Design: This study was conducted through systematic review and meta-analysis. Data Sources: Searches were conducted in May 2024 across five electronic databases, including Web of Science, Scopus, PubMed, SPORTDiscus, and Cochrane Library. Eligibility Criteria: Studies were included if they (1) involved subjects with CAI and healthy controls and (2) assessed biomechanical variables such as ground reaction forces, joint angles, and joint torques. Results: Of the 675 identified studies, 171 were included in the review, and 13 were eligible for meta-analysis. The reviewed studies clearly defined research objectives, study populations, consistent participant recruitment, and exposures, and they used valid and reliable measures for outcomes. However, areas such as sample size calculation, study sample justification, blinding in assessments, and addressing confounders were not robust. This meta-analysis involved 542 participants (healthy group: n = 251; CAI group: n = 291). Compared with healthy individuals, patients with CAI exhibited a greater peak vertical ground reaction force (peak VGRF; SMD = 0.30, 95% CI: 0.07-0.53, p = 0.009), reduced hip flexion angles (SMD = -0.30, 95% CI: -0.51 to -0.17, p < 0.0001), increased trunk lateral flexion (SMD = 0.47, 95% CI: 0.05 to 0.9, p = 0.03), greater hip extension moments (SMD = 0.47, 95% CI: 0.09-0.84, p = 0.02), and increased knee extension moments (SMD = 0.39, 95% CI: 0.02-0.77, p = 0.04). Conclusion: During landing tasks, patients with CAI demonstrate increased hip extension moments and knee extension moments, decreased hip flexion angles, increased peak VGRF, and increased trunk lateral flexion angles. These biomechanical variables are associated with an elevated risk of ACL injuries. [ABSTRACT FROM AUTHOR]

Aim of study was to compare the clinical visual and radiographic diagnostic technique with histological analysis of early proximal carious lesions. Materials and method. Study group included 96 proximal surfaces (48 teeth obtained from dental extractions for orthodontic or periodontal reasons). The proximal surfaces were examined by visual clinical examen and radiographic examen. A histological assessment was performed as gold standard. The sensivity and specificity values were calculated for clinical and radiographic examen. The values were analysed using McNemar test, with significance threshold p < 0.05. Results. Significant statistical differences were obtained when comparing both the sensitivity and specificity of the radiological detection method compared to the clinical method (p=0.0001

Introduction: Interproximal contacts between primary teeth have traditionally been reported as broad and flat. A new system of classification for contacts called OXIS- O (open contact), X (point contact), I (straight contact), and S (curved contact) was introduced in 2018, based on the shapes observed occlusally. Understanding interproximal contacts in primary teeth is essential to comprehend the caries risk of the individual. Aim: To assess the prevalence of OXIS contact areas between non carious primary molars in 3 to 9 years old children and to determine the most common type of contact before and after the eruption of the first permanent molar. Materials and Methods: A cross-sectional study was conducted to determine the prevalence of the types of contacts between primary teeth through direct observation in a sample size of 260 contact areas. The study was carried out in the Department of Paediatric and Preventive Dentistry, Navi Mumbai, India, between August 2022 to February 2023. Ethical clearance from the university was obtained. A single calibrated examiner examined photographs of the interproximal contacts between primary molars. The contacts were assessed as O (open contact), X (point contact), I (straight contact), and S (curved contact) using the OXIS classification system. The prevalence of each contact type was recorded. Statistical analysis was performed using Statistical Package for Social Sciences (SPSS) 18.0 software. The prevalence of contact types was recorded in numbers and percentages. A comparison of contact types before and after the eruption of the first permanent molar was conducted using the Chi-square test. Result: The most common contact type was I (65.00%) both before and after the eruption of the first permanent molar. This was followed by S (19.62%), X (11.15%), and O (4.23%) in the primary dentition. After the eruption of the first permanent molars, I contact was the highest at 66.41%, followed by S (20.90%), X (12.68%), and O (0%). Conclusion: This study confirms the presence of O, X, I, and S types of interproximal contact areas in caries-free primary molars in 3 to 9 years old children.

Introduction: Interproximal contacts between primary teeth have traditionally been reported as broad and flat. A new system of classification for contacts called OXIS-O (open contact), X (point contact), I (straight contact), and S (curved contact) was introduced in 2018, based on the shapes observed occlusally. Understanding interproximal contacts in primary teeth is essential to comprehend the caries risk of the individual. Aim: To assess the prevalence of OXIS contact areas between non carious primary molars in 3 to 9 years old children and to determine the most common type of contact before and after the eruption of the first permanent molar. Materials and Methods: A cross-sectional study was conducted to determine the prevalence of the types of contacts between primary teeth through direct observation in a sample size of 260 contact areas. The study was carried out in the Department of Paediatric and Preventive Dentistry, Navi Mumbai, India, between August 2022 to February 2023. Ethical clearance from the university was obtained. A single calibrated examiner examined photographs of the interproximal contacts between primary molars. The contacts were assessed as O (open contact), X (point contact), I (straight contact), and S (curved contact) using the OXIS classification system. The prevalence of each contact type was recorded. Statistical analysis was performed using Statistical Package for Social Sciences (SPSS) 18.0 software. The prevalence of contact types was recorded in numbers and percentages. A comparison of contact types before and after the eruption of the first permanent molar was conducted using the Chi-square test. Result: The most common contact type was I (65.00%) both before and after the eruption of the first permanent molar. This was followed by S (19.62%), X (11.15%), and O (4.23%) in the primary dentition. After the eruption of the first permanent molars, I contact was the highest at 66.41%, followed by S (20.90%), X (12.68%), and O (0%). Conclusion: This study confirms the presence of O, X, I, and S types of interproximal contact areas in caries-free primary molars in 3 to 9 years old children. [ABSTRACT FROM AUTHOR]

BACKGROUND: The proximal tubules eliminate protein-bound toxins and drugs through secretion. Measurements or estimates of GFR do not necessarily reflect the physiologically distinct process of secretion. Clinical assessment of this important intrinsic kidney function requires endogenous markers that are highly specific for secretory transport. METHODS: We used metabolomics profiling to identify candidate markers of tubular secretory clearance in 50 participants from a kidney pharmacokinetics study. We measured metabolites in three sequential plasma samples and a concurrent 10-hour timed urine sample using hydrophilic interaction liquid chromatography/high-resolution mass spectrometry. We quantified the association between estimated kidney clearance and normalized plasma peak height of each candidate solute to the clearance of administered furosemide, a protein-bound, avidly secreted medication. RESULTS: We identified 528 metabolites present in plasma and urine, excluding pharmaceuticals. We found seven highly (>50%) protein-bound and 49 poorly bound solutes with clearances significantly associated with furosemide clearance and 18 solute clearances favoring an association with furosemide clearance by the 90th percentile compared with GFR. We also found four highly bound and 42 poorly bound plasma levels that were significantly associated with furosemide clearance. CONCLUSIONS: We found several candidate metabolites whose kidney clearances or relative plasma levels are highly associated with furosemide clearance, an avidly secreted tracer medication of the organic anion transporters, highlighting their potential as endogenous markers of proximal tubular secretory clearance.

Eccrine angiomatous hamartoma is an uncommon, benign clinical entity constituting a nodular proliferation of eccrine glands and vascular structures localized to the dermis that typically present as unilateral, flesh-colored, erythematous, or violaceous papules on the extremities. These hamartomas may be associated with pain, hyperhidrosis, joint deformity, or functional impairment depending on the severity of the disease process. We present a case of bilaterally symmetric, asymptomatic eccrine angiomatous hamartomas involving all proximal interphalangeal joints of both hands. To date, there are only four prior cases of bilaterally symmetric eccrine angiomatous hamartomas reported in the literature, suggesting that the distribution experienced by our patient may represent a previously undescribed syndrome.

This article examines different diagnostic methods for detecting early proximal carious lesions. The study compares clinical visual and radiographic techniques with histological analysis. The results show that radiographic methods are more effective in detecting these lesions compared to clinical methods. The article emphasizes the importance of using both visual examination and radiography for diagnosing carious lesions. Additionally, the article discusses the use of radiographic examinations, such as bitewing radiography and orthopantomography, in detecting carious lesions in children and patients with increased cariogenic risk. However, there are differing opinions on the effectiveness of orthopantomography in detecting non-cavitated carious lesions. Overall, the article concludes that radiographic methods have higher validity in detecting early proximal carious lesions compared to clinical methods. [Extracted from the article]

The promotion of food from underutilized plants can help combat biodiversity loss, foster cultural preservation, and empower farmers in the face of market pressures and sustainable production conditions. The nutritional and aromatic characterization of two undervalued types of Sorbus domestica fruits, differentiated by their apple and pear shapes, has been carried out. Official Association of Analytical Communities methods have been used for proximate composition and mineral analysis determinations, and gas chromatography was used for the analysis of volatile components in three states of ripeness and compared with the aromas of fresh apple and quince jam. S. domestica fruits are a good source of K, Ca, Fe, and fiber and are an important source of antioxidants in the human diet. S. domestica fruits have proven to be very distinctive in the aromatic fraction. 1-hexanol, hexyl 1,3-octanediol, phenylacetaldehyde, nonanal, hexanal, and α-farnesene are the most potent odor compounds in the overripening stage of the fruits. The aroma profiles of immature S. domestica fruits were dominated by aldehydes, while in the overripe stage, the fruit accumulated abundant esters, alcohols, and sesquiterpenoids. S. domestica fruits could be introduced as an alternative to seasonal fruit consumption and could generate sustainable production and consumption alternatives while recovering cultural and food heritage.

Proximal tibiofibular synostosis is a rare condition. It is often misdiagnosed or difficult to diagnose and its treatment is not widely known. There is no surgical procedure clearly reported in the literature. Our article will start by describing two cases we have seen, explaining their long clinical histories and illustrating them with the imaging tests performed. We will then describe our unique surgical technique which consists of resectioning the synostosis and interposing an allograft in the proximal tibiofibular joint. In this section, we will describe the cases of two patients operated on in our department in the last three years. In both cases, the patients presented with latent pain in the posterolateral part of the knee. The pain was always associated with a sporting activity. Diagnosis was not easy and complementary tests needed to be prescribed. We will then go on to give a detailed explanation of our unique surgical procedure consisting of the resection of the proximal tibiofibular synostosis and interposition of a fascia lata allograft in the pseudo-articulation. Proximal tibiofibular synostosis is not widely known and time to treatment is often too long. The purpose of our article is to inform practitioners about the availability of a successful surgical treatment.Kindly check and confirm the edit made in the title.yes Please confirm if all the author names are presented accurately and in the correct sequence (given name, middle name/initial, family name). yes [ABSTRACT FROM AUTHOR]

Background: Malignant tumours within the proximal pancreas traditionally require pancreaticoduodenectomy (PD) for cure. For smaller lesions with borderline malignant potential the risk/benefit of PD becomes difficult to justify. Robotic approaches to these lesions allow for parenchymal preserving resection with reduced complication profile without oncological compromise. Methods: A review of a single surgeons prospectively collated database across two institutions of consecutive robotic enucleations or parenchyma preserving resections of the proximal pancreas was performed between July 2018 and October 2021. Standard demographic data, preoperative variables, intraoperative parameters, post‐operative outcomes, morbidity and mortality were recorded. Results: Thirteen patients (8 female and 5 male) underwent robotic enucleation (EN) (8) and/or uncinectomy (UN) (5) in the proximal pancreas. Mean BMI was 32(kg/m2). Three patients (21%) underwent preoperative prophylactic pancreatic duct stenting. One patient required conversion to open. The median operative time in the EN group was 170 min (108–224 min) and the UN group was 160 min (110–204 min). The majority (8) of lesions were pNETs. Three lesions were IPMNs, with 1 solitary fibrous tumour and a serous cystic neoplasm (SCN) respectively. Median tumour size was 23 mm (11–58 mm) in the EN group, and 27 mm (17–38 mm) in the UN group. Ten of 13 patients had an R0 resection. There was no mortality in our series. Four (31%) patients across both groups developed clinically relevant POPF while none developed new endocrine or exocrine insufficiency. Average outpatient follow‐up has been 6 months (1–18 months). Conclusion: A robotic approach in proximal parenchymal preserving pancreatectomy is expanding, safe and feasible. [ABSTRACT FROM AUTHOR]

Separable convex optimization problems often arise from large scale applications, and alternating direction method of multipliers (ADMM), due to its ability to utilize the separable structure of the objective function, has become an extremely popular approach for solving this class of problems. However, the convergence of the primal iterates generated by ADMM is not guaranteed and the ADMM subproblems can be computationally demanding. Proximal ADMM (PADMM), which introduces proximal terms to the ADMM subproblems, not only guarantees convergence of both the primal and the dual iterates but also is able to take advantage of the problem structures. In this paper, by adopting a convex combination technique we propose a new variant of the classical ADMM, which we call golden ratio proximal ADMM (GrpADMM) as the golden ratio appears to be a key parameter. GrpADMM preserves all the favorable features of PADMM, such as the ability to take full use of problem structures and global convergence under relaxed parameter condition. We show that GrpADMM shares the O (1 / N) ergodic sublinear convergence rate, where N denotes the iteration counter. Furthermore, as long as one of the functions in the objective is strongly convex, the algorithm can be modified to achieve faster O (1 / N 2) ergodic convergence. Finally, we demonstrate the performance of the proposed algorithms via preliminary numerical experiments. [ABSTRACT FROM AUTHOR]

The usage of cisplatin, a highly potent chemotherapeutic, is limited by its severe nephrotoxicity. Arachidonic acid (ARA)-derived epoxyeicosatrienoic acids (EETs) and soluble epoxide hydrolase (sEH) inhibitors were shown to ameliorate this dose-limiting side effect, but both approaches have some pharmacological limitations. Analogues of EETs are an alternative avenue with unique benefits, but the current series of analogues face concerns regarding their structure and mimetic functionality. Hence, in this study, regioisomeric mixtures of four new ARA alkyl ethers were synthesized, characterized, and assessed as EET analogues against the concentration- and time-dependent toxicities of cisplatin in porcine proximal tubular epithelial cells. All four ether groups displayed bioisostere activity, ranging from marginal for methoxy- (1), good for n-propoxy- (4), and excellent for ethoxy- (2) and i-propoxy- (3). Compounds 2 and 3 displayed cytoprotective effects comparable to that of an EET regioisomeric mixture (5) against high, acute cisplatin exposures but were more potent against low to moderate, chronic exposures. Compounds 2 and 3 (and 5) acted through stabilization of the mitochondrial transmembrane potential and attenuation of reactive oxygen species, leading to reduced phosphorylation of mitogen-activated protein kinases p38 and JNK and decreased activation of caspase-9 and caspase-3. This study demonstrates that alkoxy- groups are potent and more metabolically stable bioisostere alternatives to the epoxide within EETs that enable sEH-independent activity. It also illustrates the potential of ether-based mimics of EETs and other epoxy fatty acids as promising nephroprotective agents to tackle the clinically relevant side effect of cisplatin without compromising its antineoplastic function.

The purpose of this retrospective case series was to review the demographics of alpine skiers who sustain tibial plateau fractures, evaluate the inter-observer reliability of the Schatzker classification for fractures sustained while alpine skiing, and to evaluate patient-reported outcomes. We hypothesized that most tibial plateau fractures would be low-energy fracture patterns (Schatzker I–III) and occur in women and less-experienced skiers. Charts and radiographs of patients treated surgically for tibial plateau fractures caused by alpine skiing were evaluated. Patients treated less than two years prior to review were excluded. Patients who qualified were contacted to complete a questionnaire regarding their skiing experience, their pain levels experienced following their accident, the weather conditions during the accident, and their return to sport. Forty-seven patients met the inclusion criteria. The mean age was 49, and 60% of the participants were male. There were 28 low-energy fracture patterns (Schatzker I–III) and 19 high-energy patterns (Schatzker IV–VI) with a 95.7% inter-observer reliability. Contrary to the hypothesis, tibial plateau fractures sustained while alpine skiing occurred in older, experienced riders. Approximately 40% were high-energy fractures. Although over 75% of patients reported having no pain or occasional pain at their final follow-ups, less than half of the patients returned to alpine skiing.

Aims: Total hip arthroplasty (THA) is considered the preferred treatment for displaced proximal femoral neck fractures. However, in many countries this option is economically unviable. To improve outcomes in financially disadvantaged populations, we studied the technique of concomitant valgus hip osteotomy and operative fixation (VOOF). This prospective serial study compares two treatment groups: VOOF versus operative fixation alone with cannulated compression screws (CCSs). Methods: In the first series, 98 hip fixation procedures were performed using CCS. After fluoroscopic reduction of the fracture, three CCSs were placed. In the second series, 105 VOOF procedures were performed using a closing wedge intertrochanteric osteotomy with a compression lag screw and lateral femoral plate. The alignment goal was to create a modified Pauwel’s fracture angle of 30°. After fluoroscopic reduction of fracture, lag screw was placed to achieve the calculated correction angle, followed by inter-trochanteric osteotomy and placement of barrel plate. Patients were followed for a minimum of two years. Results: Mean follow-up was 4.6 years (4.1 to 5.0) in the CCS group and 5.5 years (5.25 to 5.75) in the VOOF group. The mean Harris Hip Score at two-year follow-up was 83.85 in the CCS group versus 88.00 in the VOOF group (p < 0.001). At the latest follow-up, all-cause failure rate was 29.1% in the CCS group and 11.7% in the VOOF group (p = 0.003). The total cost of the VOOF technique was 7.2% of a THA, and total cost of the CCS technique was 6.3% of a THA. Conclusion: The VOOF technique decreased all-cause failure rate compared to CCS. The total cost of VOOF was 13.5% greater than CCS, but 92.8% less than a THA. Increased cost of VOOF was considered acceptable to all patients in this series. VOOF technique provides a reasonable alternative to THA in patients who cannot afford a THA procedure. Cite this article: Bone Jt Open 2023;4(5):329–337.

Objective: This study aimed to investigate the epidemiological characteristics and treatment options of proximal humerus fractures at a level one trauma center and to compare our data with the current literature. Methods: A retrospective review was conducted on all patients diagnosed and treated for proximal humerus fractures at Hamad General Hospital, a level one trauma center, between January 2018 and December 2019. Age, gender, mechanism of injury, fracture classification, mode of treatment, implant type, length of hospital stay, associated injuries and complications were analyzed. Results: A total of 190 patients with a mean age of 52.4 years were included; 56.8% were males. The incidence of proximal humerus fracture was 4.1/100,000 per year. Falling from a standing height was the most common cause of injury (50.5%). Additionally, Neer's two-part fracture was found to be the most common type (n = 132, 69%). Forty-one patients (21.3%) had other associated injuries. Most fractures were treated nonoperatively with an arm sling (n = 138, 72.6%). Conclusion: In summary, the incidence of proximal humerus fractures during the two-year study period was found to be 4.1 per 100,000 persons per year. Our results showed a lower incidence of proximal humerus fractures with a predominance of males and younger patients in Qatar's population compared to females and older patients in the developed countries. Our results may contribute to the development of effective strategies for preventing and treating proximal humerus fractures, and can provide important data for further high-level clinical research. Level of evidence: IV. [ABSTRACT FROM AUTHOR]

Background. Carpal tunnel syndrome (CTS) is a prevalent peripheral compressive neuropathy. In addition to an enlargement of the median nerve cross-sectional area (CSA), the carpal tunnel CSA may be a determinant of CTS. However, the findings of studies assessing the association between carpal tunnel CSA and CTS are very limited and inconclusive. Purpose. The present systematic review aimed to execute a meta-analysis of present literature to establish evidence of the association between the carpal tunnel CSA at the proximal and distal levels and CTS. Methods. PICOS strategy was used to electronically search key terms in the PubMed, Cochrane Library, Embase and Wiley Online databases with no restrictions on the publication date for case-control and cohort studies. The bias risks for these studies were assessed using the Newcastle-Ottawa Scale (NOS). Meta-analysis was performed using the RevMan5 from Cochrane. A total of 13 studies comparing the association between CSA of the carpal tunnel at the proximal and distal levels and CTS between 428 CTS participants and 324 controls with a 145/249 male-to-female ratio and a mean age of 42.2 met the inclusion criteria. Results. Overall, the studies were rated as acceptable quality, having scored 4, 6, 7, or 8 (out of 9 stars) on the NOS. Meta-analysis of the included studies indicated that the overall pooled mean difference of CSA of the carpal tunnel at the proximal level was higher in the CTS groups when compared with the control groups (0.79; 95% (confidence interval) CI 0.63-0.96; p = 0.003). Similarly, the overall pooled mean difference of CSA of the carpal tunnel at the distal level was higher in CTS individuals when compared with controls (0.54; 90%CI 0.32-0.76; p = 0.32). Conclusions. This review found evidence that an increased CSA of the carpal tunnel at the proximal and distal levels is associated with CTS. [ABSTRACT FROM AUTHOR]

Our results were obtained by determining the proximal femoral epiphysis angles on 58 dry femurs. The angle of inclination was found to range from 116.20-143.20°, the average angle value being 130.75°. The declination angle value was between 18,30-33,80°, the average angle value was 39.73°. The angle formed between the axis of the greater trochanter and the axis of the anatomical neck was found to be 62.40-90.10°, the average of the angle values being 82.38°. The angle formed between the axis of the greater trochanter and the upper edge of the anatomical neck was found to be 67.20-103.40°, with an average angle value of 86.18°. [ABSTRACT FROM AUTHOR]

The purpose of this retrospective case series was to review the demographics of alpine skiers who sustain tibial plateau fractures, evaluate the inter-observer reliability of the Schatzker classification for fractures sustained while alpine skiing, and to evaluate patient-reported outcomes. We hypothesized that most tibial plateau fractures would be low-energy fracture patterns (Schatzker I–III) and occur in women and less-experienced skiers. Charts and radiographs of patients treated surgically for tibial plateau fractures caused by alpine skiing were evaluated. Patients treated less than two years prior to review were excluded. Patients who qualified were contacted to complete a questionnaire regarding their skiing experience, their pain levels experienced following their accident, the weather conditions during the accident, and their return to sport. Forty-seven patients met the inclusion criteria. The mean age was 49, and 60% of the participants were male. There were 28 low-energy fracture patterns (Schatzker I–III) and 19 high-energy patterns (Schatzker IV–VI) with a 95.7% inter-observer reliability. Contrary to the hypothesis, tibial plateau fractures sustained while alpine skiing occurred in older, experienced riders. Approximately 40% were high-energy fractures. Although over 75% of patients reported having no pain or occasional pain at their final follow-ups, less than half of the patients returned to alpine skiing. [ABSTRACT FROM AUTHOR]

Going beyond previous work, this paper presents a systematic literature review that explores the deployment of satellites, drones, and ground-based sensors for yield prediction in agriculture. It covers multiple aspects of the topic, including crop types, key sensor platforms, data analysis techniques, and performance in estimating yield. To this end, datasets from Scopus and Web of Science were analyzed, resulting in the full review of 269 out of 1429 retrieved publications. Our study revealed that China (93 articles, >1800 citations) and the USA (58 articles, >1600 citations) are prominent contributors in this field; while satellites were the primary remote sensing platform (62%), followed by airborne (30%) and proximal sensors (27%). Additionally, statistical methods were used in 157 articles, and model-based approaches were utilized in 60 articles, while machine learning and deep learning were employed in 142 articles and 62 articles, respectively. When comparing methods, machine learning and deep learning methods exhibited high accuracy in crop yield prediction, while other techniques also demonstrated success, contingent on the specific crop platform and method employed. The findings of this study serve as a comprehensive roadmap for researchers and farmers, enabling them to make data-driven decisions and optimize agricultural practices, paving the way towards a fully digitized yield prediction. [ABSTRACT FROM AUTHOR]

Proximal renal tubular acidosis (pRTA) is characterized by a defect in the ability of the proximal convoluted tubule to reabsorb bicarbonate. The biochemical hallmark of pRTA is hyperchloremic metabolic acidosis with a normal anion gap, accompanied by appropriate acidification of the urine (simultaneous urine pH <5.3). Isolated defects in bicarbonate transport are rare, and pRTA is more often associated with Fanconi syndrome (FS), which is characterized by urinary loss of phosphate, uric acid, glucose, amino acids, low-molecular-weight proteins, and bicarbonate. Children with pRTA may present with rickets, but pRTA is often overlooked as an underlying cause of this condition. We report six children with rickets and short stature due to pRTA. One case was idiopathic, while the remaining five had a specific underlying condition: Fanconi-Bickel syndrome, Dent's disease, nephropathic cystinosis, type 1 tyrosinemia, and sodium-bicarbonate cotransporter 1-A (NBC1-A) defect. Five of these six children had features of FS, while the one with NBC1-A defect had isolated pRTA. [ABSTRACT FROM AUTHOR]

Purpose: In the case of stemmed implants for lower limb joint arthroplasty procedures, implant stability and survivorship generally rely on the strength of fixation in the medullary canal regardless of whether the procedure is primary or revision surgery. This study aimed to investigate the relationship between the proximal (Dorr classification) and distal (Citak classification) femoral canal geometry classification systems. Methods: A total of 200 patients who received standing long leg radiographs (hip to ankle) at our institution were identified using our institutional electronic radiology database. Patients were recruited into 4 groups. There were 100 male and 100 female patients with each of those being split into 50 right-sided and 50 left-sided long-leg standing anteroposterior (AP) radiographs. Two independent, blinded observers reviewed each radiograph on two separate occasions, with a minimum of a one-week interval between sittings to review each respective radiograph. Results: No statistically significant correlation was found between demographic data and clinical measurements. A statistically significant correlation was found between the patient's age and BMI results and Citak and Dorr measurements. There was excellent inter-observer and intra-observer agreement for the Citak and Dorr Classifications. The mean Cronbach's α coefficient was 0.96 (range 0.93–0.98) for the Citak Classification and 0.95 (range 0.83–0.97) for the Dorr Classification. There was also an excellent intra-observer agreement with 95% average pairwise per cent agreement for the Citak Classification and 95% average pairwise per cent agreement for the Dorr classification. A statistically significant positive correlation was found between Dorr Calcar Isthmus and Citak Ratio (p < 0.05). Conclusion: In this study, the Dorr and Citak classifications are put into relation to each other for the first time. The morphology of the femur was investigated in its entirety and it was shown that there was a positive correlation between the anatomical shape of the proximal and distal medullary canals. [ABSTRACT FROM AUTHOR]

Background: The aim of the study is to evaluate the proximal part of the ulna bone of the present and 13th century Byzantine period using the attachment points of the muscles and to evaluate the morphological changes. Materials and Methods: A total of 81 ulnae, 29 of which belong to the contemporary and unknown gender, and 52 from the thirteenth-century late Byzantine period are included in the study. The parameters were measured in millimeter on the photos with the ImageJ software. For the statistical analysis, SPSS 22.0 (IBM) software was used (p<0.005). Results:The descriptive values of the variables were given aMaters mean±standard deviation and minimum-maximum values. According to the results of the statistical analysis, there is no difference in the right and left sides. Except for the angle between the the most prominent anterior point of the olecranon (MAPO) - the most posterior point of the olecranon (MPPO) - the point of the maximum anterior angulation (MAA) parameter, the rest of the parameters were higher in the Byzantine period ulnae. Conclusions: In this study, we showed the period differences on the proximal part of the ulna especially the olecranon because of the using the extensor muscle of the forearm and the stabilizer muscle of the elbow. We believe that the data obtained will functional perspective help different disciplines, especially anthropologists and anatomists. [ABSTRACT FROM AUTHOR]

SGLT2 inhibitors are antihyperglycemic drugs that protect kidneys and the heart of patients with or without type 2 diabetes and preserved or reduced kidney function from failing. The involved protective mechanisms include blood glucose-dependent and -independent mechanisms: SGLT2 inhibitors prevent both hyper- and hypoglycemia, with expectedly little net effect on HbA1C. Metabolic adaptations to induced urinary glucose loss include reduced fat mass and more ketone bodies as additional fuel. SGLT2 inhibitors lower glomerular capillary hypertension and hyperfiltration, thereby reducing the physical stress on the filtration barrier, albuminuria, and the oxygen demand for tubular reabsorption. This improves cortical oxygenation, which, together with lesser tubular gluco-toxicity, may preserve tubular function and glomerular filtration rate in the long term. SGLT2 inhibitors may mimic systemic hypoxia and stimulate erythropoiesis, which improves organ oxygen delivery. SGLT2 inhibitors are proximal tubule and osmotic diuretics that reduce volume retention and blood pressure and preserve heart function, potentially in part by overcoming the resistance to diuretics and atrial-natriuretic-peptide and inhibiting Na-H exchangers and sympathetic tone.

Observations and measurements on active volcanoes are commonly conducted at a distance considered safe from the inherent dangers linked to volcanic explosions. This reduction in proximity adds a degree of uncertainty to the interpretation of monitoring data due to enhanced signal path effects. Here, we describe custom-built, drone-deployable sensor platforms designed to acquire data at high proximity to volcanic vents. They are equipped with an environmental sensor capable of measuring temperature, relative humidity and barometric pressure, a microphone (6 Hz–20 kHz) to reconstruct the acoustic pressure, and an electrical resonant circuit to detect electrical signals in the 500 kHz frequency band. Communication and data transfer is achieved through a radio link between the sensor platform and the base station. Our sensor platforms may be employed in the collection of data of near-vent characteristics of volcanic explosions, observations that are essential for quantifying and understanding the driving forces underlying volcanic explosions.

Congenital radioulnar synostosis is a rare musculoskeletal disorder of the elbow, occurring as a result of variable degree and length of the congenital fusion of the proximal radioulnar joint. Patients presents early to the hospital depending on the severity of the synostosis and its effect on elbow function. It may have psychosocial effects on the affected individuals as they grow older especially when the deformity is dramatic. Treatment may be conservative, surgical (which may have a variable degree of success) and psychotherapy.

Diabetic nephropathy (DN) is the leading cause of chronic kidney disease. Although hyperglycaemia has been determined as the most important risk factor, hypoxia also plays a relevant role in the development of this disease. In this work, a comprehensive metabolomic study of the response of HK-2 cells, a human cell line derived from normal proximal tubular epithelial cells, to hyperglycemic, hypoxic diabetic-like milieu has been performed. Cells simultaneously exposed to high glucose (25 mM) and hypoxia (1% O2) were compared to cells in control conditions (5.5 mM glucose/18.6% O2) at 48 h. The combination of advanced metabolomic platforms (GC-TOF MS, HILIC- and CSH-QExactive MS/MS), freely available metabolite annotation tools, novel databases and libraries, and stringent cut-off filters allowed the annotation of 733 metabolites intracellularly and 290 compounds in the extracellular medium. Advanced bioinformatics and statistical tools demonstrated that several pathways were significantly altered, including carbohydrate and pentose phosphate pathways, as well as arginine and proline metabolism. Other affected metabolites were found in purine and lipid metabolism, the protection against the osmotic stress and the prevention of the activation of the β-oxidation pathway. Overall, the effects of the combined exposure of HK-cells to high glucose and hypoxia are reasonably compatible with previous in vivo works.

The innate and adaptive immunities have been documented to participate in the pathogenesis of nephrotoxic acute kidney injury (AKI); however, the mechanisms controlling these processes have yet to be established. In our cisplatin-induced AKI mouse model, we show pathological damage to the kidneys, with the classical markers elevated, consistent with the response to cisplatin treatment. Through assessments of the components of the immune system, both locally and globally, we demonstrate that the immune microenvironment of injured kidneys was associated with an increased infiltration of CD4+ T cells and macrophages concomitant with decreased Treg cell populations. Our cell-based assays and animal studies further show that cisplatin exposure downregulated the protein levels of programmed death-ligand 1 (PD-L1), an immune checkpoint protein, in primary renal proximal tubular epithelial cells, and that these inhibitions were dose-dependent. After orthotopic delivery of PD-L1 gene into the kidneys, cisplatin-exposed mice displayed lower levels of both serum urea nitrogen and creatinine upon PD-L1 expression. Our data suggest a renoprotective effect of the immune checkpoint protein, and thereby provide a novel therapeutic strategy for cisplatin-induced AKI.

PURPOSE:The purpose of this study was to assess the effect on femoral torsion by rotational osteotomies at three different levels as measured in 3D using both the mechanical and the anatomic axes. METHODS:Ten cadaveric lower extremities underwent femoral osteotomies perpendicular to the anatomic axis (AA) at three levels: subtrochanteric, mid-diaphyseal and supracondylar. Parallel pins were placed, one in each femur segment. Computed tomography (CT) was acquired in post-osteotomies neutral position, then post-external rotation of the femur at each osteotomy level. Femurs were returned to neutral rotation between imaging exams. Using 3D CT reconstructions, custom software calculated femoral torsion (angle between the femoral neck axis and the posterior condylar axis in the transverse plane) and pin angle between segments, reoriented to both the mechanical axis (MA) and the AA. Pin angle and torsion change were compared for the three osteotomy locations (regression analysis and ANOVA performed). RESULTS:Two specimens were omitted (inadequate imaging); the remaining eight donors were 55-90 years old (mean: 64 ± 15 years), CT confirmed no bony defects. All three levels of osteotomy demonstrated significant correlations between the amount of rotation at the osteotomy (pin angle change) and the resulting change in femoral torsion (R square range 0.658-0.847). No significant differences were found between osteotomy level in torsion (MA:p = 0.285, AA:p = 0.156) or in pin angle (MA:p = 0.756, AA:p = 0.753). CONCLUSIONS:Performing a corrective rotational osteotomy orthogonal to the AA achieves the desired effect on MA regardless of location. This suggests that a surgeon's osteotomy level choice may be based on other risks/benefits of the various techniques.

BackgroundInterstitial fibrosis (IF) on kidney biopsy is one of the most potent risk factors for kidney disease progression. The furosemide stress test (FST) is a validated tool that predicts the severity of acute kidney injury (especially at 2 h) in critically ill patients. Since furosemide is secreted through the kidney tubules, the response to FST represents the tubular secretory capacity. To our knowledge there is no data on the correlation between functional tubular capacity assessed by the FST with IF on kidney biopsies from patients with chronic kidney disease (CKD). The aim of this study was to determine the association between urine output (UO), Furosemide Excreted Mass (FEM) and IF on kidney biopsies after a FST.MethodsThis study included 84 patients who underwent kidney biopsy for clinical indications and a FST. The percentage of fibrosis was determined by morphometry technique and reviewed by a nephropathologist. All patients underwent a FST prior to the biopsy. Urine volume and urinary sodium were measured in addition to urine concentrations of furosemide at different times (2, 4 and 6 h). We used an established equation to determine the FEM. Values were expressed as mean, standard deviation or percentage and Pearson Correlation.ResultsThe mean age of the participants was 38 years and 44% were male. The prevalence of diabetes mellitus, hypertension and diuretic use was significantly higher with more advanced degree of fibrosis. Nephrotic syndrome and acute kidney graft dysfunction were the most frequent indications for biopsy. eGFR was inversely related to the degree of fibrosis. Subjects with the highest degree of fibrosis (grade 3) showed a significant lower UO at first hour of the FST when compared to lower degrees of fibrosis (p = 0.015). Likewise, the total UO and the FEM was progressively lower with higher degrees of fibrosis. An inversely linear correlation between FEM and the degree of fibrosis (r = - 0.245, p = 0.02) was observed.ConclusionsOur findings indicate that interstitial fibrosis correlates with total urine output and FEM. Further studies are needed to determine if UO and FST could be a non-invasive tool to evaluate interstitial fibrosis.Trial registrationClinicalTrials.gov NCT02417883.

Simultaneous ipsilateral fractures of the proximal and distal humerus, known as 'floating arm', are rarely seen in adolescents and are considered challenging to manage. Most of the published cases have involved proximal humerus and distal supracondylar fractures. This paper presents a special case of floating arm injury in a 14-year-old boy following a motor vehicle accident that was managed in a well-established trauma center. The injury consisted of displaced proximal humerus and open distal T-condylar intraarticular fractures. The patient was discharged in good condition and regained functionality with no reported complications. [ABSTRACT FROM AUTHOR]

Though most known for heartburn and regurgitation, gastroesophageal reflux disease (GERD) is attributed to countless atypical, extra-esophageal (EE) manifestations like cough and throat clearing. While GERD has been studied extensively, the relationship between reflux character and symptom manifestation remains poorly understood. The aim of this study was to examine proximal reflux frequency and its relationship with typical or atypical symptoms. 540 (75.1% female, 24.9% male) pH-impedance monitoring studies from the last 3-years were divided by symptom indication and retrospectively reviewed for proximal reflux frequency, total acid exposure time, mean nocturnal baseline impedance, and total reflux episodes in both abnormal and normal, and borderline studies. Baseline characteristics were also collected. Both total reflux events and mean proximal reflux frequency were found to differ significantly between those with typical versus atypical symptoms. Total reflux events [median (IQR)] were 43.5 (24.0–74.0) in typical patients and 35.0 (20.0–57.0) in atypical patients (P -value 0.0369). Proximal reflux frequency [median (IQR)] was 12.0 (4.0–19.0) typical and 7.0 (3.0–17.0) atypical (P -value 0.0348). Results for exclusively abnormal studies also favored typical patients but not significantly. Baseline characteristics and use of gastric acid control did not differ significantly. Proximal reflux frequency was observed to increase among those with typical GERD symptoms. Total acid reflux events were also significantly higher on average with typical patients. Our findings that proximal reflux frequency is reduced in patients with atypical symptoms compared with patients with typical symptoms suggest that proximal reflux exposure may play a significant role in the symptom presentation of typical classic heartburn and regurgitation symptoms. The differential diagnosis for atypical EE symptoms is vast and can be multifactorial. Our results indicate proximal reflux events may contribute to atypical EE symptoms less than previously reported. [ABSTRACT FROM AUTHOR]

The spleen is the most commonly injured organ in blunt abdominal trauma. Its management depends on hemodynamic stability. According to the American Association for the Surgery of Trauma-Organ Injury Scale (AAST-OIS ≥ 3), stable patients with high-grade splenic injuries may benefit from preventive proximal splenic artery embolization (PPSAE). This ancillary study, using the SPLASH multicenter randomized prospective cohort, evaluated the feasibility, safety, and efficacy of PPSAE in patients with high-grade blunt splenic trauma without vascular anomaly on the initial CT scan. All patients included were over 18 years old, had high-grade splenic trauma (≥AAST-OIS 3 + hemoperitoneum) without vascular anomaly on the initial CT scan, received PPSAE, and had a CT scan at one month. Technical aspects, efficacy, and one-month splenic salvage were studied. Fifty-seven patients were reviewed. Technical efficacy was 94% with only four proximal embolization failures due to distal coil migration. Six patients (10.5%) underwent combined embolization (distal + proximal) due to active bleeding or focal arterial anomaly discovered during embolization. The mean procedure time was 56.5 min (SD = 38.1 min). Embolization was performed with an Amplatzer™ vascular plug in 28 patients (49.1%), a Penumbra occlusion device in 18 patients (31.6%), and microcoils in 11 patients (19.3%). There were two hematomas (3.5%) at the puncture site without clinical consequences. There were no rescue splenectomies. Two patients were re-embolized, one on Day 6 for an active leak and one on Day 30 for a secondary aneurysm. Primary clinical efficacy was, therefore, 96%. There were no splenic abscesses or pancreatic necroses. The splenic salvage rate on Day 30 was 94%, while only three patients (5.2%) had less than 50% vascularized splenic parenchyma. PPSAE is a rapid, efficient, and safe procedure that can prevent splenectomy in high-grade spleen trauma (AAST-OIS) ≥ 3 with high splenic salvage rates. [ABSTRACT FROM AUTHOR]

Introduction: Surgical margin positivity incidence is reported between 5 snd 20% in gastric cancer surgery. Although some studies showed that presence of positive surgical margins affects overall survival negatively, others reported no effect. The aim of this study is to investigate the relationship between surgical margin and the survival of patients who underwent laparoscopic gastrectomy in our clinic. Materials and Methods: Between 2015 and 2022 years, patients who underwent laparoscopic gastrectomy because of gastric cancer were included in this study. Surgical resection margin (diameter) width, microscopic evaluation of the surgical margin, pathological tumor stage, resected lymph nodes numbers and involvement, and overall survival were analyzed. Results: After patients with benign disorders and inadequate lymph nodes resection were excluded from the study, 136 patients were included the study. Median surgical margin length width? was 2.3 (0.1-10) cm, and 13 (9.6%) patients had positive surgical margin after pathological evaluation. Median survival was 51.00±18.56 months in patients with positive surgical margins and 46.00±2.99 months in patients with negative surgical margins (p=0.977). The 1, 3, and 5-year survival rates of patients with negative versus positive surgical margins (78.9% vs. 69.2%, p=0.426), (46.3% vs. 46.2%, p=0.990), and (17.1% vs. 30.8%, p=0.225), respectively. Surgical margin was positive in 3 (7.7%) patients with proximal tumors, and in 10 (10.3%) patients with distal located tumors. Conclusion: While most studies emphasized surgical margin positivity in proximal tumors, the rate of distal surgical margin positivity was found to be higher in this study. In conclusion, no correlation was found between surgical margin positivity and overall survival. [ABSTRACT FROM AUTHOR]

Proteinuria is an important risk factor for renal and cardiovascular disease. It is associated with a risk for glomerulonephritis, chronic kidney disease, and end-stage renal disease. Therefore, if persistent proteinuria is detected, kidney biopsy is considered to diagnose and treat the underlying disease. Recently, variants in the cubilin (CUBN) gene, which is associated with albuminuria, have been reported. This gene encodes cubilin, a membrane glycoprotein receptor expressed in the renal proximal tubules. Cubilin is a component of the megalin and cubilin-amnionless complex that mediates albumin reabsorption into the proximal tubules through endocytosis. A defect in cubilin leads to a reduction in albumin reuptake, resulting in albumin-dominant proteinuria. Although numerous controversies exist, several reports suggest that cubilin defects lead to proteinuria with a high portion of albuminuria but may not impair renal filtration function. If albuminuria due to reduced cubilin function is confirmed as a benign condition, we can consider using genetic studies to detect CUBN mutations in patients with proteinuria and they may not require any treatment or kidney biopsy. Here, we review recent papers on CUBN mutations and discuss the prognosis and management of individuals with this mutation. [ABSTRACT FROM AUTHOR]

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The multispecific organic anion transporters, OAT1 (SLC22A6) and OAT3 (SLC22A8), the main kidney elimination pathways for many common drugs, are often considered to have largely-redundant roles. However, whereas examination of metabolomics data from Oat-knockout mice (Oat1 and Oat3KO) revealed considerable overlap, over a hundred metabolites were increased in the plasma of one or the other of these knockout mice. Many of these relatively unique metabolites are components of distinct biochemical and signaling pathways, including those involving amino acids, lipids, bile acids, and uremic toxins. Cheminformatics, together with a "logical" statistical and machine learning-based approach, identified a number of molecular features distinguishing these unique endogenous substrates. Compared with OAT1, OAT3 tends to interact with more complex substrates possessing more rings and chiral centers. An independent "brute force" approach, analyzing all possible combinations of molecular features, supported the logical approach. Together, the results suggest the potential molecular basis by which OAT1 and OAT3 modulate distinct metabolic and signaling pathways in vivo As suggested by the Remote Sensing and Signaling Theory, the analysis provides a potential mechanism by which "multispecific" kidney proximal tubule transporters exert distinct physiological effects. Furthermore, a strong metabolite-based machine-learning classifier was able to successfully predict unique OAT1 versus OAT3 drugs; this suggests the feasibility of drug design based on knockout metabolomics of drug transporters. The approach can be applied to other SLC and ATP-binding cassette drug transporters to define their nonredundant physiological roles and for analyzing the potential impact of drug-metabolite interactions.

Sodium-glucose co-transporter 2 (SGLT2) inhibitors immediately reduce the glomerular filtration rate (GFR) in patients with type 2 diabetes mellitus. When given chronically, they confer benefit by markedly slowing the rate at which chronic kidney disease progresses and are the first agents to do so since the advent of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs). Salutary effects on the kidney were first demonstrated in cardiovascular outcomes trials and have now emerged from trials enriched in subjects with type 2 diabetes mellitus and chronic kidney disease. A simple model that unifies the immediate and long-term effects of SGLT2 inhibitors on kidney function is based on the assumption that diabetic hyperfiltration puts the kidney at long-term risk and evidence that hyperfiltration is an immediate response to a reduced signal for tubuloglomerular feedback, which occurs to the extent that SGLT2 activity mediates a primary increase in sodium and fluid reabsorption by the proximal tubule. This model will likely continue to serve as a useful description accounting for the beneficial effect of SGLT2 inhibitors on the diabetic kidney, similar to the hemodynamic explanation for the benefit of ACEIs and ARBs. A more complex model will be required to incorporate positive interactions between SGLT2 and sodium-hydrogen exchanger 3 in the proximal tubule and between sodium-glucose co-transporter 1 (SGLT1) and nitric oxide synthase in the macula densa. The implication of these latter nuances for day-to-day clinical medicine remains to be determined.

Simple Summary: The aim of this study was to investigate factors that affect the local and systemic prognoses for conventional, central CSs (those that arise from within the medulla of the bone) of the proximal humerus. Our results show that proximal humeral grade 1 CSs behave as a more benign tumour, having no cases of LR nor death due to disease. Grade 2 CSs of the proximal humerus act as a low-grade tumour, being locally aggressive with higher rates of LR than grade 1 CSs but still having a low incidence of mortality and high rates of DSS. The LR does not affect the DSS; therefore, the surgical management in proximal humeral grade 2 CSs should have a greater focus on function but still aim for a margin free resection. Chondrosarcoma (CS) is the second most common primary malignant bone tumour and, in the absence of reliable chemotherapy and radiotherapy, is effectively a surgical disease. Overall disease specific survival (DSS) is affected by tumour grade, whilst resection margin contributes to local recurrence free survival (LRFS). The aim of this study was to investigate factors that affect the local and systemic prognoses for conventional central CSs arising from the proximal humerus. A multi-centre, retrospective study from three international collaborative sarcoma centres identified 110 patients between 1995 and 2020 undergoing treatment for a conventional central CS of the proximal humerus; 58 patients (53%) had a grade 1 tumour, 36 (33%) had a grade 2 tumour, and 16 patients (13%) had a grade 3 CS. The mean age of patients was 50 years (range 10–85). The incidence of local recurrence (LR) was 9/110 (8.2%), and the disease specific mortality was 6/110 (5.5%). The grade was a statistically significant factor for LRFS (p < 0.001). None of the grade 1 tumours developed LR. The DSS was affected by the grade (p < 0.001) but not by the LR (p = 0.4). Only one patient with a grade 2 tumour died from the disease. The proximal humeral grade 1 CS behaved as a benign tumour, having no cases of LR nor death due to disease. Grade 2 CSs of the proximal humerus behaved in a more indolent way when compared with comparable grade tumours elsewhere in the appendicular skeleton, being locally aggressive with a higher LR rate than grade 1 CSs but still having very low mortality and a high rate of DSS. The LR in grade 2 CSs did not affect the DSS; therefore, surgical management in proximal humeral grade 2 CSs should have a greater emphasis on preserving function whilst maintaining an adequate margin for resection. The proximal humeral grade 3 CS was, as elsewhere in the skeleton, an aggressive, high-grade tumour. Therefore, surgical management should include en bloc resection with clear margins to avoid LR. [ABSTRACT FROM AUTHOR]

We analysed the differences in clinical presentation between proximal (above elbow) and distal (below elbow) upper limb metastases in a retrospective review of patients presenting to our centre from 2011 to 2019. There were 55 cases, 64% involving the humerus and 62% occurring in men. The median age at the time of diagnosis was 64 years. Thirty-one per cent of the cases were proximal lesions. Distal upper limb metastases were more likely to be soft tissue lesions (71%) compared with proximal lesions (8%). The median age of patients with distal lesions was significantly lower at 58 years compared with 65 years for proximal lesions. Overall, non-small cell lung carcinoma was the most common primary malignancy (25%), however haematological cancers were most common in the distal group (29%). Distal upper limb metastases have distinct features that distinguish them from proximal lesions. Level of evidence : IV [ABSTRACT FROM AUTHOR]

Background: Humeral shaft fractures occur frequently in older patients. The more proximal end of the shaft is prone to non-union when compared with more distal fractures. We provide an overview of several key features of this significant patient group. Method: Our institutional fracture database was searched for all cases of proximal third humeral shaft fractures in patients over 60 years of age. Retrospective evaluation of patient demographics, management, length of stay and incidence of non-union was performed. Results: 75 patients (61 female) were analysed. 33 patients were 'frail' (Clinical Frailty Scores of >4). Non-union occurred in 19 of 45 non-surgically treated fractures and in 1 of 37 cases treated surgically. Mean length of stay was 5.9 days (non-operative) and 6.6 days (operative). Proximal extension into the humeral head is common. Conclusion: Non-surgical management of proximal third humeral shaft fractures is associated with an increased risk of non-union. We detail an operative technique and case example supporting early fixation of displaced proximal third humeral shaft fractures in older patients that can be utilized for both primary and delayed fixation. In view of the significant association of non-union a well-constructed prospective cohort study with outcome assessment would be of value to further characterize this emerging injury population. Level of Evidence: Level IV, retrospective case series [ABSTRACT FROM AUTHOR]