SNAC1-OsERF103-OsSDG705 module mediates drought response in rice.

Drought stress profoundly hampers both plant growth and crop yield. To combat this, plants have evolved intricate transcriptional regulation mechanisms as a pivotal strategy. Through a genetic screening with rice genome-scale mutagenesis pool under drought stress, we identified an APETALA2/Ethylene Responsive Factor, namely OsERF103, positively responds to drought tolerance in rice. Combining chromatin immunoprecipitation sequencing and RNA sequencing analyses, we pinpointed c. 1000 genes directly influenced by OsERF103. Further results revealed that OsERF103 interacts with Stress-responsive NAC1 (SNAC1), a positive regulator of drought tolerance in rice, to synergistically regulate the expression of key drought-related genes, such as OsbZIP23. Moreover, we found that OsERF103 recruits a Su(var)3-9,enhancer of zeste and trithorax-domain group protein 705, which encodes a histone 3 lysine 4 (H3K4)-specific methyltransferase to specifically affect the deposition of H3K4me3 at loci like OsbZIP23 and other genes linked to dehydration responses. Additionally, the natural alleles of OsERF103 are selected during the domestication of both indica and japonica rice varieties and exhibit significant geographic distribution. Collectively, our findings have unfurled a comprehensive mechanistic framework underlying the OsERF103-mediated cascade regulation of drought response. This discovery not only enhances our understanding of drought signaling but also presents a promising avenue for the genetic improvement of drought-tolerant rice cultivars.

Effects of a neuromuscular joint-protective exercise therapy program for treatment of wrist osteoarthritis: a randomized controlled trial.

BACKGROUND: Individuals with wrist osteoarthritis (OA) can suffer from pain, muscular weakness, and impaired motion of the wrist, which can reduce the quality of life. While there is strong evidence that all patients with OA should receive first-line treatment with education and exercises, this approach has not yet been proposed for individuals with wrist OA. Therefore, this trial aimed to evaluate the effectiveness of a first line neuromuscular joint-protective exercise therapy program compared to a training program with range of motion (ROM) exercises in patients with wrist OA. METHODS: In this randomized controlled trial (RCT), 48 patients with symptomatic and radiographically confirmed wrist OA were randomly allocated to a 12-week self-management program with either a neuromuscular joint-protective exercise therapy program (intervention group) or a training program with ROM exercises only (control group). Our primary outcome measure was the Patient-Rated Wrist Evaluation (PRWE) with secondary outcome measures of grip strength, range of wrist motion, the Numerical Pain Rating, Scale (NPRS), the Disabilities of the Arm, Shoulder, and Hand (DASH) and the Generalized Self-Efficacy Scale (GSES). The outcome measures were evaluated by a blinded assessor at baseline and 12 weeks. Between-groups differences were analyzed using the Mann-Whitney U test and within-group differences were analyzed with the Wilcoxon signed-rank test. RESULTS: A total of 41 participants were analyzed at 12 weeks. There were no significant differences in PRWE between the groups at 12 weeks (p = 0.27). However, DASH improved significantly in the intervention group compared to the control group (p = 0.02) and NPRS on load within the intervention group (p = 0.006). The difference in DASH should be interpreted with caution since it could be due to a non-significant increase (worsening) from baseline in the control group in combination with a non-significant decrease (improvement) in the intervention group. CONCLUSIONS: This RCT showed that the novel neuromuscular joint-protective exercise therapy program was not superior in reducing pain and improving function compared to a training program with ROM exercises at 12 weeks. Future research is warranted to evaluate the effectiveness of forthcoming exercise therapy treatment programs for patients with wrist OA. TRIAL REGISTRATION: ClinicalTrials.gov, NCT05367817. Retrospectively registered on 10/05/2022. https://clinicaltrials.gov .

The Synthesis of SNAC Phenolate Salts and the Effect on Oral Bioavailability of Semaglutide.

PURPOSE: Sodium N-[8-(2-hydroxybenzoyl)amino]caprylate (SNAC) is a well-known penetration enhancer widely used in commercial applications. This study aims to broaden its properties through a novel strategy of converting it into its phenolate salts. The objective is to investigate the synthesis of SNAC phenolate salts, specifically SNAC-choline (SNAC-CH), SNAC-sodium (SNAC-Na), and SNAC-phosphatidylcholine (SNAC-PC), and to explore their potential application in improving the oral absorption of semaglutide. METHODS: The synthesis of SNAC phenolate salts was confirmed through 1H-NMR, FTIR, and an elemental analysis of C, H, N, and O. In vivo testing was conducted to assess the oral delivery of semaglutide using these synthesized SNAC phenolate salts. Pharmacokinetic (PK) values were measured to evaluate the impact on drug absorption. RESULTS: The synthesis of SNAC phenolate salts (SNAC-CH, SNAC-Na, and SNAC-PC) was successfully achieved under appropriate conditions, and their structures were confirmed using analytical techniques such as IR, NMR, and CHN elemental analysis. The paradigm of their use was evaluated through an oral pharmacokinetic (PK) in vivo study using SNAC phenolate salts, which did not impair the original SNAC PK values. This suggests that this strategy holds promise as a potential new effective enhancer for oral absorption. CONCLUSIONS: The utilization of SNAC phenolate salts presents a novel and promising strategy for extending the verity of penetration enhancers' molecules and properties. Synthesizing phenolate salts represents a new chemical strategy that may open new avenues in molecular development. This approach holds future potential to enhance the oral delivery of peptide drugs like semaglutide without compromising therapeutic efficacy. Overall, it offers significant advancements in the field by providing a potential alternative to injectable peptides through oral delivery systems.

IPA1 improves drought tolerance by activating SNAC1 in rice.

Drought is a major abiotic stress to rice (Oryza sativa) during growth. Ideal Plant Architecture (IPA1), the first cloned gene controlling the ideal plant type in rice, has been reported to function in both ideal rice plant architecture and biotic resistance. Here, we report that the IPA1/OsSPL14, encoding a transcriptional factor, positively regulates drought tolerance in rice. The IPA1 is constitutively expressed and regulated by H2O2, abscisic acid, NaCl and polyethylene glycol 6000 treatments in rice. Furthermore, the IPA1-knockout plants showed much greater accumulation of H2O2 as measured by 3,3'-diaminobenzidine staining in leaves compared with WT plants. Yeast one-hybrid, dual-luciferase and electrophoretic mobility shift assays indicated that the IPA1 directly activates the promoter of SNAC1. Expression of SNAC1 is significantly down-regulated in IPA1 knockout plants. Further investigation indicated that the IPA1 plays a positive role in drought-stress tolerance by inducing reactive oxygen species scavenging in rice. Together, these findings indicated that the IPA1 played important roles in drought tolerance by regulating SNAC1, thus activating the antioxidant system in rice.

SNAC for Enhanced Oral Bioavailability: An Updated Review.

The delivery of proteins and peptides via an oral route poses numerous challenges to improve the oral bioavailability and patient compliance. To overcome these challenges, as well as to improve the permeation of proteins and peptides via intestinal mucosa, several chemicals have been studied such as surfactants, fatty acids, bile salts, pH modifiers, and chelating agents, amongst these medium chain fatty acid like C10 (sodium caprate) and Sodium N-[8-(2-hydroxybenzoyl) amino] caprylate (SNAC) and its derivatives that have been well studied from a clinical perspective. This current review enumerates the challenges involved in protein and peptide delivery via the oral route, i.e., non-invasive routes of protein and peptide administration. This review also covers the chemistry behind SNAC and toxicity as well as mechanisms to enhance the oral delivery of clinically proven molecules like simaglutide and other small molecules under clinical development, as well as other permeation enhancers for efficient delivery of proteins and peptides.

Risk of Total Wrist Arthrodesis Following Proximal Row Carpectomy: An Analysis of 1,070 Patients.

PURPOSE: Proximal row carpectomy (PRC) is a motion-sparing procedure with good patient-reported and clinical outcomes. Although some studies have investigated the risk of conversion to total wrist arthrodesis (TWA) after PRC, additional larger studies evaluating the specific risk factors that lead to failure are required. This study aimed to investigate the patient and procedure factors that are associated with increased risk for conversion to TWA in a large cohort of patients who underwent PRC. METHODS: The current procedural technology codes identified patients in a National Veteran's Health database undergoing a PRC over a 26-year period. Risk factors of interest comprised age, posterior interosseous nerve neurectomy, wrist arthritis pattern, bilateral surgery, smoking, comorbidities, and preoperative opioid use. The primary outcome was the rate of conversion to TWA. Cox proportional hazard regression was used to create hazard ratios of selected factors for reoperation. RESULTS: There were 1,070 PRCs performed, with a mean follow-up of 79.8 ± 59.6 months. A total of 5.3% (57/1,070) wrists underwent conversion to TWA. Younger age at the time of PRC (<50 years) significantly increased the risk of TWA (hazard ratio, 3.8; 95% confidence interval, 2.2-6.6). With every 1-year increase in age, there was a reduction of 4% (hazard ratio, 0.96; 95% confidence interval: 0.94-0.98) in the hazard of conversion to TWA. No other factors, including concomitant posterior interosseous nerve neurectomy or bilateral PRC, increased the risk of conversion to TWA. CONCLUSIONS: Proximal row carpectomy is a motion-preserving salvage procedure with a low rate of conversion to wrist arthrodesis. Younger patient age increases the risk of conversion to arthrodesis, whereas posterior interosseous nerve neurectomy, bilateral PRCs, and comorbidity status do not appear to have an impact on the risk of arthrodesis. TYPE OF STUDY/LEVEL OF EVIDENCE: Prognostic II.

Ni2+ Catalyzed Cleavage of TrpLE-Fused Small Transmembrane Peptides.

In addition to a membrane anchor, the transmembrane domain (TMD) of single-pass transmembrane proteins (SPTMPs) recently has shown essential roles in the cross-membrane activity or receptor assembly/clustering. However, these small TMD peptides are generally hydrophobic and dynamic, difficult to be expressed and purified. Here, we have integrated the power of TrpLE fusion protein and a sequence-specific nickel-assisted cleavage (SNAC)-tag to produce small TMD peptides in a highly efficient way under mild conditions, which uses Ni2+ as the cleavage reagent, avoiding the usage of toxic cyanogen bromide (CNBr). Furthermore, this method simplifies the downstream protein purification and reconstitution. Two representative TMDs, including the Spike-TMD from severe acute respiratory syndrome coronavirus 2 (SARS2), were successfully produced with high-quality nuclear magnetic resonance (NMR) spectra. Therefore, our study provides a more efficient and practical approach for general structural characterization of the small TM proteins.

A new era for oral peptides: SNAC and the development of oral semaglutide for the treatment of type 2 diabetes.

Glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1RAs) were first introduced for the treatment of type 2 diabetes (T2D) in 2005. Despite the high efficacy and other benefits of GLP-1RAs, their uptake was initially limited by the fact that they could only be administered by injection. Semaglutide is a human GLP-1 analog that has been shown to significantly improve glycemic control and reduce body weight, in addition to improving cardiovascular outcomes, in patients with T2D. First approved as a once-weekly subcutaneous injection, semaglutide was considered an ideal peptide candidate for oral delivery with a permeation enhancer on account of its low molecular weight, long half-life, and high potency. An oral formulation of semaglutide was therefore developed by co-formulating semaglutide with sodium N-(8-[2-hydroxybenzoyl]amino)caprylate, a well-characterized transcellular permeation enhancer, to produce the first orally administered GLP-1RA. Pharmacokinetic analysis showed that stable steady-state concentrations could be achieved with once-daily dosing owing to the long half-life of oral semaglutide. Upper gastrointestinal disease and renal and hepatic impairment did not affect the pharmacokinetic profile. In the phase III PIONEER clinical trial program, oral semaglutide was shown to reduce glycated hemoglobin and body weight compared with placebo and active comparators in patients with T2D, with no new safety signals reported. Cardiovascular efficacy and safety are currently being assessed in a dedicated outcomes trial. The development of an oral GLP-1RA represents a significant milestone in the management of T2D, providing an additional efficacious treatment option for patients.

In Silico-Based Experiments on Mechanistic Interactions between Several Intestinal Permeation Enhancers with a Lipid Bilayer Model.

Oral administration of drugs is generally considered convenient and patient-friendly. However, oral administration of biological drugs exhibits low oral bioavailability (BA) due to enzymatic degradation and low intestinal absorption. A possible approach to circumvent the low BA of oral peptide drugs is to coformulate the drugs with permeation enhancers (PEs). PEs have been studied since the 1960s and are molecules that enhance the absorption of hydrophilic molecules with low permeability over the gastrointestinal epithelium. In this study, we investigated the impact of six PEs on the structural properties of a model membrane using molecular dynamics (MD) simulations. The PEs included were the sodium salts of the medium chain fatty acids laurate, caprate, and caprylate and the caprylate derivative SNAC─all with a negative charge─and neutral caprate and neutral sucrose monolaurate. Our results indicated that the PEs, once incorporated into the membrane, could induce membrane leakiness in a concentration-dependent manner. Our simulations suggest that a PE concentration of at least 70-100 mM is needed to strongly affect transcellular permeability. The increased aggregation propensity seen for neutral PEs might provide a molecular-level mechanism for the membrane disruptions seen at higher concentrations in vivo. The ability for neutral PEs to flip-flop across the lipid bilayer is also suggestive of possible intracellular modes of action other than increasing membrane fluidity. Taken together, our results indicate that MD simulations are useful for gaining insights relevant to the design of oral dosage forms based around permeability enhancer molecules.

Development and validation of a nomogram for prognosis of sinonasal adenocarcinoma (a nomogram for sinonasal adenocarcinoma).

BACKGROUND: The incidence of sinonasal adenocarcinoma is low, and there are few studies on survival and prognosis. Therefore, we aim to develop and validate a prognostic model for predicting the overall survival of sinonasal adenocarcinoma and provide guidance for clinical management. METHODS: Patients who were diagnosed as sinonasal adenocarcinoma through Surveillance, Epidemiology, and End Results database between 1975 and 2015 were randomly divided into a training group and validation group. Univariate, multivariate survival analysis was performed to screen independent survival factors. A nomogram was established to predict the overall survival rate of sinonasal adenocarcinoma. Receiver operating characteristic curve and calibration plot were performed to verify the discrimination and accuracy of the model. A decision curve analysis was performed to verify the clinical applicability of the model. RESULTS: A total of 423 patients with sinonasal adenocarcinoma were randomly divided into training group (n = 299) and verification group (n = 124). We established and verified the Nomo map including age, marriage, grade, surgery and tumour size. The c-index of Surveillance, Epidemiology, and End Results stage, T stage and this model are 0.635, 0.626 and 0.803, respectively. The survival rate of the high-risk group scored by this model was lower than that of the low-risk group (P < 0.001). Decision curve analysis shows that the model has advantages in predicting survival rates. CONCLUSION: Our model is considered to be a useful tool for predicting the overall survival of sinonasal adenocarcinoma, with good discrimination and clinical applicability. We hope that this model will help rhinologists to make clinical decisions and manage patients diagnosed with sinonasal adenocarcinoma.

Penetration Enhancement Strategies for Intradermal Delivery of Cromolyn Sodium.

This study aimed to explore the use of chemical and physical enhancement strategies for the intradermal delivery of cromolyn sodium (CS) for treatment of atopic dermatitis. CS gels were formulated to individually contain 2.5 and 9% salcaprozate sodium (SNAC) as a potential chemical enhancer. The effect of microneedles, alone and in combination with SNAC, was investigated via in vitro permeation studies. Skin impedance and FTIR evaluation of SNAC-treated stratum corneum (SC) was done and compared to the control. The amount of drug delivered in the dermis after 24 h by the 2.5% and 9% SNAC gels was 23.29 ± 1.89 µg/cm2 and 35.87 ± 2.23 µg/cm2, respectively, which were significantly higher than the control (p < 0.05) but were not remarkably different from each other (p > 0.05). Microneedles enhanced permeation in both the control and 2.5% SNAC groups (p < 0.05); however, no synergistic enhancement was observed when microneedle and SNAC treatments were combined (p > 0.05). Over 24 h of treating the SC with 2.5% SNAC, FTIR evaluation showed stretches on the CH2 asymmetric and symmetric stretching vibrations observed at 2920.23 cm-1 and 2850.79 cm-1 respectively in untreated SC, which shifted to higher wavenumbers and indicated some lipid fluidizing effect. However, no significant drop in skin impedance was seen with SNAC as compared to the control (p > 0.05). SNAC was concluded to have skin permeation enhancement effect on CS, while microneedles effectively enhanced CS permeation even in the absence of SNAC.

Predictors for functional decline after an injurious fall: a population-based cohort study.

BACKGROUND: The functional consequences of injurious falls are well known. However, studies of the factors that can modify trajectories of disability after an injury from a fall are scarce. AIMS: We aimed to investigate whether sociodemographic and health-related factors may impact this association. METHODS: The study population consisted of 1426 community-dwelling older adults (≥ 60 years) from the SNAC-K cohort study in Stockholm, Sweden. Functional status over 12 years of follow-up was assessed using the number of limitations in basic and instrumental activities of daily living. Sex, cohabitation status, physical activity, and self-rated health were assessed at baseline. Injurious falls were defined as falls requiring healthcare and were assessed over 3 years starting at baseline. Data were analyzed using linear-mixed effects models. RESULTS: The fastest increase in the number of disabilities was observed in those who had endured an injurious fall and were living alone (ß coefficient = 0.408; p < 0.001), been physically inactive (ß coefficient = 0.587; p < 0.001), and had poor self-rated health (ß coefficient = 0.514; p < 0.001). The negative impact of these factors was more pronounced among fallers compared to non-fallers. DISCUSSION: Living alone, being physically inactive, and having poor self-rated health magnifies the negative effect of an injurious fall on functional status. Among individuals who endure an injurious fall, the heterogeneity in long-term functional status is substantial, depending on the individuals' characteristics and behaviors. CONCLUSIONS: These findings emphasize the need for a person-centered approach in care provision and can guide secondary prevention within health care.

Influence of Bile Composition on Membrane Incorporation of Transient Permeability Enhancers.

Transient permeability enhancers (PEs), such as caprylate, caprate, and salcaprozate sodium (SNAC), improve the bioavailability of poorly permeable macromolecular drugs. However, the effects are variable across individuals and classes of macromolecular drugs and biologics. Here, we examined the influence of bile compositions on the ability of membrane incorporation of three transient PEs-caprylate, caprate, and SNAC-using coarse-grained molecular dynamics (CG-MD). The availability of free PE monomers, which are important near the absorption site, to become incorporated into the membrane was higher in fasted-state fluids than that in fed-state fluids. The simulations also showed that transmembrane perturbation, i.e., insertion of PEs into the membrane, is a key mechanism by which caprylate and caprate increase permeability. In contrast, SNAC was mainly adsorbed onto the membrane surface, indicating a different mode of action. Membrane incorporation of caprylate and caprate was also influenced by bile composition, with more incorporation into fasted- than fed-state fluids. The simulations of transient PE interaction with membranes were further evaluated using two experimental techniques: the quartz crystal microbalance with dissipation technique and total internal reflection fluorescence microscopy. The experimental results were in good agreement with the computational simulations. Finally, the kinetics of membrane insertion was studied with CG-MD. Variation in micelle composition affected the insertion rates of caprate monomer insertion and expulsion from the micelle surface. In conclusion, this study suggests that the bile composition and the luminal composition of the intestinal fluid are important factors contributing to the interindividual variability in the absorption of macromolecular drugs administered with transient PEs.

3D analysis of Osteosyntheses material using semi-automated CT segmentation: a case series of a 4 corner fusion plate.

BACKROUND: Scaphoidectomy and midcarpal fusion can be performed using traditional fixation methods like K-wires, staples, screws or different dorsal (non)locking arthrodesis systems. The aim of this study is to test the Aptus four corner locking plate and to compare the clinical findings to the data revealed by CT scans and semi-automated segmentation. METHODS: This is a retrospective review of eleven patients suffering from scapholunate advanced collapse (SLAC) or scaphoid non-union advanced collapse (SNAC) wrist, who received a four corner fusion between August 2011 and July 2014. The clinical evaluation consisted of measuring the range of motion (ROM), strength and pain on a visual analogue scale (VAS). Additionally, the Disabilities of the Arm, Shoulder and Hand (QuickDASH) and the Mayo Wrist Score were assessed. A computerized tomography (CT) of the wrist was obtained six weeks postoperatively. After semi-automated segmentation of the CT scans, the models were post processed and surveyed. RESULTS: During the six-month follow-up mean range of motion (ROM) of the operated wrist was 60°, consisting of 30° extension and 30° flexion. While pain levels decreased significantly, 54% of grip strength and 89% of pinch strength were preserved compared to the contralateral healthy wrist. Union could be detected in all CT scans of the wrist. While X-ray pictures obtained postoperatively revealed no pathology, two user related technical complications were found through the 3D analysis, which correlated to the clinical outcome. CONCLUSION: Due to semi-automated segmentation and 3D analysis it has been proved that the plate design can keep up to the manufacturers' promises. Over all, this case series confirmed that the plate can compete with the coexisting techniques concerning clinical outcome, union and complication rate.

Impact of Sodium N-[8-(2-Hydroxybenzoyl)amino]-caprylate on Intestinal Permeability for Notoginsenoside R1 and Salvianolic Acids in Caco-2 Cells Transport and Rat Pharmacokinetics.

For drugs with high hydrophilicity and poor membrane permeability, absorption enhancers can promote membrane permeability and improve oral bioavailability. Sodium N-[8-(2-hydroxybenzoyl)amino]caprylate (SNAC) is a new kind of absorption enhancer that has good safety. To investigate the absorption enhancement effect of SNAC on non-polar charged and polar charged drugs and establish the absorption enhancement mechanism of SNAC, SNAC was synthesized and characterized. Two representative hydrophilic drugs-notoginsenoside R1 (R1) and salvianolic acids (SAs)-were selected as model drugs. In vitro Caco-2 cells transport and in vivo rat pharmacokinetics studies were conducted to examine the permeation effect of SNAC on R1 and SAs. R1, rosmarinic acid (RA), salvianolic acid B (SA-B) and salvianolic acid B (SA-A) were determined to compare the permeation enhancement of different drugs. The MTT assay results showed that SNAC had no toxicity to Caco-2 cells. The transepithelial electrical resistance (TEER) of Caco-2 cell monolayer displayed that SNAC facilitated passive transport of polar charged SAs through the membrane of epithelial enterocytes. The pharmacokinetics results demonstrated that area under the curve (AUC) of RA, SA-B and SA-A with administration of SAs containing SNAC was 35.27, 8.72 and 9.23 times than administration of SAs. Tmax of RA, SA-B and SA-A were also prolonged. The AUC of R1 with administration of R1 containing SNAC was 2.24-times than administration of R1. SNAC is more effective in promoting absorption of SAs than R1. The study demonstrated that SNAC significantly improved bioavailability of R1 and SAs. What's more, the effect of SNAC on absorption enhancement of charged drugs was larger than that of non-charged drugs. The current findings not only confirm the usefulness of SNAC for the improved delivery of R1 and SAs but also demonstrate the importance of biopharmaceutics characterization in the dosage form development of drugs.

Impact of tooth loss on walking speed decline over time in older adults: a population-based cohort study.

BACKGROUND: Tooth loss has been linked to poor health such as chronic diseases and mobility limitations. Prospective evidence on the association between tooth loss and walking speed decline is however lacking. AIMS: To examine the impact of tooth loss on walking speed over time and explore whether inflammation may account for this association. METHODS: This study included 2695 persons aged 60 years and older, who were free from severe mobility limitation at baseline. Information on dental status was assessed through self-report during the nurse interview at baseline. Walking speed baseline and at 3- and 6-year follow-ups was assessed when participants walked at their usual pace. Covariates included age, sex, education, lifestyle-related factors, and chronic diseases. Blood samples were taken, and C-reactive protein (CRP) was tested. RESULTS: At baseline, 389 (13.1 %) participants had partial tooth loss and 204 (6.9 %) had complete tooth loss. Mixed-effects models showed that tooth loss was associated with a greater decline in walking speed over time after adjustment for lifestyle-related factors and chronic diseases (p = 0.001 for interaction between time and tooth loss on walking speed decline); however, when further adjusting for inflammation (CRP), the association was attenuated and no longer significant. CONCLUSION: Tooth loss was associated with an accelerated decline in walking speed in older adults. Inflammation may play a role in the association between tooth loss and walking speed decline.

Four-corner fusion of the wrist: clinical and radiographic outcome of 31 patients.

BACKGROUND: Four-corner fusion is a rational surgical option for the management of degenerative conditions of the wrist. Most related studies have compared four-corner fusion with scaphoid excision or proximal row carpectomy, with a variety of reported results. To enhance the literature, we performed this study to evaluate a series of patients with degenerative conditions of the wrist treated with four-corner fusion using 3 surgical techniques and to discuss the clinical and radiographic outcome of the patients. MATERIALS AND METHODS: We retrospectively studied 31 patients (24 men, 7 women; mean age, 43 years; 9 heavy manual laborers) who underwent four-corner fusion of their wrists for degenerative conditions from 2005 to 2015. Internal fixation was done using multiple Kirschner wires (14 patients), headless compressive screws (8 patients), or a circular plate (9 patients). Mean follow-up was 4 years (1-11 years). We evaluated the clinical outcome with the Patient-Rated Wrist Evaluation (PRWE) score and fusion with radiographs. RESULTS: All patients experienced improvement of their pain, function, range of motion and grip strength (p < 0.05). Twenty-three patients (74 %) reported no pain, and eight patients reported mild, occasional pain. Twenty-one patients (68 %) were able to do usual and specific activities. Mean wrist motion improved to 70 % and mean grip strength improved to 85 % of opposite wrist. Two heavy manual labor patients requested a job modification because of wrist impairment. Radiographs of the wrist showed fusion of all fused joints in 28 (90.3 %) patients and partial fusion in three patients (9.7 %). No patient with partial fusion required a reoperation for symptomatic nonunion until the period of this study. Three patients experienced complications (10 %). Two patients treated with a circular plate experienced complex regional pain syndrome and painful implant impingement; another patient treated with Kirschner wires and headless compression screws experienced radiolunate arthritis from impingement of the lunate screw to the radius. CONCLUSIONS: Four-corner fusion is a reliable limited wrist fusion technique that provides pain relief, grip strength and satisfactory range of motion in patients with degenerative conditions of the wrist. Partial union is more common with Kirschner wire fixation and complications are more common with circular plate fixation.

Vascularized bone grafting and distal radius osteotomy for scaphoid nonunion advanced collapse.

PURPOSE: To determine the outcome of an alternative treatment for wrists with stages I to III scaphoid nonunion advanced collapse using a closing-wedge osteotomy of the distal radius and a vascularized bone graft for scaphoid reconstruction. METHODS: Twelve patients with scaphoid nonunion advanced collapse (stage I, 3; stage II, 7; stage III, 2) treated with a vascularized bone graft interposition for the scaphoid and a closing-wedge osteotomy for the distal radius were retrospectively reviewed. Data were obtained and analyzed from the radiographs, and we assessed the pre- and postoperative range of motion, grip strength, visual analog scale pain score, as well as the Mayo and Disabilities of the Arm, Shoulder, and Hand (DASH) functional scores. RESULTS: Follow-up ranged from 2 to 11 years. All scaphoid nonunions united after an average of 9 weeks, and all osteotomies united after an average of 8 weeks. Although there was radiographic progression of the scaphoid nonunion advanced collapse stage in 5 of 12 cases, there was major improvement in visual analog scale pain score (from 6.1 to 0.8) and in both Mayo (from 64 to 85) and DASH (from 40 to 9) functional scores. The range of motion remained unchanged, and grip strength trended toward minor improvement. The carpal height was preserved, and the dorsal intercalated segmental instability was corrected. CONCLUSIONS: Scaphoid reconstruction with vascularized bone graft combined with closing-wedge distal radius osteotomy preserved wrist function for scaphoid nonunion advanced collapse. The method offers pain relief and does not compromise wrist motion or grip strength. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV.

Perilunate Fracture-Dislocation: Results at Mean Follow-Up of 7 Years after ORIF.

Background: Perilunate fracture-dislocations are frequently associated with a high risk of developing post-traumatic arthritis. Current studies indicate that during mid-term follow-ups, radiological signs of arthritis do not appear to correspond with functional score. The aim of this study was to assess the occurrence of posttraumatic arthritis and the wrist function after perilunate dislocations (PLD) and fracture dislocations at a mid-term follow-up of 7 years. Methods: We report the clinical and radiological outcomes of 17 wrists treated for PLD or fracture-dislocation by open reduction and internal fixation through a dorsal approach with dorsal ligament repair. Functional outcomes were evaluated using the short version of the Quick Disabilities of the Arm, Shoulder and Hand questionnaire (QuickDASH), the Patient-Rated Wrist Evaluation questionnaire (PRWE) and the Mayo Wrist Score (MWS). Results of radiographs were assessed using the Herzberg Radiological Scoring Chart. Results: The MWS showed five excellent, five good, five fair and two poor results with an average score of 81%. Radiological analysis using the Herzberg classification revealed midcarpal and/or radiocarpal arthritis in 65% of cases, lunate collapse in 59% and an increase in the mean ulnar translocation ratio in 53% of the cases. Complications included one case of lunate osteonecrosis and one case of stage 3 scapholunate advanced collapse that required revision surgery. Conclusions: Although the clinical and functional outcomes are favourable at mid-term follow-up, radiological evaluation shows a progression towards osteoarthritis (OA). Further research is warranted to refine treatment strategies and investigate factors influencing the development of OA. Level of Evidence: Level IV (Therapeutic).

Development and evaluation of C10 and SNAC erodible tablets for gastric delivery of a GIP/GLP1 peptide in monkeys.

The permeation enhancers (PEs) sodium caprate (C10) and sodium N-[8-(2-hydroxybenzoyl) amino] caprylate (SNAC) have been utilized for the intestinal and gastric delivery of macromolecules, respectively. However, the potential of C10 for the gastric delivery of a peptide and the ability of SNAC to deliver other peptides to the stomach beyond semaglutide have not been investigated. In this study, we have developed and evaluated C10 and SNAC-containing erodible tablets for the gastricdelivery of a glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GIP/GLP1) dual agonist peptide (LY) in cynomolgus monkeys. We also evaluated the impact of release rates on the in vivo performance of C10 and SNAC. Furthermore, we compared the oral exposure of the LY peptide and semaglutide with different proteolytic stabilities using a SNAC erodible tablet. Additionally, we investigated the mechanism of action of SNAC for improving gastric absorption of the LY peptide via tissue distribution in monkey. C10 and SNAC tablets released the peptide and PE by erosion from the tablet surface with 100 % release within 60 min at pH 6.8. Following a single oral administration to monkeys, C10 and SNAC erodible tablets at 300 mg exhibited similar LY mean absolute oral bioavailability of 5.7 % and 4.2 %, respectively. The C10 immediate release capsule (500 mg) with faster dissolution profile (10 min) showed a decrease in the LY oral bioavailability; however, a faster dissolution profile (15 min) with erodible SNAC tablet resulted in a relatively higher LY oral bioavailability compared to the slow-release erodible tablets (60 min). Using SNAC as the PE, the combination of slow-release tablet design and LY peptide with higher pepsin stability resulted in about 4-fold higher mean oral bioavailability in the monkeys than semaglutide (4.2 % vs 1.2 %, respectively). In the monkey gastric tissue, SNAC was found to reduce tight junction protein levels and increase the peptide uptake into the gastric epithelium suggesting its permeation enhancing mechanism via both paracellular and transcellular pathways. Taking these data altogether, the enhanced proteolytic stability of the LY peptide combined with the optimal erodible tablets enabled the gastric delivery of the LY peptide with a higher oral bioavailability than semaglutide.