Real-world HbA1c changes and prescription characteristics among type 2 diabetes mellitus patients initiating treatment with once weekly semaglutide for diabetes.

Purpose: The purpose of this study was to evaluate patient, prescriber, and dose characteristics and evaluate changes in glycated hemoglobin (HbA1c) for patients prescribed once weekly semaglutide for diabetes (OW sema T2D). Methods: This study was a retrospective claims-based study using the Optum Research Database. The sample included adult patients who had at least one claim for OW sema T2D between Jan 1, 2018, and Dec 31, 2019, were continuously enrolled in the health plan and had a diagnosis of type 2 diabetes (T2DM) during the pre-index or post-index periods. Demographic and clinical characteristics of patients using OW sema T2D were collected, as were the dose and prescriber specialty and the change between pre-index and post-index HbA1c measures was calculated. Results were stratified by the latest pre-index HbA1c measurement (HbA1c greater than or equal to 9.0%, uncontrolled vs. HbA1c less than 9%, controlled). Statistical comparisons between HbA1c groups were conducted. Results: Most patients, 76.3%, were prescribed a 0.25/0.50 mg dose of OW sema T2D. Patients had an overall decrease in HbA1c of 0.8% and patients with uncontrolled diabetes had a greater reduction in mean HbA1c compared to those with controlled diabetes (-2.1% vs. -0.3%, p < 0.001). Most patients had their index dose of OW sema T2D prescribed by endocrinologists (27.6%) primary care providers (24.6%) and internal medicine providers (21.6%). Conclusions: OW sema T2D is an effective real-world T2DM treatment. Future research should further investigate real-world use patterns of this medication.

Real-World Treatment Patterns Among Patients with Type 2 Diabetes Mellitus Initiating Treatment with Oral Semaglutide.

INTRODUCTION: The treatment landscape for type 2 diabetes mellitus (T2DM) is complex and constantly evolving, and real-world evidence of prescribing patterns is limited. The objectives of this study were to characterize lines of therapy (LOTs), calculate the length of time spent on each LOT, and identify the reasons for the LOT end among patients who initiated oral semaglutide for T2DM. METHODS: This retrospective, claims-based study included commercial and Medicare Advantage adults with T2DM. Data from November 1, 2019, and June 30, 2020, were obtained from Optum Research Database. Patients with ≥ 1 claim for oral semaglutide and continuous health plan enrollment for ≥ 12 months prior to (baseline period) and ≥ 6 months following (follow-up period) the date of the first oral semaglutide claim were included. LOT 1 began on the date of the first oral semaglutide claim. The start date of any subsequent LOTs was the date of the first claim for an additional non-insulin anti-diabetic drug class or a reduction in drug class with use of commitment medications. The LOT ended at the first instance of medication class discontinuation, change in regimen or end of follow-up. RESULTS: Of the 1937 patients who initiated oral semaglutide, 950 (49.0%) remained on their initial regimen over the 6-month follow-up period, 844 (43.6%) had at least one subsequent LOT, and 89 (4.6%) had at least two subsequent LOTs. Among patients with more than one LOT, approximately 20%-25% used oral semaglutide as monotherapy or combination therapy during LOTs 2 and 3. Metformin was frequently used during treatment across all LOTs. CONCLUSION: This study provides insight for physicians and payers into the real-world prescribing practices within the first 6 months following oral semaglutide initiation and fills the gap in understanding the frequency of regimen changes in the constantly evolving and complex environment of T2DM care.

Type 2 diabetes mellitus is a disease which, over time, can cause higher than normal levels of sugar in the blood (hyperglycemia) which can be harmful if not treated. Treatment for type 2 diabetes mellitus can be complex, and how doctors prescribe medications is always changing. For some people with type 2 diabetes mellitus who are overweight or obese, it is recommended for patients to use certain medications that can help with weight management such as semaglutide and metformin. This study aims to fill gaps in current treatment knowledge about type 2 diabetes mellitus patients and their treatment of oral semaglutide. Researchers in this study explored how patients treated with oral semaglutide differentiated among line of therapies, how long patients stuck to them and why they stopped. The study found that those patients who started with oral semaglutide, almost half of those patients stuck to their initial treatment plan for the entire 6 months. When it came to the top ten treatment plans, about 20% of patients used oral semaglutide alone and about 25% of patients used oral semaglutide plus an additional treatment option. Metformin was frequently used during treatment across all line of therapies. There is little information on the real-life setting of treatment after the start of therapy for type 2 diabetes mellitus. The results from this study show what happens when patients start using oral semaglutide and helps healthcare providers understand how often treatment plans can change in type 2 diabetes mellitus care.

Patient-specific tissue engineered vascular graft for aortic arch reconstruction.

Objectives: The complexity of aortic arch reconstruction due to diverse 3-dimensional geometrical abnormalities is a major challenge. This study introduces 3-dimensional printed tissue-engineered vascular grafts, which can fit patient-specific dimensions, optimize hemodynamics, exhibit antithrombotic and anti-infective properties, and accommodate growth. Methods: We procured cardiac magnetic resonance imaging with 4-dimensional flow for native porcine anatomy (n = 10), from which we designed tissue-engineered vascular grafts for the distal aortic arch, 4 weeks before surgery. An optimal shape of the curved vascular graft was designed using computer-aided design informed by computational fluid dynamics analysis. Grafts were manufactured and implanted into the distal aortic arch of porcine models, and postoperative cardiac magnetic resonance imaging data were collected. Pre- and postimplant hemodynamic data and histology were analyzed. Results: Postoperative magnetic resonance imaging of all pigs with 1:1 ratio of polycaprolactone and poly-L-lactide-co-ε-caprolactone demonstrated no specific dilatation or stenosis of the graft, revealing a positive growth trend in the graft area from the day after surgery to 3 months later, with maintaining a similar shape. The peak wall shear stress of the polycaprolactone/poly-L-lactide-co-ε-caprolactone graft portion did not change significantly between the day after surgery and 3 months later. Immunohistochemistry showed endothelization and smooth muscle layer formation without calcification of the polycaprolactone/poly-L-lactide-co-ε-caprolactone graft. Conclusions: Our patient-specific polycaprolactone/poly-L-lactide-co-ε-caprolactone tissue-engineered vascular grafts demonstrated optimal anatomical fit maintaining ideal hemodynamics and neotissue formation in a porcine model. This study provides a proof of concept of patient-specific tissue-engineered vascular grafts for aortic arch reconstruction.

A Systematic Guideline by the ASPN Workgroup on the Evidence, Education, and Treatment Algorithm for Painful Diabetic Neuropathy: SWEET.

Introduction: Painful diabetic neuropathy (PDN) is a leading cause of pain and disability globally with a lack of consensus on the appropriate treatment of those suffering from this condition. Recent advancements in both pharmacotherapy and interventional approaches have broadened the treatment options for PDN. There exists a need for a comprehensive guideline for the safe and effective treatment of patients suffering from PDN. Objective: The SWEET Guideline was developed to provide clinicians with the most comprehensive guideline for the safe and appropriate treatment of patients suffering from PDN. Methods: The American Society of Pain and Neuroscience (ASPN) identified an educational need for a comprehensive clinical guideline to provide evidence-based recommendations for PDN. A multidisciplinary group of international experts developed the SWEET guideline. The world literature in English was searched using Medline, EMBASE, Cochrane CENTRAL, BioMed Central, Web of Science, Google Scholar, PubMed, Current Contents Connect, Meeting Abstracts, and Scopus to identify and compile the evidence for diabetic neuropathy pain treatments (per section as listed in the manuscript) for the treatment of pain. Manuscripts from 2000-present were included in the search process. Results: After a comprehensive review and analysis of the available evidence, the ASPN SWEET guideline was able to rate the literature and provide therapy grades for most available treatments for PDN utilizing the United States Preventive Services Task Force criteria. Conclusion: The ASPN SWEET Guideline represents the most comprehensive review of the available treatments for PDN and their appropriate and safe utilization.

Real-world glycated haemoglobin changes among type 2 diabetes mellitus patients treated with a maintenance dose of 7 mg or 14 mg of oral semaglutide.

AIM: To describe the change in glycated haemoglobin (HbA1c) among patients with type 2 diabetes following treatment with a 7 or 14 mg maintenance dose of oral semaglutide. MATERIALS AND METHODS: This retrospective, claims-based study included adult patients with type 2 diabetes with a pre-index HbA1c of ≥7%, initiating treatment with oral semaglutide between 1 November 2019 and 30 June 2020; the patients had continuous health plan enrolment for ≥12 months before (pre-index) and ≥6 months following (post-index) the date of the first oral semaglutide claim (index). Patients were required to have a maintenance dose of 7 or 14 mg. Pre-index demographic and clinical characteristics were captured, as were doses at initiation and prescriber specialty. The change in HbA1c between the latest post-index and pre-index HbA1c measurements was calculated among all patients and among those with ≥90 days of continuous treatment (persistent patients). RESULTS: This study included 520 patients, most of whom had a complex medical history, experienced a range of comorbidities and received an average of 11.5 different classes of medications during the pre-index period. The mean HbA1c reduction during the 6-month post-initiation period was 1.2% (p < .001) for all patients and 1.4% (p < .001) for persistent patients. CONCLUSIONS: In this real-world study, patients with a pre-index HbA1c ≥7% who initiated treatment with oral semaglutide with a 7 or 14 mg maintenance dose had significantly lower HbA1c levels following treatment.

The relationship between medical marijuana use and prescription pain reliever use among U.S. adults: A retrospective analysis utilizing the 2015-2019 National Survey on Drug Use and Health (NSDUH).

Background: Despite a number of states in the U.S. enacting medical marijuana policies, there is currently a lack of research outlining the role that individual-level factors play in predicting medical marijuana use, especially regarding use and misuse of prescription pain relievers. The overall aim of this study was to assess the prevalence of medical marijuana use in the U.S. and to identify clinical, social, and demographic predictors. Methods: A retrospective secondary database analysis was conducted utilizing five years of the National Survey on Drug Use and Health (NSUDH). A multivariable logistic regression model assessed the association between prescription pain reliever use and medical marijuana in the adult U.S. population while adjusting for substance use factors, psychiatric factors, and demographic characteristics. Results: Within the U.S. adult population from 2015 to 2019, medical marijuana use increased from 1.6% to 2.4%, while appropriate prescription pain reliever use decreased from 33.4% to 27.5%, and prescription pain reliever misuse decreased from 4.7% to 3.7%. Of all marijuana users, 15.1% resided within non-medical marijuana states. Medical marijuana users are more likely to have a serious mental illness (14.0% vs. 4.4%) and a non-marijuana related substance dependence (5.3% vs. 1.2%). Past-year medical marijuana use was significantly more likely to be reported among appropriate users of prescription pain relievers (OR = 1.99, p < .001) and misusers (OR = 1.94, p < .001) (relative to nonusers). Conclusions: Prescription pain reliever appropriate use and misuse were associated with higher odds of medical marijuana use. This study identified a potential treatment gap among individuals residing in states with no medical marijuana availability. These study findings highlight the potential benefits of medical marijuana legalization that future research can build on to guide policy making decisions.

The role of specific isoforms of CaV2 and the common C-terminal of CaV2 in calcium channel function in sensory neurons of Aplysia.

The presynaptic release apparatus can be specialized to enable specific synaptic functions. Habituation is the diminishing of a physiological response to a frequently repeated stimulus and in Aplysia, habituation to touch is mediated by a decrease in transmitter release from the sensory neurons that respond to touch even after modest rates of action potential firing. This synaptic depression is not common among Aplysia synaptic connections suggesting the presence of a release apparatus specialized for this depression. We found that specific splice forms of ApCaV2, the calcium channel required for transmitter release, are preferentially used in sensory neurons, consistent with a specialized release apparatus. However, we were not able to find a specific ApCaV2 splice uniquely required for synaptic depression. The C-terminus of ApCaV2 alpha1 subunit retains conserved binding to Aplysia rab-3 interacting molecule (ApRIM) and ApRIM-binding protein (ApRBP) and the C-terminus is required for full synaptic expression of ApCaV2. We also identified a splice form of ApRIM that did not interact with the ApCav2 alpha 1 subunit, but it was not preferentially used in sensory neurons.

Mechanism of Action of Temporary Peripheral Nerve Stimulation.

PURPOSE OF REVIEW: Peripheral nerve stimulation (PNS) refers to the technique of utilizing electrical stimulation of peripheral nerves to inhibit the transmission of pain signals. PNS is used to treat chronic intractable pain and post-surgical or post-traumatic pain alongside a variety of other pain conditions, including headaches, facial pain, pelvic and urogenital pain, chest wall pain, residual limb or phantom limb pain, and back pain. RECENT FINDINGS: More recently, PNS has been used temporarily for periods of time less than 60 days to treat acute post-surgical pain. Peripheral nerve stimulation is believed to be effective due to its effects on both central and peripheral pathways. Centrally, it is proposed that the electrical pulses of PNS inhibit alpha-delta and C fibers, which decreases pain signaling in the higher centers of the central nervous system. Peripherally, gate theory is applied as it is theorized that PNS downregulates inflammatory mediators, endorphins, and neurotransmitters associated with pain signaling to decrease the transmission of efferent nociception and reduce pain sensations.

Real-World Hemoglobin A1c Changes, Prescribing Provider Types, and Medication Dose Among Patients with Type 2 Diabetes Mellitus Initiating Treatment with Oral Semaglutide.

INTRODUCTION: Given the lack of real-world data on oral semaglutide use outside clinical trials, the purpose of this study was to describe dose, prescriber specialty, and change in hemoglobin A1c (HbA1c) after 6 months of oral semaglutide treatment for patients with type 2 diabetes mellitus (T2DM). METHODS: This was a retrospective study among adult patients with T2DM with ≥ 1 claim for oral semaglutide between November 1, 2019`1-June 30, 2020. Patients had continuous health plan enrollment ≥ 12 months prior to (pre-index) and ≥ 6 months following (post-index) the date of the first oral semaglutide claim (index). Dose at initiation and specialty of the prescribing provider were captured. Change in HbA1c between the last post- and pre-index HbA1c measurement was calculated. Patients were stratified by pre-index HbA1c ≥ 9% (poorly controlled) and HbA1c < 9%. RESULTS: A total of 744 HbA1c < 9% and 268 poorly controlled patients were included in the study. Most patients had an initial oral semaglutide dose of 7 mg (49.3%) or 3 mg (42.9%), prescribed most frequently by a primary care provider (27.8%). Mean HbA1c reduction was 0.8% (p < 0.001). Patients with poorly controlled T2DM had greater HbA1c reductions than patients with HbA1c < 9% (2.0% versus 0.4%, p < 0.001). Patients persistent with oral semaglutide (≥ 90 days continuous treatment) had a mean HbA1c reduction of 0.9% (p < 0.001); persistent patients with poorly controlled T2DM had a mean reduction of 2.5%. CONCLUSIONS: Patients with T2DM in this study experienced significant reductions in HbA1c within 6 months following initiation of oral semaglutide. Patients with a higher starting HbA1c experienced greater HbA1c reductions. The initial dose of oral semaglutide was higher than prescribing instructions indicated for more than half of the study patients.

Palaeoenvironments and hominin evolutionary dynamics in southeast Asia.

Secure environmental contexts are crucial for hominin interpretation and comparison. The discovery of a Denisovan individual and associated fauna at Tam Ngu Hao 2 (Cobra) Cave, Laos, dating back to 164-131 ka, allows for environmental comparisons between this (sub)tropical site and the Palearctic Denisovan sites of Denisova Cave (Russia) and Baishiya Karst Cave (China). Denisovans from northern latitudes foraged in a mix of forested and open landscapes, including tundra and steppe. Using stable isotope values from the Cobra Cave assemblage, we demonstrate that, despite the presence of nearby canopy forests, the Denisovan individual from Cobra Cave primarily consumed plants and/or animals from open forests and savannah. Using faunal evidence and proxy indicators of climates, results herein highlight a local expansion of rainforest at ~ 130 ka, raising questions about how Denisovans responded to this local climate change. Comparing the diet and habitat of the archaic hominin from Cobra Cave with those of early Homo sapiens from Tam Pà Ling Cave (46-43 ka), Laos, it appears that only our species was able to exploit rainforest resources.

Overcoming defensive responding in the estimation of prevalence of non-medical use of prescription stimulants.

BACKGROUND: Prevalence of Non-Medical Use of Prescription Stimulants (NMUPS) is estimated to be high among young adults enrolled in college. However, precise estimation of the prevalence of NMUPS is challenging owing to biases affecting self-report of sensitive and potentially illegal behaviors. OBJECTIVE: This study aimed to estimate the prevalence and risk factors of NMUPS using the crosswise randomized response technique (CRRT) and compare findings to the traditionally-used direct self-report (DSR) method. METHODS: This study utilized a cross-sectional, randomized experimental design to survey adult undergraduate students at a major southeastern university in the United States. Eligible respondents were randomly assigned to a DSR group or a CRRT group. Those in the DSR group were presented a direct question about NMUPS, but those in the CRRT group were asked to indicate whether their response to the NMUPS question was the 'same' or 'different' compared to a random non-sensitive question. RESULTS: Prevalence of NMUPS was found to be 18.6% (95% CI:18.5%-18.7%) in the DSR group and 32.5% (95% CI:32.1%-32.9%; p = 0.003) in the CRRT group. Logistic regression analysis predicting NMUPS in the DSR group showed that it was significantly associated with positive expectancies (OR:3.50; 95% CI:2.44-5.02), negative expectancies (OR:0.49; 95% CI:0.35-0.68), perceived norms (OR:1.71; 95% CI:1.27-2.29), and religious beliefs (OR:0.69; 95% CI:0.52-0.92). CONCLUSIONS: The setting and mechanism of the survey is likely closely related to the validity of prevalence estimation of sensitive behaviors. This study found that prevalence of sensitive behaviors such as NMUPS is significantly higher when respondents are provided increased anonymity.

Early presence of Homo sapiens in Southeast Asia by 86-68 kyr at Tam Pà Ling, Northern Laos.

The timing of the first arrival of Homo sapiens in East Asia from Africa and the degree to which they interbred with or replaced local archaic populations is controversial. Previous discoveries from Tam Pà Ling cave (Laos) identified H. sapiens in Southeast Asia by at least 46 kyr. We report on a recently discovered frontal bone (TPL 6) and tibial fragment (TPL 7) found in the deepest layers of TPL. Bayesian modeling of luminescence dating of sediments and U-series and combined U-series-ESR dating of mammalian teeth reveals a depositional sequence spanning ~86 kyr. TPL 6 confirms the presence of H. sapiens by 70 ± 3 kyr, and TPL 7 extends this range to 77 ± 9 kyr, supporting an early dispersal of H. sapiens into Southeast Asia. Geometric morphometric analyses of TPL 6 suggest descent from a gracile immigrant population rather than evolution from or admixture with local archaic populations.

Influence of Social Media on Applicant Perceptions of Anesthesiology Residency Programs During the COVID-19 Pandemic: Quantitative Survey.

BACKGROUND: Social media may be an effective tool in residency recruitment, given its ability to engage a broad audience; however, there are limited data regarding the influence of social media on applicants' evaluation of anesthesiology residency programs. OBJECTIVE: This study evaluates the influence of social media on applicants' perceptions of anesthesiology residency programs during the COVID-19 pandemic to allow programs to evaluate the importance of a social media presence for residency recruitment. The study also sought to understand if there were differences in the use of social media by applicant demographic characteristics (eg, race, ethnicity, gender, and age). We hypothesized that given the COVID-19 pandemic restrictions on visiting rotations and the interview process, the social media presence of anesthesiology residency programs would have a positive impact on the recruitment process and be an effective form of communication about program characteristics. METHODS: All anesthesiology residency applicants who applied to Mayo Clinic Arizona were emailed a survey in October 2020 along with statements regarding the anonymity and optional nature of the survey. The 20-item Qualtrics survey included questions regarding subinternship rotation completion, social media resource use and impact (eg, "residency-based social media accounts positively impacted my opinion of the program"), and applicant demographic characteristics. Descriptive statistics were examined, and perceptions of social media were stratified by gender, race, and ethnicity; a factor analysis was performed, and the resulting scale was regressed on race, ethnicity, age, and gender. RESULTS: The survey was emailed to 1091 individuals who applied to the Mayo Clinic Arizona anesthesiology residency program; there were 640 unique responses recorded (response rate=58.6%). Nearly 65% of applicants reported an inability to complete 2 or more planned subinternships due to COVID-19 restrictions (n=361, 55.9%), with 25% of applicants reporting inability to do any visiting student rotations (n=167). Official program websites (91.5%), Doximity (47.6%), Instagram (38.5%), and Twitter (19.4%) were reported as the most used resources by applicants. The majority of applicants (n=385, 67.3%) agreed that social media was an effective means to inform applicants, and 57.5% (n=328) of them indicated that social media positively impacted their perception of the program. An 8-item scale with good reliability was created, representing the importance of social media (Cronbach α=.838). There was a positive and statistically significant relationship such that male applicants (standardized ß=.151; P=.002) and older applicants (ß=.159; P<.001) had less trust and reliance in social media for information regarding anesthesiology residency programs. The applicants' race and ethnicity were not associated with the social media scale (ß=-.089; P=.08). CONCLUSIONS: Social media was an effective means to inform applicants, and generally positively impacted applicants' perception of programs. Thus, residency programs should consider investing time and resources toward building a social media presence to improve resident recruitment.

Impact of food affordability on diabetes-related preventable hospitalization.

OBJECTIVES: This study aims to estimate the burden of food affordability on diabetes-related preventable hospitalizations among Medicaid enrollees in the United States. STUDY DESIGN: This study used a retrospective observational design with Medicaid administrative claims data from 17 states from 2014. METHODS: Data were linked with county-level social determinants of health (SDOH) from the American Community Survey. The rate of diabetes-related preventable hospitalizations was measured using the Agency for Healthcare Research and Quality's Prevention Quality Diabetes Composite, which includes hospitalization for short-term complications, long-term complications, lower extremity amputations, and uncontrolled diabetes. Multivariable logistic regression was used to predict the occurrence of diabetes-related preventable hospitalization. RESULTS: Among the 16 million eligible individuals, diabetes-related preventable hospitalizations were identified at the rate of 1.91 per 1000 individuals and contributed to more than $160 million in charges. Rates were higher among men compared with women (0.25% vs 0.15%; P < .001) and among Black adults compared with White adults (0.29% vs 0.18%; P < .001). Compared with individuals residing in counties with low food affordability, those residing in counties with high (odds ratio [OR], 0.84; 95% CI, 0.78-0.91; P < .001) or medium (OR, 0.85; 95% CI, 0.81-0.90; P < .001) food affordability had lower odds of hospitalization. CONCLUSIONS: This study provides real-world evidence about the impact of SDOH on diabetes-related preventable hospitalizations. Federal and state policies that can help improve accessibility of healthy foods are needed to ameliorate the burden of diabetes on society.

A Middle Pleistocene Denisovan molar from the Annamite Chain of northern Laos.

The Pleistocene presence of the genus Homo in continental Southeast Asia is primarily evidenced by a sparse stone tool record and rare human remains. Here we report a Middle Pleistocene hominin specimen from Laos, with the discovery of a molar from the Tam Ngu Hao 2 (Cobra Cave) limestone cave in the Annamite Mountains. The age of the fossil-bearing breccia ranges between 164-131 kyr, based on the Bayesian modelling of luminescence dating of the sedimentary matrix from which it was recovered, U-series dating of an overlying flowstone, and U-series-ESR dating of associated faunal teeth. Analyses of the internal structure of the molar in tandem with palaeoproteomic analyses of the enamel indicate that the tooth derives from a young, likely female, Homo individual. The close morphological affinities with the Xiahe specimen from China indicate that they belong to the same taxon and that Tam Ngu Hao 2 most likely represents a Denisovan.

Intraoperative Capnothorax during Robotic Diaphragmatic Endometriosis Excision.

Laparoscopic surgery is performed quite commonly and is known to have numerous advantages over traditional open surgery. Albeit rare, there are life-threatening complications as a result of laparoscopic surgery including those associated with the cardiopulmonary system. In our case, we present hemodynamically unstable capnothorax that occurred during robotic diaphragmatic endometriosis excision which was treated conservatively. It is critical for anesthesia providers to recognize when capnothorax occurs and to understand the implications and treatment in order to minimize unnecessary procedures and morbidity associated with such.

Novel reinforcement of corrugated nanofiber tissue-engineered vascular graft to prevent aneurysm formation for arteriovenous shunts in an ovine model.

Objective: Many patients who require hemodialysis treatment will often require a prosthetic graft after multiple surgeries. However, the patency rate of grafts currently available commercially has not been satisfactory. Tissue engineering vascular grafts (TEVGs) are biodegradable scaffolds created to promote autologous cell proliferation and functional neotissue regeneration and, accordingly, have antithrombogenicity. Therefore, TEVGs can be an alternative prosthesis for small diameter grafts. However, owing to the limitations of the graft materials, most TEVGs are rigid and can easily kink when implanted in limited spaces, precluding future clinical application. Previously, we developed a novel corrugated nanofiber graft to prevent graft kinking. Reinforcement of these grafts to ensure their safety is required in a preclinical study. In the present study, three types of reinforcement were applied, and their effectiveness was examined using large animals. Methods: In the present study, three different reinforcements for the graft composed of corrugated poly-ε-caprolactone (PCL) blended with poly(L-lactide-co-ε-caprolactone) (PLCL) created with electrospinning were evaluated: 1) a polydioxanone suture, 2) a 2-0 polypropylene suture, 3) a polyethylene terephthalate/polyurethane (PET/PU) outer layer, and PCL/PLCL as the control. These different grafts were then implanted in a U-shape between the carotid artery and jugular vein in seven ovine models for a total of 14 grafts during a 3-month period. In evaluating the different reinforcements, the main factors considered were cell proliferation and a lack of graft dilation, which were evaluated using ultrasound examinations and histologic and mechanical analysis. Results: No kinking of the grafts occurred. Overall, re-endothelialization was observed in all the grafts at 3 months after surgery without graft rupture or calcification. The PCL/PLCL grafts and PCL/PLCL grafts with a polydioxanone suture showed high cell infiltration; however, they had become dilated 10 weeks after surgery. In contrast, the PCL/PLCL graft with the 2-0 suture and the PCL/PLCL graft covered with a PET/PU layer did not show any graft expansion. The PCL/PLCL graft covered with a PET/PU layer showed less cell infiltration than that of the PCL/PLCL graft. Conclusions: Reinforcement is required to create grafts that can withstand arterial pressure. Reinforcement with suture materials has the potential to maintain cell infiltration into the graft, which could improve the neotissue formation of the graft.

Extruded poly (glycerol sebacate) and polyglycolic acid vascular graft forms a neoartery.

In the ongoing search for the optimal biomaterial for tissue engineered vascular grafts (TEVGs), poly (glycerol sebacate) (PGS) has emerged as a new potential candidate. We have utilized a novel method to create unique, pore-free, extruded PGS grafts with and without a supportive exterior layer of polyglycolic acid (PGA). The 1 mm diameter by 5 mm length TEVGs were implanted in a rat model of infrarenal abdominal aorta interposition grafting. Three months after implantation, TEVGs comprised of extruded PGS with an external PGA braid demonstrated a patency rate of 9/10 (90%) with no signs of dilatation, dehiscence, or rupture. The PGS/PGA graft was remodeled into a neoartery with complete endothelialization of the neoartery lumen and formation of smooth muscle actinin multilayers as demonstrated via immunohistochemistry. Formation and maturation of extracellular matrix material were also observed, with amounts of elastin and collagen comparable to native rat aorta. No significant host inflammatory response was observed. These findings suggest the combination of an extruded PGS tube with an external reinforcing PGA braid is a promising material for small diameter TEVGs.

Trophic ecology of a Late Pleistocene early modern human from tropical Southeast Asia inferred from zinc isotopes.

Tam Pà Ling, a cave site in northeastern Laos, has yielded the earliest skeletal evidence of Homo sapiens in mainland Southeast Asia. The reliance of Pleistocene humans in rainforest settings on plant or animal resources is still largely unstudied, mainly due to poor collagen preservation in fossils from tropical environments precluding stable nitrogen isotope analysis, the classical trophic level proxy. However, isotopic ratios of zinc (Zn) in bioapatite constitute a promising proxy to infer trophic and dietary information from fossil vertebrates, even under adverse tropical taphonomic conditions. Here, we analyzed the zinc isotope composition (66Zn/64Zn expressed as δ66Zn value) in the enamel of two teeth of the Late Pleistocene (63-46 ka) H. sapiens individual (TPL1) from Tam Pà Ling, as well as 76 mammal teeth from the same site and the nearby Nam Lot cave. The human individual exhibits relatively low enamel δ66Zn values (+0.24‰) consistent with an omnivorous diet, suggesting a dietary reliance on both plant and animal matter. These findings offer direct evidence of the broad utilization of resources from tropical rainforests by one of the earliest known anatomically modern humans in Southeast Asia.

Excitatory postsynaptic calcium transients at Aplysia sensory-motor neuron synapses allow for quantal examination of synaptic strength over multiple days in culture.

A more thorough description of the changes in synaptic strength underlying synaptic plasticity may be achieved with quantal resolution measurements at individual synaptic sites. Here, we demonstrate that by using a membrane targeted genetic calcium sensor, we can measure quantal synaptic events at the individual synaptic sites of Aplysia sensory neuron to motor neuron synaptic connections. These results show that synaptic strength is not evenly distributed between all contacts in these cultures, but dominated by multiquantal sites of synaptic contact, likely clusters of individual synaptic sites. Surprisingly, most synaptic contacts were not found opposite presynaptic varicosities, but instead at areas of pre- and postsynaptic contact with no visible thickening of membranes. The release probability, quantal size, and quantal content can be measured over days at individual synaptic contacts using this technique. Homosynaptic depression was accompanied by a reduction in release site probability, with no evidence of individual synaptic site silencing over the course of depression. This technique shows promise in being able to address outstanding questions in this system, including determining the synaptic changes that maintain long-term alterations in synaptic strength that underlie memory.