Gene therapy targeting SARM1 blocks pathological axon degeneration in mice

Axonal degeneration (AxD) following nerve injury, chemotherapy, and in several neurological disorders is an active process driven by SARM1, an injury-activated NADase. Axons of SARM1-null mice exhibit greatly delayed AxD after transection and in models of neurological disease, suggesting that inhibiting SARM1 is a promising strategy to reduce pathological AxD. Unfortunately, no drugs exist to target SARM1. We, therefore, developed SARM1 dominant-negatives that potently block AxD in cellular models of axotomy and neuropathy. To assess efficacy in vivo, we used adeno-associated virus-mediated expression of the most potent SARM1 dominant-negative and nerve transection as a model of severe AxD. While axons of vehicle-treated mice degenerate rapidly, axons of mice expressing SARM1 dominant-negative can remain intact for \u3e10 d after transection, similar to the protection observed in SARM1-null mice. We thus developed a novel in vivo gene therapeutic to block pathological axon degeneration by inhibiting SARM1, an approach that may be applied clinically to treat manifold neurodegenerative diseases characterized by axon loss

A Comparative Look at Various Countries\u27 Legal Regimes Governing Automated Vehicles

News and commentary about automated vehicles (AVs) focus on how they look and appear to operate, along with the companies developing and testing them. Behind the scenes are legal regimes—laws, regulations, and implementing bodies of different kinds—that literally and figuratively provide the rules of the road for AVs. Legal regimes matter because public welfare hinges on aspects of AV design and operation. Legal regimes can provide gatekeeping for AV developers and operators seeking to use public roads, and they can allocate liability when something goes wrong. Guiding and complementing legal regimes is public policy. Policy documents such as articulations of national strategies are sometimes used to address issues related to legal regimes and to demonstrate a jurisdiction’s support for AV development. Building on its long history analyzing AV policy issues, RAND (with support of its Institute for Civil Justice) collaborated with the University of Michigan Law School’s Law and Mobility Program to study the nature of different AV legal regimes around the world. It selected countries known to be active in this domain. The research team reviewed and shared scholarly and gray literature (which is a type of scholarship produced by an entity in which commercial publications are not the primary focus, such as white papers from a government agency), and it also consulted experts in these regimes from the public and private sectors. Under the supervision of the Law and Mobility Fellow (a lawyer), law students collected and studied materials associated with country-specific legal regimes and drafted summaries guided by RAND’s enumeration of key factors. Availability of information about legal regimes varies—access to documentation, especially in English, is uneven, even for officials in different countries working collaboratively on these issues. That constrained availability is reflected in published legal comparisons, and it motivated the research team’s systematic research, which drew from materials in English and other languages. This article summarizes the makeup of AV legal regimes of Australia, China, France, Germany, Japan, and the United Kingdom. It highlights some key contrasts, which will be developed further as the project continues. It focuses on law and policy relating to highly to fully automated vehicles (SAE Levels 4 and 5). Although guided by a common set of topics for each country, each profile reflects the material available and the factors that differentiate national approaches. The remainder of this article introduces the legal regimes of the covered countries in turn. It then provides an overview of key points of comparison and outlines future work

Differences in Arterial Occlusion Pressure of the Superficial Femoral Artery Between the Dominant and Non-Dominant Legs

The arterial occlusion pressure (AOP) is dependent on limb circumference. Previous research seldom reports the AOP of both limbs. PURPOSE: The purpose of this study was to compare the superficial femoral artery AOP measured in the dominant and non-dominant legs. METHODS: Ultrasound (GE LOGIQ) was used to detect blood flow through the superficial femoral artery of both legs in a random order in 20 males and 20 females. Circumference of the upper thigh, leg volume, and skinfold thickness were measured in both legs. Blood pressure was continuously monitored using a CNAP device. An inflatable cuff was placed around the upper thigh. The cuff was inflated to 50 mmHg and then inflated continuously (10 mmHg/10 s) until arterial blood flow and pulse waves were no longer detectable by the ultrasound. The AOP was then measured in the opposite leg. The AOP data were analyzed with a mixed model analysis of variance while maintaining a family-wise p-value of 0.05. RESULTS: In males, the AOP of the dominant (209.4 ± 29.4 mmHg) and non-dominant legs (206.8 ± 32.5 mmHg) were not significantly different (p=0.790). Likewise, in females the AOP of the dominant (212.3 ± 58.3 mmHg) and non-dominant legs (203.5 ± 50.9 mmHg) were not significantly different (p=0.386). When combining the data for males and females, the AOP of the dominant (210.9 ± 45.6 mmHg) and non-dominant legs (205.2 ± 40.7 mmHg) were not significantly different (p=0.412). Thigh circumference was the only variable that significantly (p=0.027) contributed to AOP. In both males and females, there were no differences in thigh skinfold thickness, circumference, and volume between the dominant and non-dominant legs. The dominant leg was larger in 24 (60%) of the subjects; the larger leg had a higher AOP in 19 (47.5%) of the subjects; and the dominant leg had a higher AOP in 26 (65%) of the subjects. Although the AOP between the dominant and nondominant legs was not statistically significant, the largest difference in AOP between the two legs was 124 mmHg. CONCLUSION: There were no significant differences in AOP of the superficial femoral artery between the dominant and non-dominant legs in either males or females. Because of the potentially larger differences in the AOP between the two legs, we recommend measuring the AOP in both limbs when using blood flow restriction during exercise

Sex Differences in the Superficial Femoral Artery Occlusion Pressure

The measurement of arterial occlusion pressure (AOP) prior to the use of blood flow restriction during exercise is recommended. Not all previous studies that have included both male and female participants have reported sex differences in AOP. PURPOSE: The purpose of this study was to compare the superficial femoral artery AOP of the dominant and non-dominant legs between males and females. METHODS: Ultrasound (GE LOGIQ) was used to detect blood flow through the superficial femoral artery of both legs in a random order in 20 males and 20 females. Circumference of the upper thigh, leg volume, and skinfold thickness were measured in both legs. Blood pressure was continuously monitored using a CNAP device. An inflatable cuff was placed around the upper thigh. The cuff was inflated to 50 mmHg and then inflated continuously (10 mmHg/10 s) until arterial blood flow and pulse waves were no longer detectable by the ultrasound. The AOP was then measured in the opposite leg. The AOP data were analyzed with a mixed model analysis of variance while maintaining a family-wise p-value of 0.05. RESULTS: The AOP of the dominant leg in males (209.4 ± 29.4 mmHg) and females (212.3 ± 8.3 mmHg) were not significantly different (p=0.844). Likewise, the AOP of the non-dominant leg in males (206.8 ± 32.5 mmHg) was not significantly different (p=0.804) than the AOP in the non-dominant legs of females (203.5 ± 50.9 mmHg). When combining the data for the dominant and non-dominant legs, the average AOP for males (208.1 ± 30.6 mmHg) and females (207.9 ± 53.1 mmHg) were not significantly different (p=0.986). Thigh circumference was the only variable that significantly (p=0.027) contributed to AOP. On the average the thigh circumference in the dominant and non-dominant legs of males (59.6 ± 5.5; 59.2 ± 5.2 cm) was greater than that for females (56.0 ± 2.9; 55.6 ± 3.2 cm), respectively. There were no sex differences in thigh skinfold thickness or thigh volume between males and females in either the dominant or non-dominant legs. CONCLUSION: There were no significant differences in AOP of the superficial femoral artery of the dominant and non-dominant legs between males females despite males having larger legs. Factors other than limb circumference likely have a role in determining AOP

Differences in Arterial Occlusion Pressure Using Two Different Cuff Inflation Protocols

The occlusion pressure used during blood flow restriction during exercise is based on the arterial occlusion pressure (AOP). Although previous studies have measured AOP using two different cuff inflation protocols, no studies have compared the AOP measured using both protocols. PURPOSE: The purpose of this study was to compare the superficial femoral artery AOP when measured using two different cuff inflation protocols. METHODS: Ultrasound (GE LOGIQ) was used to detect blood flow through the superficial femoral artery of both legs in 20 males and 20 females. An inflatable cuff was placed on the upper thigh. The superficial femoral artery was occluded using two different cuff inflation protocols in a random order in both legs. The continuous (CONT) protocol involved inflating the cuff to 50 mmHg then continuously inflating the cuff at a rate of 10 mmHg/10 s until blood flow could no longer be detected using the ultrasound. The incremental (INCR) protocol involved inflating the cuff to 50 mmHg for 30 s, and then deflating the cuff for 10 s. The cuff was then inflated incrementally with each subsequent inflation increasing by 30 mmHg for 30 s followed by deflating the cuff for 10 s. Once blood flow was occluded, cuff pressure was decreased in increments of 10 mmHg until there was evidence of blood flow. The cuff was then gradually inflated until blood flow was no longer detected. RESULTS: In males, the AOP measured in the dominant (209.4 ± 29.4; 208.2 ± 27.1) and non-dominant (206.8 ± 32.5; 206.2 ± 32.7) legs using the CONT and INCR cuff inflation protocols, respectively, were not significantly different (p\u3e0.05). Likewise, in females the AOP measured in the dominant (212.3 ± 58.3; 213.7 ± 53.9) and non-dominant (203.5 ± 50.9; 207.0 ± 50.2) legs using the CONT and INCR protocol, respectively, were not significantly different (p\u3e0.05). When combining male and female data, there were no significant differences in the AOP between the CONT and INCR cuff inflation protocols in either leg or when combining legs. CONCLUSION: Using a continuous or incremental protocol for occluding the superficial femoral artery resulted in similar AOP values. Either protocol can be used in future research as well as in settings where AOP is determined prior to the use of blood flow restriction during exercise

Exit rates of accountable care organizations that serve high proportions of beneficiaries of racial and ethnic minority groups

Importance: The Medicare Shared Savings Program provides financial incentives for accountable care organizations (ACOs) to reduce costs of care. The structure of the shared savings program may not adequately adjust for challenges associated with caring for patients with high medical complexity and social needs, a population disproportionately made up of racial and ethnic minority groups. If so, ACOs serving racial and ethnic minority groups may be more likely to exit the program, raising concerns about the equitable distribution of potential benefits from health care delivery reform efforts. Objective: To evaluate whether ACOs with a high proportion of beneficaries of racial and ethnic minority groups are more likely to exit the Medicare Shared Savings Program and identify characteristics associated with this disparity. Design, Setting, and Participants: This retrospective observational cohort study used secondary data on Medicare Shared Savings Program ACOs from January 2012 through December 2018. Bivariate and multivariate cross-sectional regression analyses were used to understand whether ACO racial and ethnic composition was associated with program exit, and how ACOs with a high proportion of beneficaries of racial and ethnic minority groups differed in characteristics associated with program exit. Exposures: Racial and ethnic composition of an ACO\u27s beneficiaries. Main Outcomes and Measures: Shared savings program exit before 2018. Results: The study included 589 Medicare Shared Savings Program ACOs. The ACOs in the highest quartile of proportion of beneficaries of racial and ethnic minority groups were designated high-proportion ACOs (145 [25%]), and those in the lowest 3 quartiles were designated low-proportion ACOs (444 [75%]). In unadjusted analysis, a 10-percentage point increase in the proportion of beneficiaries of racial and ethnic minority groups was associated with a 1.12-fold increase in the odds of an ACO exit (95% CI, 1.00-1.25; P = .04). In adjusted analysis, there were significant associations among high-proportion ACOs between characteristics such as patient comorbidities, disability, and clinician composition and a higher likelihood of exit. Conclusions and Relevance: The study results suggest that ACOs that served a higher proportion of beneficaries of racial and ethnic minority groups were more likely to exit the Medicare Shared Savings Program, partially because of serving patients with greater disease severity and complexity. These findings raise concerns about how current payment reform efforts may differentially affect racial and ethnic minority groups

Differences in Arterial Occlusion Pressure as Measured using Ultrasound and a Hand-Held Doppler Device

In the research lab and clinical settings, expensive ultrasound machines are used to measure arterial occlusion pressure (AOP) prior to the use of blood flow restriction during exercise. Alternatively, inexpensive hand-held Doppler ultrasound devices may be used to measure AOP in various applications and settings. PURPOSE: The purpose of this study was to compare the superficial femoral artery AOP as measured using ultrasound and a hand-held Doppler device. METHODS: Participants included 20 males and 20 females. An inflatable cuff was placed on the upper thigh. The superficial femoral artery was occluded by inflating the cuff to 50 mmHg then continuously inflating the cuff at a rate of 10 mmHg/10 s. A GE LOGIQ ultrasound was used to detect blood flow in the superficial femoral artery just below the cuff. A hand-held Doppler device was used simultaneously to detect blood flow (pulse waves) at the anterior medial malleolar artery of the ankle. The pressure at which blood flow could no longer be detected using the ultrasound and the hand-held Doppler were recorded as the AOP. The measurement of AOP using both devices simultaneously was performed on both legs in a random order. The data were analyzed with a mixed model analysis of variance while maintaining a family-wise p-value of 0.05. RESULTS: On the average, the AOP measured using the hand-held Doppler device was significantly (pCONCLUSION:Although the differences in the AOP measured using the Ultrasound and the hand-held Doppler in both legs in males and females was statistically significant, for all practical purposes, the small differences were of not practical importance. In settings in which blood flow restriction during exercise is employed, a hand-held Doppler device is a viable alternative to using expensive ultrasound machines to measure AOP

Reliability of Arterial Occlusion Pressure Measurements Using Two Different Cuff Inflation Protocols

Although previous studies have used two different cuff inflation protocols to measure AOP, no studies have reported the reliability of AOP measurements using both protocols. PURPOSE: The purpose of this study was to evaluate the reliability of two measurements of AOP in the superficial femoral artery using two different cuff inflation protocols. METHODS: Ultrasound (GE LOGIQ) was used to detect blood flow through the superficial femoral artery of both legs in 20 males and 20 females. The AOP of the artery was measured twice in each leg. The artery was occluded using a continuous (CONT) cuff inflation protocol in one leg and an increment (INCR) cuff inflation protocol in the opposite leg. The CONT protocol involved inflating the cuff to 50 mmHg then continuously inflating the cuff at a rate of 10 mmHg/10 s until blood flow could no longer be detected using the ultrasound. The INCR protocol involved initially inflating the cuff to 50 mmHg for 30 s, and then deflating the cuff for 10 s. The cuff was then inflated incrementally with each subsequent inflation increasing by 30 mmHg for 30 s followed by deflating the cuff for 10 s. Once blood flow was occluded, cuff pressure was decreased in increments of 10 mmHg until there was evidence of blood flow. The cuff was then gradually inflated until blood flow was no longer detected. The pressure at which blood flow could no longer be detected was recorded as the AOP. The data were analyzed with a mixed model analysis of variance while maintaining a family-wise p-value of 0.05. RESULTS: The difference in the two measurements of AOP using the CONT and INCR cuff inflation protocols in males (0.9 ± 5.4 and 0.5 ± 5.1 mmHg) and females (1.9 ± 11.4 and 2.3 ± 12.2 mmHg), or when combining the data from males and females (0.4 ± 8.9 and 0.9 ± 9.3 mmHg), respectively, were not statistically significant. The correlations between the two measurements of AOP using the CONT and INCR cuff inflation protocols all exceeded 0.99. CONCLUSION: Measurements of AOP using a continuous or increment cuff inflation protocol are highly reliable. Either cuff inflation protocol can be used when making multiple measurements of AOP

Measuring Brachial Artery Occlusion Pressure Using a Hand-held Doppler and Pulse Oximeter

The measurement of arterial occlusion pressure (AOP) is recommended for the safe and effective use of blood flow restriction (BFR) during training. PURPOSE: This study compared measurements of brachial artery AOP using Doppler ultrasound (US), a hand-held Doppler (HHDOP) and a pulse oximeter (PO). METHODS: The AOP of the brachial artery was measured simultaneously using US, HHDOP, and a PO in the dominant arm of males (n=36) and females (n=49). The blood flow restriction cuff was inflated using a continuous cuff inflation protocol. RESULTS: A mixed model ANOVA revealed small but significant (p \u3c 0.05) overall main effects (combined males and females) between AOP measured using US (119.8 ± 13.2 mmHg), HHDOP (119.1 ± 13.1 mmHg) and PO (118.0 ±13.2 mmHg), and between males (125.3 ± 13.1 mmHg) and females (114.3 ± 11.1 mmHg). The differences in AOP between males and females was consistent across all three methods of measuring AOP (US, HHDP, PO) and may be attributed to sex differences in limb circumference and systolic blood pressure. The small overall difference between US and HHDOP (0.74 ± 2.7 mmHg) was not significant but the difference between US and PO (1.81 ± 3.3 mmHg) measures of AOP was significant (

Measurements of Arterial Occlusion Pressure Using Hand-held Devices

Use of blood flow restriction (BFR) during training has become increasingly popular due to the benefits over a wide range of applications. An essential component to the safe and effective use of BFR is the measurement of arterial occlusion pressure (AOP). PURPOSE: This study compared measures of AOP of the brachial artery using three devices and two cuff inflation methods. METHODS: Brachial artery AOP was measured in 20 males and 21 females simultaneously using Doppler ultrasound (US), a handheld Doppler (HHDOP) and a pulse oximeter (PO) once when inflating the cuff with a clinical grade Hokanson (HOK) rapid cuff inflation system and twice manually (MAN) with a sphygmomanometer. RESULTS: A mixed model ANOVA revealed small but significant (p \u3c 0.05) overall main effects between AOP measured using the HOK (120.4 ± 1.98) and MAN (122.2 ± 2.0) cuff inflation methods, between US (122.0 ± 1.97), HHDOP (121.6 ± 2.0) and PO (120.5 ± 2.0) measurements of AOP, and between males (127.6 ± 2.83) and females (115.2 ± 2.7). Further analyses indicated that the small overall difference between US and PO (1.56 ± 0.52) measures of AOP was significant (pp\u3e0.05). Trial-to-trial variance in measures of AOP using US, HHDOP and PO were negligible. Bland-Altman plots revealed reasonable limits of agreement for both HHDOP (±4.46 mmHg) and PO (±5.47 mmHg) measures of AOP. CONCLUSIONS: The small differences in US, HHDOP and PO measures of AOP measurements using HOK and MAN cuff inflation methods are of little practical significance. Manual inflation of the pressure cuff provides comparable AOP values compared to when using a clinical grade cuff inflation system. Practitioners can be confident in measures of AOP using a quality hand-held doppler or pulse oximeter prior to blood flow restriction training