The sodium chloride cotransporter SLC12A3: new roles in sodium, potassium, and blood pressure regulation.

SLC12A3 encodes the thiazide-sensitive sodium chloride cotransporter (NCC), which is primarily expressed in the kidney, but also in intestine and bone. In the kidney, NCC is located in the apical plasma membrane of epithelial cells in the distal convoluted tubule. Although NCC reabsorbs only 5 to 10% of filtered sodium, it is important for the fine-tuning of renal sodium excretion in response to various hormonal and non-hormonal stimuli. Several new roles for NCC in the regulation of sodium, potassium, and blood pressure have been unraveled recently. For example, the recent discoveries that NCC is activated by angiotensin II but inhibited by dietary potassium shed light on how the kidney handles sodium during hypovolemia (high angiotensin II) and hyperkalemia. The additive effect of angiotensin II and aldosterone maximizes sodium reabsorption during hypovolemia, whereas the inhibitory effect of potassium on NCC increases delivery of sodium to the potassium-secreting portion of the nephron. In addition, great steps have been made in unraveling the molecular machinery that controls NCC. This complex network consists of kinases and ubiquitinases, including WNKs, SGK1, SPAK, Nedd4-2, Cullin-3, and Kelch-like 3. The pathophysiological significance of this network is illustrated by the fact that modification of each individual protein in the network changes NCC activity and results in salt-dependent hypotension or hypertension. This review aims to summarize these new insights in an integrated manner while identifying unanswered questions.

Assessing injury risks of reclined occupants in a frontal crash preceded by braking with varied seatbelt designs using the SAFER Human Body Model.

OBJECTIVE: This study investigated the effects of different seatbelt geometries and load-limiting levels on the kinematics and injury risks of a reclined occupant during a whole-sequence frontal crash scenario, using simulations with the Active SAFER Human Body Model (Active SHBM). METHODS: The Active SHBM was positioned in a reclined position (50°) on a semi-rigid seat model. A whole-sequence frontal crash scenario, an 11 m/s2 Automated Emergency Braking (AEB) phase followed by a frontal crash at 50 km/h, was simulated. The seatbelt geometry was varied using either a B-pillar-integrated (BPI) or Belt-in-seat (BIS) design. The shoulder belt load-limiting level of the BPI seatbelt was also varied to achieve either similar shoulder belt forces (BPI_Lower_LL) or comparable upper body displacements (BPI_Higher_LL) to the BIS seatbelt. Kinematics of different body regions and seatbelt forces were compared. The risks of sustaining a mild traumatic brain injury (mTBI), two or more fractured ribs (NFR2+), and lumbar spine vertebral fractures were also compared. RESULTS: During the pre-crash phase, head, first thoracic vertebra, and first lumbar vertebra displacements were greater with the BPI seatbelt than with the BIS, mainly due to the lack of initial contact between the torso and the seatbelt. Pelvis pre-crash displacements, however, remained consistent across seatbelt types. In the in-crash phase, variations in shoulder belt forces were directly influenced by the different load-limiting levels of the shoulder belt. The mTBI (around 20%) and NFR2+ (around 70-100%) risks were amplified with BPI seatbelts, especially at higher load-limiting force. However, the BPI design demonstrated reduced lumbar spine fracture risks (from 30% to 1%). CONCLUSIONS: The BIS seatbelt appears promising, as seen with the reduced mTBI and NFR2+ risks, for ensuring the protection of reclined occupants in frontal crashes. However, additional solutions, such as lap belt load limiting, should be considered to reduce lumbar spine loading.

Rib and sternum fracture risks for restrained occupants in frontal car crashes.

OBJECTIVE: Most car occupant fatalities occur in frontal crashes and the thorax is the most frequently injured body region. The objectives of the study were, firstly, to quantify the relation between risk factors (such as speed and occupant age) and rib and sternum fracture injury probability in frontal car crashes, and, secondly, to evaluate whether rib fracture occurrence can predict sternum fractures. METHODS: Weighted German data from 1999-2021 were used to create the injury risk curves to predict both, at least moderate and at least serious, rib and sternum fracture risks. A contingency table for rib and sternum fractures allowed the calculation of sensitivity, specificity, and precision, as well as testing for the association. RESULTS: Elderly occupants (≥65 years old) had increased rib and sternum fracture risk compared to mid aged occupants (18-64 years old). Besides occupant age, delta-V was always and sex sometimes a significant predictor for skeletal thoracic injury. Sternum fractures were more common than rib fractures and more likely to occur at any given delta-V. Sternum fractures occurred often in isolation. Female occupants were at higher risk than males to sustain at least moderate rib and sternum fractures together and sternum fractures in isolation. Rib and sternum fractures were associated, but low sensitivity and precision show that rib fractures do not predict sternum fractures well. CONCLUSIONS: Elderly and female occupants were at the highest risk and should be targeted by thoracic injury criteria and thresholds for frontal crash occupant protection. Rib and sternum fractures were not associated. Therefore, sternum fractures need to be predicted and evaluated separately from rib fractures.

Injury risk curves to guide safe speed limits on Swedish roads using German crash data supplemented with estimated non-injury crashes.

Vision Zero postulates that no one should be killed or seriously injured in road traffic; therefore, it is necessary to define evidence-based speed limits to mitigate impact severity. The overall aims to guide the definition of safe speeds limits by establishing relations between impact speed and the risk of at-least-moderate (MAIS2+) and at-least-severe (MAIS3+) injuries for car occupants in frontal and side crashes in Sweden. As Swedish in-depth data are unavailable, the first objective was to assess the applicability of German In-depth Accident Study (GIDAS) data to Sweden. The second was to create unconditional injury risk curves (risk of injury given involvement in any crash), rather than risk curves conditional on the GIDAS sampling criterion of suspected-injury crashes. Thirdly, we compared the unconditional and conditional risk curves to quantify the practical implications of this methodological choice. Finally, we provide an example to demonstrate how injury risk curves facilitate the definition of safe, evidence-based speed limits in Sweden. Characteristics important for the injury outcome were similar between GIDAS and Swedish data; therefore, the injury risk curves using German GIDAS data are applicable to Sweden. The regression models yielded the following results for unconditional injury risk curves: 10 % MAIS2+ at 25 km/h impact speed for frontal head-on crashes, 20 km/h for frontal car-to-object crashes, 55 km/h in far-side crashes, and 45 km/h in near-side crashes. A 10 % MAIS3+ risk was reached between 70 and 75 km/h for all crash types. Conditional injury risk curves gave substantially different results; the 10 % MAIS3+ risk in near-side crashes was 140 km/h, twice the unconditional value. For example, if a 10 % MAIS3+ risk was acceptable, treating remaining uncertainty conservatively, assuming compliance with speed limits and that Automated Emergency Braking takes 20 km/h of the travel speed before impact in longitudinal traffic, the safe speed limit for car occupants on most Swedish roads would be 80 km/h and 60 km/h in intersections.

K+-induced natriuresis is preserved during Na+ depletion and accompanied by inhibition of the Na+-Cl- cotransporter.

During hypovolemia and hyperkalemia, the kidneys defend homeostasis by Na(+) retention and K(+) secretion, respectively. Aldosterone mediates both effects, but it is unclear how the same hormone can evoke such different responses. To address this, we mimicked hypovolemia and hyperkalemia in four groups of rats with a control diet, low-Na(+) diet, high-K(+) diet, or combined diet. The low-Na(+) and combined diets increased plasma and kidney ANG II. The low-Na(+) and high-K(+) diets increased plasma aldosterone to a similar degree (3-fold), whereas the combined diet increased aldosterone to a greater extent (10-fold). Despite similar Na(+) intake and higher aldosterone, the high-K(+) and combined diets caused a greater natriuresis than the control and low-Na(+) diets, respectively (P < 0.001 for both). This K(+)-induced natriuresis was accompanied by a decreased abundance but not phosphorylation of the Na(+)-Cl(-) cotransporter (NCC). In contrast, the epithelial Na(+) channel (ENaC) increased in parallel with aldosterone, showing the highest expression with the combined diet. The high-K(+) and combined diets also increased WNK4 but decreased Nedd4-2 in the kidney. Total and phosphorylated Ste-20-related kinase were also increased but were retained in the cytoplasm of distal convoluted tubule cells. In summary, high dietary K(+) overrides the effects of ANG II and aldosterone on NCC to deliver sufficient Na(+) to ENaC for K(+) secretion. K(+) may inhibit NCC through WNK4 and help activate ENaC through Nedd4-2.

Effects of angiotensin II on kinase-mediated sodium and potassium transport in the distal nephron.

PURPOSE OF REVIEW: The aim is to review the recently reported effects of angiotensin II (Ang II) on sodium and potassium transport in the aldosterone-sensitive distal nephron, including the signaling pathways between receptor and transporter, and the (patho)physiological implications of these findings. RECENT FINDINGS: Ang II can activate the sodium chloride cotransporter (NCC) through phosphorylation by Ste20-related, proline-alanine rich kinase (SPAK), an effect that is independent of aldosterone but dependent on with no lysine kinase 4 (WNK4). A low-sodium diet (high Ang II) activates NCC, whereas a high-potassium diet (low Ang II) inhibits NCC. NCC activation also contributes to Ang-II-mediated hypertension. Ang II also activates the epithelial sodium channel (ENaC) additively to aldosterone, and this effect appears to be mediated through protein kinase C and superoxide generation by nicotinamide adenine dinucleotide phosphate oxidase. While aldosterone activates the renal outer medullary potassium channel (ROMK), this channel is inhibited by Ang II. The key kinase responsible for this effect is c-Src, which phosphorylates ROMK and leaves WNK4 unphosphorylated to further inhibit ROMK. SUMMARY: The effects of Ang II on NCC, ENaC, and ROMK help explain the renal response to hypovolemia which is to conserve both sodium and potassium. Pathophysiologically, Ang-II-induced activation of NCC appears to contribute to salt-sensitive hypertension.

Repositioning forward-leaning passengers by seatbelt pre-pretensioning.

OBJECTIVE: The study determined the seatbelt pre-pretensioner force needed and the time required to reposition average male front-seat passengers from forward-leaning to upright using finite element simulations of the Active SAFER Human Body Model (Active SHBM). METHODS: The Active SHBM was positioned in an initial forward-leaning position (29° forward from upright) on a deformable vehicle seat. A pre-pretensioner was modeled as a pre-loaded spring and its ability to reposition the forward-leaning Active SHBM to an upright position was simulated for twenty-four different pre-crash conditions. Four parameters were varied: (1) Automated Emergency Braking (AEB) active with 11 m/s2 or no AEB, (2) type of seatbelt system: Belt-In-Seat or B-pillar, (3) pre-pretensioner activation time (200 ms before, 100 ms before, or at the same time as AEB ramp-up), and (4) pre-pretensioner force (200 N, 300 N, 400 N, 600 N). The first thoracic vertebra fore-aft (T1 X) trajectories were compared against a reference upright position to determine the force and time needed to reposition and the effectiveness of repositioning in the different conditions. RESULTS: The lowest force enabling repositioning in all simulations was 400 N (no AEB, Belt-In-Seat). It took about 350 ms. In the presence of AEB, activating the pre-pretensioner 200 ms before AEB and using 600 N pre-pretensioner force was needed for repositioning (taking 200 ms with Belt-In-Seat and 260 ms with B-pillar installations). Repositioning was faster and thus more effective with the Belt-In-Seat seatbelt in all simulations. CONCLUSIONS: All four parameters (presence of AEB, type of seatbelt system, pre-pretensioner activation time and force) affected the repositioning ability and time required. Far from all combinations repositioned a forward-leaning average male occupant model, but those found to be effective and fast appear as a feasible option for vehicle safety systems to reposition out-of-position occupants during pre-crash events.

Evaluation of full-face, open-face, and airbag-equipped helmets for facial impact protection.

OBJECTIVE: Two-wheeler riders frequently sustain injuries to the head and face in real-world crashes, including traumatic brain injury, basilar skull fracture, and facial fracture. Different types of helmets exist today, which are recognized as preventing head injuries in general; however, their efficacy and limitations in facial impact protection are underexplored. Biofidelic surrogate test devices and assessment criteria are lacking in current helmet standards. This study addresses these gaps by applying a new, more biofidelic test method to evaluate conventional full-face helmets and a novel airbag-equipped helmet design. Ultimately, this study aims to contribute to better helmet design and testing standards. METHODS: Facial impact tests at two locations, mid-face and lower face, were conducted with a complete THOR dummy. Forces applied to the face and at the junction of the head and neck were measured. Brain strain was predicted by a finite element head model taking both linear and rotational head kinematics as input. Four helmet types were evaluated: full-face motorcycle and bike helmets, a novel design called a face airbag (an inflatable structure integrated into an open-face motorcycle helmet), and an open-face motorcycle helmet. The unpaired, two-sided student's t-test was performed between the open-face helmet and the others, which featured face-protective designs. RESULTS: A substantial reduction in brain strain and facial forces was found with the full-face motorcycle helmet and face airbag. Upper neck tensile forces increased slightly with both full-face motorcycle (14.4%, p >.05) and bike helmets (21.7%, p =.039). The full-face bike helmet reduced the brain strain and facial forces for lower-face impacts, but not for mid-face impacts. The motorcycle helmet reduced mid-face impact forces while slightly increasing forces in the lower face. SIGNIFICANCE OF RESULTS: The chin guards of full-face helmets and the face airbag protect by reducing facial load and brain strain for lower face impact; however, the full-face helmets' influence on neck tension and increased risk for basilar skull fracture need further investigation. The motorcycle helmet's visor re-directed mid-face impact forces to the forehead and lower face via the helmet's upper rim and chin guard: a thus-far undescribed protective mechanism. Given the significance of the visor for facial protection, an impact test procedure should be included in helmet standards, and the use of helmet visors promoted. A simplified, yet biofidelic, facial impact test method should be included in future helmet standards to ensure a minimum level of protection performance.

Assessing the applicability of impact speed injury risk curves based on US data to defining safe speeds in the US and Sweden.

Vision Zero is an approach to road safety that aims to eliminate all traffic-induced fatalities and lifelong injuries. To reach this goal, a multi-faceted safe system approach must be implemented to anticipate and minimize the risk associated with human mistakes. One aspect of a safe system is choosing speed limits that keep occupants within human biomechanical limits in a crash scenario. The objective of this study was to relate impact speed and maximum delta-v to risk of passenger vehicle (passenger cars and light trucks and vans) occupants sustaining a moderate to fatal injury (MAIS2+F) in three crash modes: head-on vehicle-vehicle, frontal vehicle-barrier, and front-to-side vehicle-vehicle crashes. Data was extracted from the Crash Investigation Sampling System, and logistic regression was used to construct the injury prediction models. Impact speed was a statistically significant predictor in head-on crashes, but was not a statistically significant predictor in vehicle-barrier or front-to-side crashes. Maximum delta-v was a statistically significant predictor in all three crash modes. A head-on impact speed of 62 km/h yielded 50% (±27%) risk of moderate to fatal injury for occupants at least 65 years old. A head-on impact speed of 82 km/h yielded 50% (±31%) risk of moderate to fatal injury for occupants younger than 65 years. Compared to the impact speeds, the maximum delta-v values yielding the same level of risk were lower within the head-on crash population. A head-on delta-v of 40 km/h yielded 50% (±21%) risk of moderate to fatal injury for occupants at least 65 years old. A head-on delta-v of 65 km/h yielded 50% (±33%) risk of moderate to fatal injury for occupants younger than 65 years. A maximum delta-v value of approximately 30 km/h yielded 50% (±42%) risk of MAIS2+F injury for passenger car occupants in vehicle-vehicle front-to-side crashes. A maximum delta-v value of approximately 44 km/h yielded 50% (±24%) risk of MAIS2+F injury for light truck and van occupants, respectively, in vehicle-vehicle front-to-side crashes.

Aldosterone does not require angiotensin II to activate NCC through a WNK4-SPAK-dependent pathway.

We and others have recently shown that angiotensin II can activate the sodium chloride cotransporter (NCC) through a WNK4-SPAK-dependent pathway. Because WNK4 was previously shown to be a negative regulator of NCC, it has been postulated that angiotensin II converts WNK4 to a positive regulator. Here, we ask whether aldosterone requires angiotensin II to activate NCC and if their effects are additive. To do so, we infused vehicle or aldosterone in adrenalectomized rats that also received the angiotensin receptor blocker losartan. In the presence of losartan, aldosterone was still capable of increasing total and phosphorylated NCC twofold to threefold. The kinases WNK4 and SPAK also increased with aldosterone and losartan. A dose-dependent relationship between aldosterone and NCC, SPAK, and WNK4 was identified, suggesting that these are aldosterone-sensitive proteins. As more functional evidence of increased NCC activity, we showed that rats receiving aldosterone and losartan had a significantly greater natriuretic response to hydrochlorothiazide than rats receiving losartan only. To study whether angiotensin II could have an additive effect, rats receiving aldosterone with losartan were compared with rats receiving aldosterone only. Rats receiving aldosterone only retained more sodium and had twofold to fourfold increase in phosphorylated NCC. Together, our results demonstrate that aldosterone does not require angiotensin II to activate NCC and that WNK4 appears to act as a positive regulator in this pathway. The additive effect of angiotensin II may favor electroneutral sodium reabsorption during hypovolemia and may contribute to hypertension in diseases with an activated renin-angiotensin-aldosterone system.

Crash characteristics and injury risk of adult car occupants in near-side impacts.

OBJECTIVE: In the US, 27% of car occupant fatalities occur in side-impacts. Near-side impacts cause more serious injuries than far-side impacts. Car occupant safety overall has improved, but rear-seat occupant protection lags behind front-seat protection. The current study had two aims: first, to describe crash characteristics and injury outcomes for near-side rear-seated restrained occupants before and after side-impact regulations (FMVSS-214) were mandated; and secondly, to estimate injury risks in near-side impact depending on seating position, delta-v, and other predictors. METHODS: The National Automotive Sampling System - Crashworthiness Data System (NASS - CDS) database for 1995 to 2015 was analyzed. The descriptive statistics focused on rear-seated restrained adults, comparing old (<1997) and new (≥1997) vehicles exposed to near-side impacts. Weighted logistic regression models including all front and rear-seat occupants were used to predict the occurrence of at least moderate injury in near-side impacts. RESULTS: Rear-seated restrained adults in new vehicles were exposed to higher delta-v and intrusion levels compared to old vehicles. Moreover, injuries to rear-seat occupants in new vehicles were more distributed across body regions, compared to old vehicles (mainly thorax and head). The risk of sustaining injuries increased significantly with delta-v and occupant age, when not using a seatbelt, when seated in a passenger car and when hit in the passenger compartment. The risk increased by trend, but not significantly, when seated in a newer vehicle, when seated in the rear-seat and when the crash opponent was an SUV or van. CONCLUSIONS: Trends and risk factors for at least moderate injuries in near-side impacts were identified to guide future directions for occupant protection in side-impacts and its assessments.

Can non-crash naturalistic driving data be an alternative to crash data for use in virtual assessment of the safety performance of automated emergency braking systems?

INTRODUCTION: Developers of in-vehicle safety systems need to have data allowing them to identify traffic safety issues and to estimate the benefit of the systems in the region where it is to be used, before they are deployed on-road. Developers typically want in-depth crash data. However, such data are often not available. There is a need to identify and validate complementary data sources that can complement in-depth crash data, such as Naturalistic Driving Data (NDD). However, few crashes are found in such data. This paper investigates how rear-end crashes that are artificially generated from two different sources of non-crash NDD (highD and SHRP2) compare to rear-end in-depth crash data (GIDAS). METHOD: Crash characteristics and the performance of two conceptual automated emergency braking (AEB) systems were obtained through virtual simulations - simulating the time-series crash data from each data source. RESULTS: Results show substantial differences in the estimated impact speeds between the artificially generated crashes based on both sources of NDD, and the in-depth crash data; both with and without AEB systems. Scenario types also differed substantially, where the NDD have many fewer scenarios where the following-vehicle is not following the lead vehicle, but instead catches-up at high speed. However, crashes based on NDD near-crashes show similar pre-crash criticality (time-to-collision) to in-depth crash data. CONCLUSIONS: If crashes based on near-crashes are to be used in the design and assessment of preventive safety systems, it has to be done with great care, and crashes created purely from small amounts of everyday driving NDD are not of much use in such assessment. PRACTICAL APPLICATIONS: Researchers and developers of in-vehicle safety systems can use the results from this study: (a) when deciding which data to use for virtual safety assessment of such systems, and (b) to understand the limitations of NDD.

Angiotensin II induces phosphorylation of the thiazide-sensitive sodium chloride cotransporter independent of aldosterone.

We studied here the independent roles of angiotensin II and aldosterone in regulating the sodium chloride cotransporter (NCC) of the distal convoluted tubule. We adrenalectomized three experimental and one control group of rats. Following surgery, the experimental groups were treated with either a high physiological dose of aldosterone, a non-pressor, or a pressor dose of angiotensin II for 8 days. Aldosterone and both doses of angiotensin II lowered sodium excretion and significantly increased the abundance of NCC in the plasma membrane compared with the control. Only the pressor dose of angiotensin II caused hypertension. Thiazides inhibited the sodium retention induced by the angiotensin II non-pressor dose. Both aldosterone and the non-pressor dose of angiotensin II significantly increased phosphorylation of NCC at threonine-53 and also increased the intracellular abundance of STE20/SPS1-related, proline alanine-rich kinase (SPAK). No differences were found in other modulators of NCC activity such as oxidative stress responsive protein type 1 or with-no-lysine kinase 4. Thus, our in vivo study shows that aldosterone and angiotensin II independently increase the abundance and phosphorylation of NCC in the setting of adrenalectomy; effects are likely mediated by SPAK. These results may explain, in part, the hormonal control of renal sodium excretion and the pathophysiology of several forms of hypertension.

Evaluating automated emergency braking performance in simulated car-to-two-wheeler crashes in China: A comparison between C-NCAP tests and in-depth crash data.

Automated Emergency Braking (AEB) is an effective way to prevent crashes from happening or mitigate their severity. Because riders of two-wheelers (TWs) are among the most vulnerable road users, New Car Assessment Programs, like the China New Car Assessment Program (C-NCAP), have recently introduced test scenarios for the assessment of AEB for cars encountering TWs (TW-AEB). The main aim of this study was to determine how well two different C-NCAP test scenario datasets reflect real-world crash scenarios for the purpose of assessing TW-AEB performance. We used virtual counterfactual simulations to determine whether the hypothetical TW-AEB's performance, when applied to the two C-NCAP datasets, was similar to its performance when applied to a set of reconstructed car-to-TW crashes representing real-world crashes. The test datasets were the current C-NCAP scenario set and a proposed C-NCAP scenario set; the real-world crash dataset comprised 113 reconstructed crashes from the Shanghai United Road Traffic Safety Scientific Research Center database (SHUFO). The performances were compared with respect to crash avoidance rate and the characteristics of the remaining crashes. A substantially higher proportion of crashes was avoided in the current C-NCAP scenario set than in the other two (with the sensor field of view (FoV) set to 70° and the activation time to 1.1 s TTC). In fact, with these parameter settings, no crashes remained in the current C-NCAP scenarios, while only 37% and 46% of the crashes in the proposed C-NCAP scenario set and SHUFO crash set were avoided, respectively. Our findings show that TW-AEB systems which are optimized for the current C-NCAP test scenarios are likely to provide benefits in real-world crashes. However, including additional test scenarios which reflect real-world crash situations more accurately would likely lead to a higher correlation between C-NCAP scores and real-world TW-AEB performance. In particular, we recommend the introduction of longitudinal same-direction scenarios with the car or TW turning and perpendicular scenarios with high TW traveling speed, in future C-NCAP releases. Inclusion of these scenarios in C-NCAP might reward improvements of future TW-AEBs toward systems that can save more lives. Furthermore, our study shows that there is likely to be a substantial number of crashes with an impact speed higher than 40 km/h still remaining even after the widespread application of TW-AEB. Therefore, passive safety for TW riders on Chinese roads will be still needed.

Motorcyclist injuries: Analysis of German in-depth crash data to identify priorities for injury assessment and prevention.

Globally there are more than 350,000 PTW fatalities each year. Safety concepts to protect Powered Two-Wheeler (PTW) riders exist and are being developed further, but they need appropriate procedures and test tools (Anthropometric Test Devices (ATDs) for physical testing and Human Body Models (HBMs) for virtual testing) to direct and promote those developments. To aid further development of the tools, we aim to rank the frequency of specific injuries arising from the prevalent impact types, discuss how current ATDs and HBMs are equipped to assess these injuries, and suggest what further development should be prioritized. We analyzed a sample of injured riders from the German In-depth Accident Study (GIDAS) according to the Abbreviated Injury Scale (AIS) 2015 classification, using severity thresholds of at-least-moderate (AIS2+) and at-least-serious (AIS3+). PTW rider injuries were ranked by frequency for all crashes and also for sub-samples of specific impact types (impact with passenger cars, ground, and roadside furniture). The most frequent AIS3+ injuries were: femur fracture (17%), rib cage fracture (13%), lung injury (9%), tibia fracture (7%), and cerebrum injury (7%). In all impacts together and as for impacts with the road surface, injuries to the thorax were most frequent. In impacts with cars and road furniture, thorax injuries were also frequent, but outranked by lower extremity injuries. Considering both AIS2+ and AIS3+ injuries, the priorities for PTW rider safety interventions are: fracture of the rib cage, femur fracture, tibia fracture, radius fracture, cerebrum injury, and cerebral concussion. The ATD currently used most frequently, the Hybrid III, is unlikely to provide adequate rib fracture injury assessments, but HBMs are promising in this area. Rib injury assessment may also reasonably predict other injuries that were correlated or in proximity to rib fractures: clavicle, lung, and upper abdomen organ injury. Lower extremity, upper extremity, and head injuries are likely addressable to some extent with current ATDs while HBMs hold the promise of more detailed and mechanism-specific injury assessments. Both ATDs and HBMs need more validation for use in the PTW environment.

Electrolyte disorders secondary to venetoclax.

Emerging cancer drugs introduce new forms of nephrotoxicity that may also present as electrolyte disorders. Here, we report a patient with non-Hodgkin lymphoma who developed severe hypokalaemia with concurrent hypophosphataemia, hypocalcaemia and hypomagnesaemia secondary to venetoclax. Although electrolyte disorders have been reported during treatment with venetoclax, these were ascribed to tumour lysis prophylaxis. Based on the temporal relationship and urinary studies, we show that venetoclax can cause these electrolyte disorders, likely through an effect on the proximal and distal convoluted tubule. In patients treated with venetoclax, we recommend close monitoring of electrolytes and avoiding co-medication that can contribute to electrolyte disorders.

Rib Cortical Bone Fracture Risk as a Function of Age and Rib Strain: Updated Injury Prediction Using Finite Element Human Body Models.

To evaluate vehicle occupant injury risk, finite element human body models (HBMs) can be used in vehicle crash simulations. HBMs can predict tissue loading levels, and the risk for fracture can be estimated based on a tissue-based risk curve. A probabilistic framework utilizing an age-adjusted rib strain-based risk function was proposed in 2012. However, the risk function was based on tests from only twelve human subjects. Further, the age adjustment was based on previous literature postulating a 5.1% decrease in failure strain for femur bone material per decade of aging. The primary aim of this study was to develop a new strain-based rib fracture risk function using material test data spanning a wide range of ages. A second aim was to update the probabilistic framework with the new risk function and compare the probabilistic risk predictions from HBM simulations to both previous HBM probabilistic risk predictions and to approximate real-world rib fracture outcomes. Tensile test data of human rib cortical bone from 58 individuals spanning 17-99 years of ages was used. Survival analysis with accelerated failure time was used to model the failure strain and age-dependent decrease for the tissue-based risk function. Stochastic HBM simulations with varied impact conditions and restraint system settings were performed and probabilistic rib fracture risks were calculated. In the resulting fracture risk function, sex was not a significant covariate-but a stronger age-dependent decrease than previously assumed for human rib cortical bone was evident, corresponding to a 12% decrease in failure strain per decade of aging. The main effect of this difference is a lowered risk prediction for younger individuals than that predicted in previous risk functions. For the stochastic analysis, the previous risk curve overestimated the approximate real-world rib fracture risk for 30-year-old occupants; the new risk function reduces the overestimation. Moreover, the new function can be used as a direct replacement of the previous one within the 2012 probabilistic framework.

Defining crash configurations for Powered Two-Wheelers: Comparing ISO 13232 to recent in-depth crash data from Germany, India and China.

The motorcyclist safety standard ISO 13232, based on crash data from Europe and the USA from the 1970s, still sets the direction for the development and evaluation of protective measures today. However, it is unclear how relevant the crash configurations in the standard are to present-day motorcycle crashes in Europe, the USA and other parts of the world. We analyzed recent in-depth crash data from Germany, India and China, examining powered two-wheeler (PTW) crash configurations in which at least one police-reported serious injury was present. After assessing the relevance of the ISO's PTW crash configurations to those we found in each country, we suggested new configurations to guide the development of safety systems that would be more effective at reducing PTW-related fatalities and serious injuries. In all three databases, passenger cars were among the top two most frequent collision partners and a car front impacting the side of the PTW was the most common configuration. Notably, although collisions with trucks constituted the most common scenario in India and ground impact (primary collision) was a common scenario in both Germany and India, the ISO did not include either configuration. Further, in three of the seven ISO crash configurations, one of the collision partners is stationary, although stationary collision partners were rare in our data. Our results show that the ISO crash configurations do not represent the most frequent PTW road crashes in Germany, India or China. However, the Chinese database was confined to crashes with a collision partner with four or more wheels. Further, weighting factors for these data were not available, so we could not extrapolate the frequency of the Chinese crash configurations across the entire population. A revised version of the ISO could serve as a basis for a full-scale PTW crash test program. However, the observed differences between countries imply that a single global standard may not be feasible. To optimize the evaluation of a PTW safety system, we recommend the inclusion of configurations which are frequent in the region or country of interest-in addition to common configurations occurring frequently all around the world.

Simulating Automated Emergency Braking with and without Torricelli Vacuum Emergency Braking for cyclists: Effect of brake deceleration and sensor field-of-view on accidents, injuries and fatalities.

This study estimates how many additional cyclist accidents, injuries or fatalities are avoided or mitigated by adding a system which increases braking levels, the Torricelli Vacuum Emergency Brake (VEB), to a state-of-the-art Automated Emergency Braking (AEB) system. To obtain a realistic state-of-the-art AEB system, the AEB parameter settings were defined to fulfil but not exceed the performance necessary to achieve a full score in the European New Car Assessment Program (Euro NCAP). The systems are simulated in a simple but realistic simulation model in MATLAB with varying brake deceleration and sensor field-of-view (FoV). This study utilised data from the German In-Depth Accident Study (GIDAS), released in January 2019, and the related Pre-Crash Matrix (PCM), released in February 2019. Cyclist Injury Risk Curves were created from 2,662 GIDAS accidents involving a passenger car and a cyclist. The sample of cyclist accidents from the GIDAS-PCM database used in the final simulations comprised 1,340 collisions between the front of a passenger car and a cyclist. Both data samples were weighted to be representative of Germany as a whole. Adding the VEB was found to avoid over 20% more accidents than the AEB alone. Although increasing the FoV from 75° to 180° for the AEB system increases its accident avoidance rate to a level comparable to the VEB, the VEB remains about 8-20% more effective in reducing fatalities and injuries, and thus offers greater safety benefits than simply increasing AEB FoV. While the initial accidents in the representative simulation sample are fairly evenly distributed over the vehicle front, the remaining accidents (those that cannot be prevented by AEB or VEB) are more concentrated at the vehicle corners and are further characterized by high cyclist speeds. High cyclist speeds and impact to the vehicle corners potentially increase the relative frequency of head impacts to the stiff A-pillars. We therefore recommend that, for passenger cars, VEB and other advanced AEB systems should be combined with in-crash protection, especially in the A-pillar area, to best protect cyclists from injury.

Modelling discomfort: How do drivers feel when cyclists cross their path?

Many cyclist fatalities occur on roads when crossing a vehicle path. Active safety systems address these interactions. However, the driver behaviour models that these systems use may not be optimal in terms of driver acceptance. Incorporating explicit estimates of driver discomfort might improve acceptance. This study quantified the degree of discomfort experienced by drivers when cyclists crossed their travel path. Participants were instructed to drive through an intersection in a fixed-base simulator or on a test track, following the same experimental protocol. During the experiments, three variables were controlled: 1) the car speed (30, 50 km/h), 2) the bicycle speed (10, 20 km/h), and 3) the bicycle-car encroachment sequence (bicycle clears the intersection first, potential 50 %-overlap crash, and car clears the intersection first). For each trial, a covariate, the car's time-to-arrival at the intersection when the bicycle appears (TTAvis), was calculated. After each trial, the participants were asked to report their experienced discomfort on a 7-point Likert scale ranging from no discomfort (1) to maximum discomfort (7). The effect of the three controlled variables and the effect of TTAvis on drivers' discomfort were estimated using cumulative link mixed models (CLMM). Across both experimental environments, the controlled variables were shown to significantly influence discomfort. TTAvis was shown to have a significant effect on discomfort as well; the closer to zero TTAvis was (i.e., the more critical the situation), the more likely the driver reported great discomfort. The prediction accuracies of the CLMM with all three controlled variables and the CLMM with TTAvis were similar, with an average accuracy between 40 and 50 % for the exact discomfort level and between 80 and 85 % allowing deviations by one step. Our model quantifies driver discomfort. Such model may be included in the decision-making algorithms of active safety systems to improve driver acceptance. In fact, by tuning system activation times depending on the expected level of discomfort that a driver would experience in such situation, a system is not likely to annoy a driver.