Changes in the burden of medications that may impair driving among older adults before and after a motor vehicle crash.

BACKGROUND: Medications are one of the most easily modifiable risk factors for motor vehicle crashes (MVCs) among older adults, yet limited information exists on how the use of potentially driver-impairing (PDI) medications changes following an MVC. Therefore, we examined the number and types of PDI medication classes dispensed before and after an MVC. METHODS: This observational study included Medicare fee-for-service beneficiaries aged ≥67 years who were involved in a police-reported MVC in New Jersey as a driver between 2008 and 2017. Analyses were conducted at the "person-crash" level because participants could be involved in more than one MVC. We examined the use of 36 PDI medication classes in the 120 days before and 120 days after MVC. We described the number and prevalence of PDI medication classes in the pre-MVC and post-MVC periods as well as the most common PDI medication classes started and stopped following the MVC. RESULTS: Among 124,954 person-crashes, the mean (SD) age was 76.0 (6.5) years, 51.3% were female, and 83.9% were non-Hispanic White. The median (Q1 , Q3 ) number of PDI medication classes was 2 (1, 4) in both the pre-MVC and post-MVC periods. Overall, 20.3% had a net increase, 15.9% had a net decrease, and 63.8% had no net change in the number of PDI medication classes after MVC. Opioids, antihistamines, and thiazide diuretics were the top PDI medication classes stopped following MVC, at incidences of 6.2%, 2.1%, and 1.7%, respectively. The top medication classes started were opioids (8.3%), skeletal muscle relaxants (2.2%), and benzodiazepines (2.1%). CONCLUSIONS: A majority of crash-involved older adults were exposed to multiple PDI medications before and after MVC. A greater proportion of person-crashes were associated with an increased rather than decreased number of PDI medications. The reasons why clinicians refrain from stopping PDI medications following an MVC remain to be elucidated.

Development of an interactive elective "altered anatomy" for students as part of the Z-curriculum according to the NKLM 2.0.

Objective: Many patients have undergone visceral surgery. The effects on anatomy and physiology, which can result in further surgical or gastroenterological clinical pictures, are equally significant and require special knowledge. This content should be taught in an interdisciplinary elective course. The draft of the new 2025 approval regulation and the current approval regulation specify that preclinical and clinical content should specifically be combined within the framework of a Z-curriculum and that the new elective course should meet these requirements. Methodology: Practical and theoretical aspects of recognising and treating patients with postoperative modified anatomy are to be taught and the findings are to be demonstrated using anatomical and artificial preparations. The curriculum of the preclinical course covers anatomy and physiology. The target group of the curriculum is all participating students with a special interest in topics such as anatomy, visceral surgery and gastroenterology. However, the goal is to involve student tutors of the anatomical dissection courses, who, in turn, will pass on knowledge of modified anatomy to the supervised preclinical students. Results: According to Thomas and Kern, the curriculum development process entails the following six stages: general needs assessment, targeted needs assessment, the formulation of goals and content, the description of strategies, planned implementation and evaluation. Conclusion: A "modified anatomy" curriculum for an interdisciplinary elective course in surgery, gastroenterology, and anatomy was developed. Through the training of anatomy table tutors, a "dovetailing" with the preclinical stage is to be achieved. In addition, new concepts related to the transfer of knowledge and competencies were introduced and should be evaluated for suitability.

Achilles' tendon rupture dancing the 'Jerusalema' - A case series.

INTRODUCTION AND IMPORTANCE: The weekend warrior has long been prey to musculoskeletal injuries as a result of intermittent, high intensity activity. The Achilles tendon is known to be particularly vulnerable in this population cohort but during the COVID-19 lockdowns in Ireland and all over the world there has been a certain level of detraining and deconditioning among all age groups and populations. Throughout the worldwide restrictions, viral internet challenges and dances have encapsulated the spirit of a global community with the 'Jerusalema' dance being no exception. The rise of this particular viral sensation was at the detriment of the Achilles tendons of three middle aged gentlemen on who we base our case series. PRESENTATION OF CASES: Over the space of ten days three cases of Achilles tendon rupture repair presented to the emergency department in Midlands Regional Hospital Tullamore (MRHT) with the mechanism of tendon rupture being through the 'Jerusalema' dance. These patients were surgically managed in line with local institution practice and postoperative outcomes were good with no complications noted. Follow up is ongoing. CLINICAL DISCUSSION: This retrospective case series is based on the impact of the 'Jerusalema Dance' on presentations of Achilles tendon rupture to the Emergency Department in a single regional hospital from January to March 2021. We used these cases in conjunction with a review of current literature to highlight the benefit of an integrated Achilles Tendon rehabilitation programme in this at-risk patient cohort. CONCLUSION: This paper highlights the dangers inherent when well intentioned, but physically deconditioned individuals endeavour to perform a physical exercise which is deceptively demanding. Going forward, viral challenges such as the 'Jerusalema' may contribute to new and interesting mechanisms of injuries in our 'weekend warrior' cohort. In addition to this, given the global deconditioning seen due to the COVID 19 pandemic and subsequent lockdowns we may see a higher rate of Achilles tendon injuries in the near future across a multitude of patient cohorts. Level one evidence suggests that conservative treatment is just as effective as surgical treatments in the majority of patients with an Achilles tendon rupture, as long as a protocol of rehabilitation with early weightbearing is performed. Our accelerated rehabilitation programme in MRHT is in line with others however internal audit and new literature in the future may enable us to refine it further.

The Association of Gastrocnemius Tightness, Genu Valgum and Hallux Valgus: A Prospective Case-Control Study.

There has been much debate regarding the aetiology and pathogenesis of hallux valgus and it appears to be multifactorial with contracture or tightness of the Achilles tendon and more specifically the gastrocnemius being implicated as an intrinsic factor. The purpose of this study was to look at the association of gastrocnemius tightness, genu valgum and hallux valgus. A prospective case-control study with 25 patients in each group was carried out over a 12-month period. The case group observed adult patients who were referred primarily because of symptomatic hallux valgus and were assessed for the following: hallux valgus stage; presence or absence of isolated gastrocnemius tightness; presence or absence of genu valgum. The control group excluded those with pre-existing hallux valgus, genu valgum and rheumatoid arthritis and were assessed for isolated gastrocnemius tightness. There was a statistically significant association between the presence of genu valgum and hallux valgus when comparing both groups with a p < .001. There was also a statistically significant association between the Silfverskiöld test and the presence of hallux valgus, as well as the Silfverskiöld test and the presence of genu valgum with a p < .001. This study is the first to describe the association of gastrocnemius tightness, genu valgum and hallux valgus. Further studies are required to assess this relationship but knowledge and awareness of it can be applied by clinicians when considering the most appropriate management options with patients.

Pretibial Panniculitis Ossificans-A Rare but Significant Diagnosis.

Pretibial panniculitis ossificans is a rare condition. In this report, we describe a 67-year-old male localized to his right pretibial tissue, approximately 20 years after contusion to the same area.

N-Terminal Truncated Aß4-42 Is a Substrate for Neprilysin Degradation in vitro and in vivo.

In sporadic Alzheimer's disease (AD), an imbalance between production and clearance of amyloid-ß (Aß) peptides seems to account for enhanced Aß accumulation. The metalloprotease neprilysin (NEP) is an important Aß degrading enzyme as shown by a variety of in vitro and in vivo studies. While the degradation of full-length Aß peptides such as Aß1-40 and Aß1-42 is well established, it is less clear whether NEP is also capable of degrading N-terminally truncated Aß species such as the common variant Aß4-42. In the present report, we confirmed the degradation of Aß4-x species by neprilysin using in vitro digestion and subsequent analysis using gel-based assays and mass spectrometry. By crossing Tg4-42 mice expressing only Aß4-42 peptides with homozygous NEP-knock-out mice (NEP-/-), we were able to demonstrate that NEP deficiency increased hippocampal intraneuronal Aß levels and aggravated neuron loss in the Tg4-42 transgenic mouse model of AD.

Lumbrical muscle tear: clinical presentation, imaging findings and outcome.

The incidence of lumbrical muscle tear is increasing due to the popularity of climbing sport. We reviewed data from 60 consecutive patients with a positive lumbrical stress test, including clinical examination, ultrasound and clinical outcomes in all patients, and magnetic resonance imaging in 12 patients. Fifty-seven patients were climbers. Lumbrical muscle tears were graded according to the severity of clinical and imaging findings as Grade I-III injuries. Eighteen patients had Grade I injuries (microtrauma), 32 had Grade II injuries (muscle fibre disruption) and 10 had Grade III injuries (musculotendinous disruption). The treatment consisted of adapted functional therapy. All patients completely recovered and were able to return to climbing. The healing period in Grade III injuries was significantly longer than in the patients with Grade I or II injuries ( p < 0.001). We recommend evaluation of specific clinical and imaging findings to grade the injuries and to determine suitable therapy. LEVEL OF EVIDENCE: IV.

Rock Climbing-Related Bone Marrow Edema of the Hand: A Follow-up Study.

OBJECTIVE: Sport climbers strain passive and active anatomical structures of their hands and fingers to the maximum during training or competition. This study was designed to investigate bone marrow edema (BME) in rock climbing athletes. DESIGN: Systematic detection, treatment, and follow-up investigation of rock climbing athletes with BME of the hand. SETTING: Primary-level orthopedic surgery and sports medicine division of a large academic medical center. PATIENTS: Thirty-one high-level climbers with diffuse pain in the hand and wrist joint caused by rock climbing were included in this study. INTERVENTIONS: The therapy consisted of consequent stress reduction and a break from sports. MAIN OUTCOME MEASURES: Reduction of BME shown through magnetic resonance imaging (MRI) and regaining of preinjury climbing levels (Union Internationale des Associations d' Alpinisme metric scale). RESULTS: In 28 patients, MRI revealed osseous edema because of overload at the respective area of interest, mainly in the distal radius, the distal ulna, or the carpal bones, which could not be otherwise diagnosed as inflammations, tumors, or injuries. We classified these edemas and fractures of the hamate because of overload. The edema was a stress reaction to highly intensive training and climbing with presumably high traction to the wrist area. The control MRIs demonstrated that even with a consequent stress reduction, the edemas required 3 to 4 months to disappear completely. CONCLUSIONS: Climbers with nonspecific, diffuse pain in the wrist and/or the fingers should be examined with MRI to detect or exclude the diagnosis of a BME.

Immune hyperreactivity of Aß plaque-associated microglia in Alzheimer's disease.

Alzheimer's disease (AD) is strongly associated with microglia-induced neuroinflammation. Particularly, Aß plaque-associated microglia take on an "activated" morphology. However, the function and phenotype of these Aß plaque-associated microglia are not well understood. We show hyperreactivity of Aß plaque-associated microglia upon systemic inflammation in transgenic AD mouse models (i.e., 5XFAD and APP23). Gene expression profiling of Aß plaque-associated microglia (major histocompatibility complex II+ microglia) isolated from 5XFAD mice revealed a proinflammatory phenotype. The upregulated genes involved in the biological processes (gene ontology terms) included: "immune response to external stimulus" such as Axl, Cd63, Egr2, and Lgals3, "cell motility", such as Ccl3, Ccl4, Cxcr4, and Sdc3, "cell differentiation", and "system development", such as St14, Trpm1, and Spp1. In human AD tissue with similar Braak stages, expression of phagocytic markers and AD-associated genes, including HLA-DRA, APOE, AXL, TREM2, and TYROBP, was higher in laser-captured early-onset AD (EOAD) plaques than in late-onset AD plaques. Interestingly, the nonplaque parenchyma of both EOAD and late-onset AD brains, the expression of above-mentioned markers were similarly low. Here, we provide evidence that Aß plaque-associated microglia are hyperreactive in their immune response and phagocytosis in the transgenic AD mice as well as in EOAD brain tissue. We suggest that Aß plaque-associated microglia are the primary source of neuroinflammation related to AD pathology.

Decreased cortical FADD protein is associated with clinical dementia and cognitive decline in an elderly community sample.

BACKGROUND: FADD (Fas-associated death domain) adaptor is a crucial protein involved in the induction of cell death but also mediates non-apoptotic actions via a phosphorylated form (p-Ser194-FADD). This study investigated the possible association of FADD forms with age-related neuropathologies, cognitive function, and the odds of dementia in an elderly community sample. METHODS: FADD forms were quantified by western blot analysis in dorsolateral prefrontal cortex (DLPFC) samples from a large cohort of participants in a community-based aging study (Memory and Aging Project, MAP), experiencing no-(NCI, n = 51) or mild-(MCI, n = 42) cognitive impairment, or dementia (n = 57). RESULTS: Cortical FADD was lower in subjects with dementia and lower FADD was associated with a greater load of amyloid-ß pathology, fewer presynaptic terminal markers, poorer cognitive function and increased odds of dementia. Together with the observations of FADD redistribution into tangles and dystrophic neurites within plaques in Alzheimer's disease brains, and its reduction in APP23 mouse cortex, the results suggest this multifunctional protein might participate in the mechanisms linking amyloid and tau pathologies during the course of the illness. CONCLUSIONS: The present data suggests FADD as a putative biomarker for pathological processes associated with the course of clinical dementia.

Phosphorylation of the amyloid ß-peptide at Ser26 stabilizes oligomeric assembly and increases neurotoxicity.

Aggregation and toxicity of the amyloid ß-peptide (Aß) are considered as critical events in the initiation and progression of Alzheimer's disease (AD). Recent evidence indicated that soluble oligomeric Aß assemblies exert pronounced toxicity, rather than larger fibrillar aggregates that deposit in the forms of extracellular plaques. While some rare mutations in the Aß sequence that cause early-onset AD promote the oligomerization, molecular mechanisms that induce the formation or stabilization of oligomers of the wild-type Aß remain unclear. Here, we identified an Aß variant phosphorylated at Ser26 residue (pSer26Aß) in transgenic mouse models of AD and in human brain that shows contrasting spatio-temporal distribution as compared to non-phosphorylated Aß (npAß) or other modified Aß species. pSer26Aß is particularly abundant in intraneuronal deposits at very early stages of AD, but much less in extracellular plaques. pSer26Aß assembles into a specific oligomeric form that does not proceed further into larger fibrillar aggregates, and accumulates in characteristic intracellular compartments of granulovacuolar degeneration together with TDP-43 and phosphorylated tau. Importantly, pSer26Aß oligomers exert increased toxicity in human neurons as compared to other known Aß species. Thus, pSer26Aß could represent a critical species in the neurodegeneration during AD pathogenesis.

Endothelial LRP1 transports amyloid-ß(1-42) across the blood-brain barrier.

According to the neurovascular hypothesis, impairment of low-density lipoprotein receptor-related protein-1 (LRP1) in brain capillaries of the blood-brain barrier (BBB) contributes to neurotoxic amyloid-ß (Aß) brain accumulation and drives Alzheimer's disease (AD) pathology. However, due to conflicting reports on the involvement of LRP1 in Aß transport and the expression of LRP1 in brain endothelium, the role of LRP1 at the BBB is uncertain. As global Lrp1 deletion in mice is lethal, appropriate models to study the function of LRP1 are lacking. Moreover, the relevance of systemic Aß clearance to AD pathology remains unclear, as no BBB-specific knockout models have been available. Here, we developed transgenic mouse strains that allow for tamoxifen-inducible deletion of Lrp1 specifically within brain endothelial cells (Slco1c1-CreER(T2) Lrp1(fl/fl) mice) and used these mice to accurately evaluate LRP1-mediated Aß BBB clearance in vivo. Selective deletion of Lrp1 in the brain endothelium of C57BL/6 mice strongly reduced brain efflux of injected [125I] Aß(1-42). Additionally, in the 5xFAD mouse model of AD, brain endothelial-specific Lrp1 deletion reduced plasma Aß levels and elevated soluble brain Aß, leading to aggravated spatial learning and memory deficits, thus emphasizing the importance of systemic Aß elimination via the BBB. Together, our results suggest that receptor-mediated Aß BBB clearance may be a potential target for treatment and prevention of Aß brain accumulation in AD.

Correlation of the tibial tuberosity-trochlear groove distance with the Q-angle.

PURPOSE: The Q-angle has been used for years to quantify lateralization of the patella. The tibial tuberosity-trochlea groove distance (TT-TG distance) was introduced to analyse patellar tracking. Does a significant correlation exist between these two parameters? Do other significant interrelations exist between the Q-angle/TT-TG distance, torsion of the femur and tibia, the frontal axis, overall leg length, gender, former patellar dislocation, BMI? METHODS: One hundred knees in 55 patients with patellofemoral symptoms were included in a prospective study. All patients underwent clinical examination, including measurement of the Q-angle. A torsional CT was obtained from all patients. RESULTS: The correlation coefficient was 0.33/0.34 (left/right leg), showing that the TT-TG distance tends to rise in direct ratio to a rising Q-angle. Thus, a significant correlation was found (p = 0.017). Femoral and tibial torsion had a positive effect on the TT-TG distance, but showed no significant correlation. Leg length had a significant effect on the TT-TG distance (p = 0.04). The frontal axis had a nonsignificant influence on the Q-angle or TT-TG distance. On average, the Q-angle in women was 2.38° greater than it was in men, but the difference was not significant. CONCLUSION: A significant correlation was noted between the Q-angle and the TT-TG distance. Both depend on various parameters and must be assessed for the analysis of patellofemoral maltracking. The Q-angle did not differ significantly between men and women; thus, the conclusion is that no different ranges need not be used. LEVEL OF EVIDENCE: Diagnostic study, Level III.

Loss of Munc18-1 long splice variant in GABAergic terminals is associated with cognitive decline and increased risk of dementia in a community sample.

BACKGROUND: Presynaptic terminals contribute to cognitive reserve, balancing the effects of age-related pathologies on cognitive function in the elderly. The presynaptic protein Munc18-1, alternatively spliced into long (M18L) or short (M18S) isoforms, is a critical modulator of neurotransmission. While subtle alterations in Munc18-1 have been shown to cause severe neuropsychiatric disorders with cognitive impairment, little information is known regarding the specific roles of Munc18-1 splice variants. We first investigated functional and anatomical features evidencing the divergent roles of M18L and M18S, and then evaluated their contribution to the full range of age-related cognitive impairment in the dorsolateral prefrontal cortex of a large sample of participants from a community-based aging study, including subjects with no-(NCI, n = 90), or mild-(MCI, n = 86) cognitive impairment, or with clinical dementia (n = 132). Finally, we used APP23 mutant mice to study the association between M18L/S and the time-dependent accumulation of common Alzheimer's disease pathology. RESULTS: Using isoform-specific antibodies, M18L was localized to the synaptosomal fraction, with a distribution matching lipid raft microdomains. M18S was found widely across cytosolic and synaptosomal compartments. Immunocytochemical studies identified M18L in perisomatic, GABAergic terminals, while M18S was broadly distributed in GABAergic and glutamatergic terminals. Using regression models taking into account multiple age-related pathologies, age, education and sex, global cognitive function was associated with the level of M18L (p = 0.006) but not M18S (p = 0.88). Mean M18L in dementia cases was 51 % lower than in NCI cases (p < 0.001), and each unit of M18L was associated with a lower likelihood of dementia (odds ratio = 0.68, 95 % confidence interval = 0.50-0.90, p = 0.008). In contrast, M18S balanced across clinical and pathologically diagnosed groups. M18L loss may not be caused by age-related amyloid pathology, since APP23 mice (12- and 22-months of age) had unchanged cortical levels of M18L/S compared with wild-type animals. CONCLUSIONS: M18L was localized to presynaptic inhibitory terminals, and was associated with cognitive function and protection from dementia in an elderly, community-based cohort. Lower M18L in inhibitory presynaptic terminals may be an early, independent contributor to cognitive decline.

Neprilysin deficiency alters the neuropathological and behavioral phenotype in the 5XFAD mouse model of Alzheimer's disease.

The deposition of amyloid-ß (Aß) is one of the major neuropathological hallmarks of Alzheimer's disease (AD). In the case of sporadic AD, an imbalance in Aß in production and clearance seems to be the reason for an enhanced Aß accumulation. Besides a systematic clearance through the blood-brain barrier, Aß is cleared from the brain by Aß-degrading enzymes. The metalloprotease neprilysin (NEP) is an important Aß-degrading enzyme as shown by numerous in vitro, in vivo and reverse genetics studies. 5XFAD mice represent an early-onset AD mouse model which develops plaque pathology starting with 2 months of age in addition to robust behavioral deficits at later time points. By crossing 5XFAD mice with homozygous NEP-knock-out mice (NEP-/-), we show that hemizygous NEP deficiency aggravates the behavioral and neuropathological phenotype of 5XFAD mice. We found that 5XFAD mice per se showed strongly decreased NEP expression levels compared to wildtype mice, which was aggravated by NEP reduction. 5XFAD/NEP+/- mice demonstrated impairment in spatial working memory and increased astrocytosis in all studied brain areas, in addition to an overall increased level of soluble Aß42 as well as region-specific increases in extracellular Aß deposition. Surprisingly, in young mice, a more abundant cortical Aß plaque pathology was observed in 5XFAD compared to 5XFAD/NEP+/- mice. Additionally, young 5XFAD/NEP+/- as well as hemi- and homozygous NEP knockout mice showed elevated levels of endothelin-converting enzyme 1 (ECE1), suggesting a mutual regulation of ECE1 and NEP at young ages. The present data indicate that NEP mainly degrades soluble Aß peptides, which confirms previous observations. Increased ECE1 levels correlated well with the strongly reduced extracellular plaque load in young 5XFAD/NEP+/- mice and might suggest a reciprocal effect between ECE and NEP activities in Aß degradation.

Protein signature for non-small cell lung cancer prognosis.

BACKGROUND: Current histopathological classification and TNM staging have limited accuracy in predicting survival and stratifying patients for appropriate treatment. The goal of the study is to determine whether the expression pattern of functionally important regulatory proteins can add additional values for more accurate classification and prognostication of non-small lung cancer (NSCLC). METHODS: The expression of 108 proteins and phosphoproteins in 30 paired NSCLC samples were assessed using Protein Pathway Array (PPA). The differentially expressed proteins were further confirmed using a tissue microarray (TMA) containing 94 NSCLC samples and were correlated with clinical data and survival. RESULTS: Twelve of 108 proteins (p-CREB(Ser133), p-ERK1/2(Thr202/Tyr204), Cyclin B1, p-PDK1(Ser241), CDK4, CDK2, HSP90, CDC2p34, ß-catenin, EGFR, XIAP and PCNA) were selected to build the predictor to classify normal and tumor samples with 97% accuracy. Five proteins (CDC2p34, HSP90, XIAP, CDK4 and CREB) were confirmed to be differentially expressed between NSCLC (n=94) and benign lung tumor (n=19). Over-expression of CDK4 and HSP90 in tumors correlated with a favorable overall survival in all NSCLC patients and the over-expression of p-CREB(Ser133) and CREB in NSCLC correlated with a favorable survival in smokers and those with squamous cell carcinoma, respectively. Finally, the four proteins (CDK4, HSP90, p-CREB and CREB) were used to calculate the risk score of each individual patient with NSCLC to predict survival. CONCLUSION: In summary, our data demonstrated a broad disturbance of functionally important regulatory proteins in NSCLC and some of these can be selected as clinically useful biomarkers for diagnosis, classification and prognosis.