Strategies for mitigating adverse events related to selective RET inhibitors in patients with RET-altered cancers.

The US Food and Drug Administration (FDA) approval of the selective RET inhibitors selpercatinib and pralsetinib has led to a paradigm change in the treatment of RET-altered lung and thyroid cancers through a higher response rate and a more tolerable safety and toxicity profile than multi-kinase inhibitors. Recently, selpercatinib has received a tissue-agnostic FDA approval for all RET-fusion-positive cancers, and pralsetinib has shown pan-cancer activity as well. Given the anticipated increase in the use of both drugs across multiple tumor types, it is crucial to recognize the possible side effects and approaches for their optimal management in order to maximize the clinical benefit for treated patients. In this review, we underscore potential toxicities associated with selective RET inhibitors and discuss strategies to mitigate them.

Mental health support across the sight loss pathway: a qualitative exploration of eye care patients, optometrists, and ECLOs.

BACKGROUND: The process of becoming visually impaired or blind is undoubtedly a highly emotional experience, requiring practical and psychological support. Information on mental health support provision in the UK across the sight-loss pathway, however, is largely unknown, especially amongst healthcare practitioners that are often sought after for advice: the referring optometrist and eye clinic liaison officer (ECLO). This study aims to ascertain the perceived accessibility and quality of mental health support across the sight-loss pathway. METHODS: Semi-structured individual interviews were conducted with patients with a diagnosed eye condition who had received care from a hospital eye service, referring optometrists, and ECLOs. Following interview transcription, results were synthesised in a narrative analysis. RESULTS: A total of 28 participants were included in the analysis, of which 17 were participants with various eye conditions, five were referring optometrists, and five were ECLOs. After analysis, three broad themes emerged: (1) The emotional trauma of diagnosis (2) Availability of mental health support; (3) The point where mental health support is most needed across the sight-loss pathway. Several patients reporting that they had received no offer of support nor were they signposted to any possible sources. Referring optometrists and ECLO's agreed. CONCLUSION: It is important that referring optometrists are aware of the need for mental health support services and can signpost to local support services including the third sector anytime during the referral process. Future large-scale, UK-wide research into referral practice and signposting for mental health support for patients is warranted, to identify how services can be improved in order to ensure that the wellbeing of patients is maintained.

Dosimetric Predictors of Cardiotoxicity in Thoracic Radiotherapy for Lung Cancer.

BACKGROUND: Higher cardiac radiotherapy (RT) doses when treating lung cancer are associated with worse overall survival (OS), although the direct association between cardiac dose and early cardiotoxicity is poorly understood. We hypothesized that RT doses to the heart and cardiac substructures are associated with under-reported early cardiotoxicity and worse OS. PATIENTS AND METHODS: We conducted an institutional retrospective review of lung cancer patients treated with conventionally fractionated RT from 2010 to 2015. Collected data included pre-RT cardiac risk factors, post-RT cardiotoxicities, and dose-volume parameters for cardiac substructures. Univariate and multivariate analyses were performed to identify predictors of cardiotoxicity and OS. RESULTS: Seventy-six cases were evaluated with 1.2 years median follow-up. Cardiotoxicities included atrial arrhythmia (n = 5), pericardial effusion (n = 16), and valvular disease (n = 1). In univariate analysis, significant dose-volume predictors for cardiotoxicity included mean RT dose to structure of interest, volume of structure of interest receiving ≥30 Gy RT dose, and volume of structure of interest receiving ≥45 Gy RT dose (V45) to the atria, ventricles, and pericardium. Higher ventricular V45 was associated with post-RT cardiotoxicity in multivariate analysis (hazard ratio [HR], 1.50; P = .027). Cardiotoxicity occurrence was a highly significant predictor of OS in multivariate analysis (HR, 12.7; P < .001), but higher ventricular V45 alone was not (HR, 0.78; P = .450). CONCLUSION: Early cardiac events were relatively common after lung cancer RT and associated with multiple cardiac dose-volume parameters. Occurrence of early cardiotoxicity was strongly associated with worse OS. In practice, early cardiotoxicity is under-reported, supporting the need for more detailed cardiac evaluations in high-risk patients to detect and address early cardiotoxicity.

Birdsong signals individual diversity at the major histocompatibility complex.

The major histocompatibility complex (MHC) plays a key role in vertebrate immunity, and pathogen-mediated selection often favours certain allelic combinations. Assessing potential mates' MHC profiles may provide receivers with genetic benefits (identifying MHC-compatible mates and producing optimally diverse offspring) and/or material benefits (identifying optimally diverse mates capable of high parental investment). Oscine songbirds learn songs during early life, such that song repertoire content can reflect population of origin while song complexity can reflect early life condition. Thus birdsong may advertise the singer's genetic dissimilarity to others in the population (and, presumably, compatibility with potential mates), or individual genetic diversity (and thus condition-dependent material benefits). We tested whether song repertoire content and/or complexity signal MHC class IIß dissimilarity and/or diversity in male song sparrows (Melospiza melodia). Pairwise dissimilarity in repertoire content did not predict MHC dissimilarity between males, suggesting that locally rare songs do not signal rare MHC profiles. Thus, geographical variation in song may not facilitate MHC-mediated inbreeding or outbreeding. Larger repertoires were associated with intermediate MHC diversity, suggesting intermediate rather than maximal MHC diversity is optimal. This could reflect trade-offs between resisting infection and autoimmune disorders. Song complexity may advertise optimal MHC diversity, a trait affecting disease resistance and capacity for parental care.

Using persistent photoconductivity to write a low-resistance path in SrTiO3.

Materials with persistent photoconductivity (PPC) experience an increase in conductivity upon exposure to light that persists after the light is turned off. Although researchers have shown that this phenomenon could be exploited for novel memory storage devices, low temperatures (below 180 K) were required. In the present work, two-point resistance measurements were performed on annealed strontium titanate (SrTiO3, or STO) single crystals at room temperature. After illumination with sub-gap light, the resistance decreased by three orders of magnitude. This markedly enhanced conductivity persisted for several days in the dark. Results from IR spectroscopy, electrical measurements, and exposure to a 405 nm laser suggest that contact resistance plays an important role. The laser was then used as an "optical pen" to write a low-resistance path between two contacts, demonstrating the feasibility of optically defined, transparent electronics.

Chemical composition of preen wax reflects major histocompatibility complex similarity in songbirds.

In jawed vertebrates, genes of the major histocompatibility complex (MHC) play a key role in immunity by encoding cell-surface proteins that recognize and bind non-self antigens. High variability at MHC suggests that these loci may also function in social signalling such as mate choice and kin recognition. This requires that MHC genotype covaries with some perceptible phenotypic trait. In mammals and fish, MHC is signalled chemically through volatile and non-volatile peptide odour cues, facilitating MHC-dependent mate choice and other behaviours. In birds, despite evidence for MHC-dependent mating, candidate mechanisms for MHC signalling remain largely unexplored. However, feather preen wax has recently been implicated as a potential source of odour cues. We examined whether the chemical composition of preen wax correlates with MHC class IIß genotypes of wild song sparrows (Melospiza melodia). Pairwise chemical distance reflected amino acid distance at MHC for male-female dyads, although not for same-sex dyads. Chemical diversity did not reflect MHC diversity. We used gas chromatography-mass spectrometry (GC-MS) to characterize preen wax compounds, and identified four wax esters that best reflect MHC similarity. Provided songbirds can detect variation in preen wax composition, this cue may allow individuals to assess MHC compatibility of potential mates.

Manipulation of components that control feeding behavior in Drosophila melanogaster increases sensitivity to amino acid starvation.

Feeding is a complex behavior that is regulated by several internal mechanisms. Neuropeptides are able to survey quantities of stored energy and inform the organism if nutrient intake is required. In addition to this homeostatic regulation, a post-feeding reward system positively reinforces feeding. Slight adjustments to either system can tilt the balance to affect the energy reserves and survivorship in times of nutrient adversity. Neuropeptide F (NPF), a homolog of the mammalian neuropeptide Y, acts to induce feeding within the homeostatic regulation of this behavior. Drosophila and other insects bear a shorter form of NPF known as short NPF (sNPF) that can influence feeding. A neural hormone regulator, the dopamine transporter (DAT), works to clear dopamine from the synapses. This action may manipulate the post-feeding reward circuit in that lowered dopamine levels depress feeding, and excess dopamine levels encourage feeding. Here, we have overexpressed and impaired the activities of NPF, sNPF, and DAT in Drosophila, and we examined their ability to survive during conditions of amino acid starvation. Too much or too little NPF or sNPF, which are key players in homeostatic feeding regulation, leads to increased sensitivity to amino acid starvation and diminished survivorship when compared to controls. When DAT, a member of the post-feeding reward system, is either overexpressed or reduced via mutation, Drosophila has increased sensitivity to amino acid starvation. Taken together, these results indicate that subtle variation in the expression of key components of these systems impacts survivorship during adverse nutrient conditions.

'Give Me a Reason to Live!' Examining Reasons for Living Across Levels of Suicidality.

Scholarly research focusing on social psychological factors (e.g. mental health) and social environmental factors (e.g. childhood trauma) has found these measures to be correlated with suicidality. However, such literature has tended to overlook what may impact one's reasons for living. Using a sample of over 1,200 students from a Canadian university, the goal of the current study is to empirically test, by employing multivariate nested regression models (by levels of suicidal behaviour), known and relative unknown correlates with reasons for living, with a particular focus on strength of religious faith, which is a well-known predictor for suicidality, but less studied as a reason for living. Results show that, among students with serious suicidal ideation and/or a previous suicide attempt, the strongest predictor for student's reasons for living was strength of religious faith. Strength of religious faith has seldom been acknowledged or identified as an important measure in assessing one's reasons to live. These findings have implications for the role of religiosity among suicidality research, especially studies that focus on reasons for living.

PRESAGE 3D dosimetry accurately measures Gamma Knife output factors.

Small-field output factor measurements are traditionally very difficult because of steep dose gradients, loss of lateral electronic equilibrium, and dose volume averaging in finitely sized detectors. Three-dimensional (3D) dosimetry is ideal for measuring small output factors and avoids many of these potential challenges of point and 2D detectors. PRESAGE 3D polymer dosimeters were used to measure the output factors for the 4 mm and 8 mm collimators of the Leksell Perfexion Gamma Knife radiosurgery treatment system. Discrepancies between the planned and measured distance between shot centers were also investigated. A Gamma Knife head frame was mounted onto an anthropomorphic head phantom. Special inserts were machined to hold 60 mm diameter, 70 mm tall cylindrical PRESAGE dosimeters. The phantom was irradiated with one 16 mm shot and either one 4 mm or one 8 mm shot, to a prescribed dose of either 3 Gy or 4 Gy to the 50% isodose line. The two shots were spaced between 30 mm and 60 mm apart and aligned along the central axis of the cylinder. The Presage dosimeters were measured using the DMOS-RPC optical CT scanning system. Five independent 4 mm output factor measurements fell within 2% of the manufacturer's Monte Carlo simulation-derived nominal value, as did two independent 8 mm output factor measurements. The measured distances between shot centers varied by ± 0.8 mm with respect to the planned shot displacements. On the basis of these results, we conclude that PRESAGE dosimetry is excellently suited to quantify the difficult-to-measure Gamma Knife output factors.

Preliminary evaluation of the dosimetric accuracy of the in vivo plastic scintillation detector OARtrac system for prostate cancer treatments.

A promising, new, in vivo prostate dosimetry system has been developed for clinical radiation therapy. This work outlines the preliminary end-to-end testing of the accuracy and precision of the new OARtrac scintillation dosimetry system. We tested 94 calibrated plastic scintillation detector (PSD) probes before their final integration into endorectal balloon assemblies. These probes had been calibrated at The University of Texas MD Anderson Cancer Center Dosimetry Laboratory. We used a complete clinical OARtrac system including the PSD probes, charge coupled device camera monitoring system, and the manufacturer's integrated software package. The PSD probes were irradiated at 6 MV in a Solid Water® phantom. Irradiations were performed with a 6 MV linear accelerator using anterior-posterior/posterior-anterior matched fields to a maximum dose of 200 cGy in a 100 cm source-axis distance geometry. As a whole, the OARtrac system has good accuracy with a mean error of 0.01% and an error spread of ±5.4% at the 95% confidence interval. These results reflect the PSD probes' accuracy before their final insertion into endorectal balloons. Future work will test the dosimetric effects of mounting the PSD probes within the endorectal balloon assemblies.

Certification for vision impairment: researching perceptions, processes and practicalities in health and social care professionals and patients.

OBJECTIVES: To explore the patient experience, and the role of ophthalmologists and other health and social care professionals in the certification and registration processes and examine the main barriers to the timely certification of patients. DESIGN: Qualitative study. SETTING: Telephone interviews with health and social care professionals and patients in three areas in England. PARTICIPANTS: 43 health and social care professionals who are part of the certification or registration process. 46 patients certified as severely sight impaired (blind) or sight impaired (partially sighted) within the previous 12 months. RESULTS: Certification and registration are life changing for patients and the help they receive can substantially improve their lives. Despite this, ophthalmologists often found it difficult to ascertain when it is appropriate to certify patients, particularly for people with long-term conditions. Ophthalmologists varied in their comprehension of the certification process and many regarded certification as the 'final stage' in treatment. Administrative procedures meant the process of certification and registration could vary from a few weeks to many months. The avoidable delays in completing certification can be helped by Eye Clinic Liaison Officers (ECLO). CONCLUSIONS: A better understanding of the certification and registration processes can help improve standards of support and service provision for people who are severely sighted impaired or sight impaired. Better education and support are required for ophthalmologists in recognising the importance of timely referral for rehabilitative support through certification and registration. ECLOs can improve the process of certification and registration. Finally, better education is needed for patients on the benefits of certification and registration.

Morphometry of the hippocampal microvasculature in post-stroke and age-related dementias.

BACKGROUND: Optimal vascular function is vital for prevention of dementia. We hypothesized that elderly post-stroke survivors who preserve cognitive function show unperturbed cerebral microvasculature compared with those who develop dementia. METHODS: Using stereological spherical probe software, we compared the length density (Lv, cumulative vessel length per unit tissue volume) of hippocampal microvessels in post mortem brain tissue from post-stroke survivors, Alzheimer's disease (AD), vascular dementia (VaD) and normal ageing control subjects. We also assessed microvessel diameters in the same subjects. Microvessels were identified by markers of endothelial cells (glucose transporter 1; GLUT1), basement membrane (collagen IV; COL4) and smooth muscle cell α-actin (SMA). RESULTS: We found increased Lv of both GLUT1 and COL4 immunostained microvessels (P < 0.05) in the hippocampal CA1 region of post-stroke demented (PSD) and AD cases compared with post-stroke nondemented (PSND), control and VaD subjects. However, no changes were apparent in the CA2 region. We also noted significant increase in Lv in the entorhinal cortex of AD compared with PSND and PSD subjects. The mean diameter of microvessels was decreased in PSD, compared with PSND, as well as in AD and VaD compared with controls. Cumulative frequency analysis showed PSND subjects to have significantly greater proportion of microvessels with diameters, ranging from 7 to 12 µm. CONCLUSIONS: An increase in microvascular Lv in AD and PSD suggests either an increase in angiogenesis or the formation of newer microvessel loops in response to cerebral hypoperfusion. The decreased vessel diameters found in AD and VaD suggests increased vasoconstriction in dementia.

Staging and natural history of cerebrovascular pathology in dementia.

OBJECTIVE: Most pathologic studies indicate that significant vascular changes are found in the majority of elderly persons, either alone or in association with neurodegenerative processes such as Alzheimer disease (AD) or dementia with Lewy bodies (DLB). Cumulative burden of cerebrovascular lesions can explain cognitive decline described as vascular cognitive impairment, but because there is a lack of consensus in the best way to quantify vascular pathology, the relationship between cognitive decline and cerebrovascular disease remains uncertain. We developed a rating scheme for cerebrovascular lesions using postmortem brains from patients with dementia from 2 European tertiary care memory clinics. METHODS: A total of 135 brains with a neuropathologic diagnosis of vascular dementia (VaD) (n = 26), AD + VaD (n = 39), DLB + VaD (n = 21), AD + DLB + VaD (n = 9), AD (n = 19), and DLB (n = 21) were investigated in this study. Cerebrovascular lesions were rated on large sections from the hippocampus, the temporal lobe, the frontal lobe, and basal ganglia. RESULTS: In patients with dementia, vessel wall modifications such as arteriolosclerosis or amyloid angiopathy are the most common and presumably the earliest changes. Modifications in perivascular spaces and myelin loss are the next most common. Lacunar or regional infarcts may occur as a consequence of an independent process or in the final phase of small vessel diseases. CONCLUSION: A staging system based on this conceptual model of cerebrovascular pathology could enable the neuropathologic quantification of the cerebrovascular burden in dementia. Further studies are needed to determine whether this system can be used in large-scale studies to understand clinical-cerebrovascular pathologic correlations.

Slaughterfloor decontamination of pork carcases with hot water or acidified sodium chlorite - a comparison in two Australian abattoirs.

A decontamination trial on the effectiveness of hot water or acidified sodium chlorite (SANOVA) treatment on Salmonella spp., Escherichia coli and Total Viable Count (TVC) was undertaken on pork carcases prior to primary chilling in two large pork abattoirs in Australia using belly-strip excision sampling. A total of 123 samples from Abattoir A and 400 samples from Abattoir B were cultured and analysed. Test pigs were selected from herds with a known high level of on-farm Salmonella infection. At Abattoir A, Salmonella spp. were not isolated from carcases. The prevalence of E. coli on control carcases was 92.9% compared with 9.8% for hot water and 12.5% for SANOVA treated carcases. The mean log(10) E. coli concentration for control carcases was 0.89 cfu/gram, compared with -0.83 cfu/gram from hot water and -0.75 cfu/gram from SANOVA treated carcases. The mean log(10) TVC for control carcases was 4.06 compared with 1.81 cfu/gram for hot water and 2.76 cfu/gram for SANOVA treated carcases. At Abattoir B, the prevalence of Salmonella on control carcases was 16% compared with 2.7% for hot water and 7.0% for SANOVA treated carcases. The prevalence of E. coli on control carcases was 69.3% compared with 22% for hot water and 30% for SANOVA treated carcases. The mean log(10) E. coli concentration for control carcases was 0.45 cfu/gram, compared with -0.65 cfu/gram from hot water and -0.60 cfu/gram from SANOVA treated carcases. The mean log(10) TVC for control carcases was 3.00 cfu/gram compared with 2.10 cfu/gram for hot water and 2.53 cfu/gram for SANOVA treated carcases. The reductions in prevalence and mean log(10) concentrations in the present trial were all found to be statistically significant and indicate that carcases decontamination with either hot water or SANOVA are effective risk management options immediately available to the pork industry.

FTY720 and everolimus in de novo renal transplant patients at risk for delayed graft function: results of an exploratory one-yr multicenter study.

This exploratory, multicenter, open-label study evaluated the efficacy and safety of FTY720, as a part of an immunosuppressive regimen, in combination with everolimus and steroids in de novo renal transplant recipients at increased risk of delayed graft function (DGF). Patients received FTY720 (5 mg) and everolimus (4 mg) 2-12 h pre-transplantation, followed by 2.5 mg/d FTY720 and concentration-controlled everolimus (4-8 ng/mL) post-transplant for 12 months. Induction therapy was prohibited. After enrollment of 56 of the planned 200 patients between 2000 and 2002, the recruitment was terminated. The primary endpoint, rate of graft loss, or death at three months was 15.4% and the biopsy-confirmed acute rejection was 42.3%. Death or graft loss at 12 months in the DGF and non-DGF arms was 36.0% and 25.9%, respectively. The mean estimated creatinine clearance at three months was 63 and 55 mL/min in the non-DGF and DGF groups, respectively, while at 12 months it was 56 mL/min in both the groups. Although there was no comparator arm, the results from this exploratory study (compared with data from other phases II and III trials) indicated no apparent benefits of FTY720-based regimens for prevention of acute rejection and preservation of renal function in renal transplant recipients at high risk of DGF.

Arthroscopic-assisted percutaneous reduction and screw fixation of displaced scaphoid fractures.

Many scaphoid fractures can be treated with percutaneous screw insertion, but fracture displacement usually necessitates open reduction. Two surgeons treated 20 consecutive patients with displaced fractures of the scaphoid using arthroscopic-assisted percutaneous screw fixation. Thirteen patients had dorsal (antegrade) and seven had palmar (retrograde) percutaneous screw insertion. At an average follow-up of 18 (range 6-48) months, all of the fractures were healed and there were no implant problems. The early results of arthroscopic-assisted percutaneous screw fixation of displaced fractures of the scaphoid suggest that union can be obtained and good to excellent function achieved predictably without the need for open exposure. Avoidance of an open exposure limits wrist ligament injury and may preserve blood supply. Further evaluation of this procedure is merited.

Retrospective comparison of caffeine and doxapram for the treatment of hypercapnia in foals with hypoxic-ischemic encephalopathy.

BACKGROUND: Despite a lack of data regarding their efficacy, both caffeine and doxapram have been recommended for treatment of hypercapnia in equine neonates with central nervous system damage. HYPOTHESIS: Caffeine and doxapram alleviate hypercapnia in foals with hypoxic-ischemic encephalopathy. ANIMALS: Sixteen foals treated with either caffeine (n = 8) or doxapram (n = 8). METHODS: Information on age, body temperature, heart rate, respiratory rate, arterial blood gas parameters, duration of therapy, and outcome was abstracted from each medical record. RESULTS: Therapy with doxapram resulted in a significant decrease in partial pressure of carbon dioxide (PaCO2 [P= .004]), bicarbonate concentration (P= .002), and base excess (P= .005) compared with baseline values but failed to correct acidemia. In contrast, administration of caffeine did not result in significant changes from baseline values. The percentage decrease in PaCO2 and bicarbonate concentration was significantly greater in foals treated with doxapram than in foals treated with caffeine (P= .004). The proportions of foals that achieved the targeted PaCO2 (< or = 50 mmHg) were significantly higher in foals treated with doxapram than in foals treated with caffeine (P= .029). The proportion of survivors in the 2 treatment groups was not significantly different. CONCLUSIONS AND CLINICAL IMPORTANCE: Doxapram is more effective than caffeine for rapid correction of hypercapnia in foals with hypoxic-ischemic encephalopathy.

Retrospective review of 234 scaphoid fractures and nonunions treated with arthroscopy for union and complications.

The purpose of this paper is to retrospectively review 234 consecutive cases of scaphoid fractures and nonunions treated using arthroscopy with the dorsal percutaneous implantation of a headless compression screw for healing and complications. Solid union of fracture is determined by CT scan. We identified 126 acute injuries, including 65 proximal pole fractures; 67 grossly displaced fractures; 12 trans-scaphoid perilunate dislocations including four trans-scaphoid trans-capitate fractures; and ten combined scaphoid and distal radius fractures. 108 scaphoid nonunions were identified. 98 were correctly aligned and ten had a humpback deformity which was correctable using arthroscopic assisted reduction techniques at the time of surgery. 82 presented with a fracture gap 2mm or greater requiring percutaneous bone grafting. 12 cases of avascular necrosis (AVN) were identified by MRI. 20 nonunions had surgery performed at other institutions. The mean time to surgery for the nonunions was 20 months. 99% union rate of acute scaphoid fractures was obtained by 12 weeks, as determined by CT scan. Two complications were identified (3%). One case of delayed healing was identified. this delayed union was treated with percutaneous bone grafting and continued on to heal uneventfully. The other complication was a case of volar trans-scaphoid peri-lunate dislocation. While the fracture healed, the patient developed a traumatic dislocation requiring a capitate-lunate arthrodesis. Treatment of scaphoid nonunions resulted in ten cases of delayed healing, which were treated with repeat percutaneous bone grafting. This represented a 9% complication rate. of the ten cases of delayed unions that were re-bone grafted, four failed to heal by nine months. This resulted in a 96% union rate of our nonunion group by nine months. when acute fracture healing was compared to nonunions the average healing of acute fractures as determined by CT scanning measuring trabecular bridging was 12 weeks, while the average healing of non-unions was 22 weeks. We conclude that the dorsal percutaneous treatment of scaphoid fractures and nonunions using arthroscopy is safe and effective. CT scans to evaluate scaphoid healing by measuring trabecular bridging at the fracture site was determined to be an excellent modality to evaluate scaphoid healing. While not witnessed in this series, the potential for complications requires proper training.

Medullary autonomic pathology in carotid sinus hypersensitivity.

AIMS: Carotid sinus hypersensitivity (CSH) is an ageing-related autonomic disorder, rarely occurring before the age of 50 years but increasing in incidence thereafter. Clinical symptoms of CSH include falls and dizziness, thought to be precipitated by dysfunctional baroreflex responses. CSH is highly prevalent in Alzheimer's disease (AD), Parkinson's disease (PD) and dementia with Lewy bodies (DLB); diseases that are associated with variable degeneration of medullary autonomic nuclei which regulate baroreflex responses. Currently, there are no descriptions of the integrity of medullary autonomic nuclei in CSH. We hypothesized medullary autonomic degeneration is found in elderly patients with CSH. METHODS: Using in vitro digital imaging, we quantified the burden of tau, amyloid beta and alpha-synuclein in autonomic nuclei of 12 patients prospectively assessed with CSH (age 83 years) compared with 14 (80 years) control subjects. RESULTS: We found increased tau (P < 0.000) accumulation in baroreflex associated nuclei, but not the hypoglossal or raphe in the CSH patients. Medullary tau accumulation was not related to the development of AD in the CSH patients. Tau was colocalized to catecholaminergic neurones and occurred in the absence of neuronal loss. We found no difference in alpha-synuclein, amyloid beta or microglial numbers between the CSH cases and controls. CONCLUSIONS: We suggest that hyperphosphorylated tau accumulation particularly in tyrosine hydroxylase containing neurones may impair central regulation of baroreflex responses in patients with CSH. Future clinic-pathological investigations should reveal whether medullary degeneration is the cause of CSH symptoms.