Gaseous nitric oxide tumor ablation induces an anti-tumor abscopal effect.

BACKGROUND: In-situ tumor ablation provides the immune system with the appropriate antigens to induce anti-tumor immunity. Here, we present an innovative technique for generating anti-tumor immunity by delivering exogenous ultra-high concentration (> 10,000 ppm) gaseous nitric oxide (UHCgNO) intratumorally. METHODS: The capability of UHCgNO to induce apoptosis was tested in vitro in mouse colon (CT26), breast (4T1) and Lewis lung carcinoma (LLC-1) cancer cell lines. In vivo, UHCgNO was studied by treating CT26 tumor-bearing mice in-situ and assessing the immune response using a Challenge assay. RESULTS: Exposing CT26, 4T1 and LLC-1 cell lines to UHCgNO for 10 s-2.5 min induced cellular apoptosis 24 h after exposure. Treating CT26 tumors in-situ with UHCgNO followed by surgical resection 14 days later resulted in a significant secondary anti-tumor effect in vivo. 100% of tumor-bearing mice treated with 50,000 ppm UHCgNO and 64% of mice treated with 20,000 ppm UHCgNO rejected a second tumor inoculation, compared to 0% in the naive control for 70 days. Additionally, more dendrocytes infiltrated the tumor 14 days post UHCgNO treatment versus the nitrogen control. Moreover, T-cell penetration into the primary tumor was observed in a dose-dependent manner. Systemic increases in T- and B-cells were seen in UHCgNO-treated mice compared to nitrogen control. Furthermore, polymorphonuclear-myeloid-derived suppressor cells were downregulated in the spleen in the UHCgNO-treated groups. CONCLUSIONS: Taken together, our data demonstrate that UHCgNO followed by the surgical removal of the primary tumor 14 days later induces a strong and potent anti-tumor response.

Accuracy of a no-biopsy approach for the diagnosis of coeliac disease across different adult cohorts.

OBJECTIVE: We aimed to determine the predictive capacity and diagnostic yield of a 10-fold increase in serum IgA antitissue transglutaminase (tTG) antibody levels for detecting small intestinal injury diagnostic of coeliac disease (CD) in adult patients. DESIGN: The study comprised three adult cohorts. Cohort 1: 740 patients assessed in the specialist CD clinic at a UK centre; cohort 2: 532 patients with low suspicion for CD referred for upper GI endoscopy at a UK centre; cohort 3: 145 patients with raised tTG titres from multiple international sites. Marsh 3 histology was used as a reference standard against which we determined the performance characteristics of an IgA tTG titre of ≥10×ULN for a diagnosis of CD. RESULTS: Cohort 1: the sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) for IgA tTG levels of ≥10×ULN at identifying individuals with Marsh 3 lesions were 54.0%, 90.0%, 98.7% and 12.5%, respectively. Cohort 2: the sensitivity, specificity, PPV and NPV for IgA tTG levels of ≥10×ULN at identifying individuals with Marsh 3 lesions were 50.0%, 100.0%, 100.0% and 98.3%, respectively. Cohort 3: the sensitivity, specificity, PPV and NPV for IgA tTG levels of ≥10×ULN at identifying individuals with Marsh 3 lesions were 30.0%, 83.0%, 95.2% and 9.5%, respectively. CONCLUSION: Our results show that IgA tTG titres of ≥10×ULN have a strong predictive value at identifying adults with intestinal changes diagnostic of CD. This study supports the use of a no-biopsy approach for the diagnosis of adult CD.

COVID-19 Outbreak Associated with a SARS-CoV-2 R.1 Lineage Variant in a Skilled Nursing Facility After Vaccination Program - Kentucky, March 2021.

Although COVID-19 mRNA vaccines demonstrated high efficacy in clinical trials (1), they were not 100% efficacious. Thus, some infections postvaccination are expected. Limited data are available on effectiveness in skilled nursing facilities (SNFs) and against emerging variants. The Kentucky Department for Public Health (KDPH) and a local health department investigated a COVID-19 outbreak in a SNF that occurred after all residents and health care personnel (HCP) had been offered vaccination. Among 83 residents and 116 HCP, 75 (90.4%) and 61 (52.6%), respectively, received 2 vaccine doses. Twenty-six residents and 20 HCP received positive test results for SARS-CoV-2, the virus that causes COVID-19, including 18 residents and four HCP who had received their second vaccine dose >14 days before the outbreak began. An R.1 lineage variant was detected with whole genome sequencing (WGS). Although the R.1 variant has multiple spike protein mutations, vaccinated residents and HCP were 87% less likely to have symptomatic COVID-19 compared with those who were unvaccinated. Vaccination of SNF populations, including HCP, is critical to reduce the risk for SARS-CoV-2 introduction, transmission, and severe outcomes in SNFs. An ongoing focus on infection prevention and control practices is also essential.

Optimal Emotional Profiles for Peak Performance in Strength and Conditioning.

ABSTRACT: Cooper, JJ, Johnson, M, Radcliffe, J, and Fisher, J. Optimal emotional profiles for peak performance in strength and conditioning. J Strength Cond Res 35(3): 833-840, 2021-This study investigated athletes' performance-related emotions and emotional profiles for optimal performance in strength and conditioning (S&C). It is suggested that the identification and control of emotions associated with successful and unsuccessful performances are essential for achieving peak psychological states and optimal performance in sports-related tasks. The individual zone of optimal functioning (IZOF) model outlines an idiographic and comprehensive conceptual framework of interrelated dimensions that describe the structure and dynamics of subjective emotional experiences and performance-related psychobiological states. With institutional ethics approval, 13 competitive elite athletes (male, n = 7; female, n = 6: mean age = 21.7 ± 4.0 years) completed IZOF-based emotion profiling, in which subjects were asked to recall their perceived best and worst S&C session, outlining emotions and intensity within 4 global emotional categories. A significant difference was evidenced between best ever and worst ever performance within positive functional emotions (p < 0.001, d = 3.63) and negative dysfunctional emotions (p < 0.001, d = 4.92). Initial findings suggest that perceived peak performance states within S&C are associated with a high intensity of positive functional emotions (confident, motivated, and energetic) and a low intensity of negative dysfunctional emotions (worn out, sluggish, annoyed, and discouraged). Although future research is necessary to fully understand this area, the present data suggest that to assist athletes in achieving perceived peak performance states within S&C, psychological skills and strategies should be informed and developed in collaboration with sport psychologists, with the aim of achieving an optimal emotional profile.

Economic assessment of patient navigation to colonoscopy-based colorectal cancer screening in the real-world setting at the University of Chicago Medical Center.

BACKGROUND: This report details the cost effectiveness of a non-nurse patient navigation (PN) program that was implemented at the University of Chicago Medical Center to increase colonoscopy-based colorectal cancer (CRC) screening. METHODS: The authors investigated the impact of the PN intervention by collecting process measures. Individuals who received navigation were compared with a historic cohort of non-navigated patients. In addition, a previously validated data-collection instrument was tailored and used to collect all costs related to developing, implementing, and administering the program; and the incremental cost per patient successfully navigated (the cost of the intervention divided by the change in the number who complete screening) was calculated. RESULTS: The screening colonoscopy completion rate was 85.1% among those who were selected to receive PN compared with 74.3% when no navigation was implemented. With navigation, the proportion of no-shows was 8.2% compared with 15.4% of a historic cohort of non-navigated patients. Because the perceived risk of noncompletion was greater among those who received PN (previous no-show or cancellation, poor bowel preparation) than that in the historic cohort, a scenario analysis was performed. Assuming no-show rates between 0% and 50% and using a navigated rate of 85%, the total incremental program cost per patient successfully navigated ranged from $148 to $359, whereas the incremental intervention-only implementation cost ranged from $88 to $215. CONCLUSIONS: The current findings indicate that non-nurse PN can increase colonoscopy completion, and this can be achieved at a minimal incremental cost for an insured population at an urban academic medical center.

Large-Scale Variability of Inpatient Tacrolimus Therapeutic Drug Monitoring at an Academic Transplant Center: A Retrospective Study.

BACKGROUND: Inpatient tacrolimus therapeutic drug monitoring (TDM) lacks standardized guidelines. In this study, the authors analyzed variability in the preanalytical phase of the inpatient tacrolimus TDM process at their institution. METHODS: Patients receiving tacrolimus (twice-daily formulation) and tacrolimus laboratory analysis were included in the study. Times of tacrolimus administration and laboratory study collection were extracted, and time distribution plots for each step in the inpatient TDM process were generated. RESULTS: Trough levels were drawn appropriately in 25.9% of the cases. Timing between doses was consistent, with 91.9% of the following dose administrations occurring 12 ± 2 hours after the previous dose. Only 38.1% of the drug administrations occurred within 1 hour of laboratory study collection. Tacrolimus-related patient safety events were reported at a rate of 1.9 events per month while incorrect timing of TDM sample collection occurred approximately 200 times per month. Root cause analysis identified a TDM process marked by a lack of communication and coordination of drug administration and TDM sample collection. Extrapolating findings nationwide, we estimate $22 million in laboratory costs wasted annually. CONCLUSIONS: Based on this large single-center study, the authors concluded that the inpatient TDM process is prone to timing errors, thus is financially wasteful, and at its worst harmful to patients due to clinical decisions being made on the basis of unreliable data. Further work is needed on systems solutions to better align the laboratory study collection and drug administration processes.

ROC-king onwards: intraepithelial lymphocyte counts, distribution & role in coeliac disease mucosal interpretation.

OBJECTIVES: Counting intraepithelial lymphocytes (IEL) is central to the histological diagnosis of coeliac disease (CD), but no definitive 'normal' IEL range has ever been published. In this multicentre study, receiver operating characteristic (ROC) curve analysis was used to determine the optimal cut-off between normal and CD (Marsh III lesion) duodenal mucosa, based on IEL counts on >400 mucosal biopsy specimens. DESIGN: The study was designed at the International Meeting on Digestive Pathology, Bucharest 2015. Investigators from 19 centres, eight countries of three continents, recruited 198 patients with Marsh III histology and 203 controls and used one agreed protocol to count IEL/100 enterocytes in well-oriented duodenal biopsies. Demographic and serological data were also collected. RESULTS: The mean ages of CD and control groups were 45.5 (neonate to 82) and 38.3 (2-88) years. Mean IEL count was 54±18/100 enterocytes in CD and 13±8 in normal controls (p=0.0001). ROC analysis indicated an optimal cut-off point of 25 IEL/100 enterocytes, with 99% sensitivity, 92% specificity and 99.5% area under the curve. Other cut-offs between 20 and 40 IEL were less discriminatory. Additionally, there was a sufficiently high number of biopsies to explore IEL counts across the subclassification of the Marsh III lesion. CONCLUSION: Our ROC curve analyses demonstrate that for Marsh III lesions, a cut-off of 25 IEL/100 enterocytes optimises discrimination between normal control and CD biopsies. No differences in IEL counts were found between Marsh III a, b and c lesions. There was an indication of a continuously graded dose-response by IEL to environmental (gluten) antigenic influence.

An economic evaluation of the costs of training a medical scribe to work in Emergency Medicine.

OBJECTIVE: To undertake a cost analysis of training medical scribes in an ED. METHODS: This was a pilot, observational, single-centre study at Cabrini ED, Melbourne, Australia, studying the costs of initiating a scribe programme from the perspective of the hospital and Australian Health sector. Recruitment and training occurred between August 2015 and February 2016 and comprised of a prework course (1 month), prework training sessions and clinical training shifts for scribe trainees (2-4 months, one shift per week) who were trained by emergency physicians. Costs of start-up, recruitment, administration, preclinical training, clinical training shifts and productivity changes for trainers were calculated. RESULTS: 10 trainees were recruited to the prework course, 9 finished, 6 were offered clinical training after simulation assessment, 5 achieved competency. Scribes required clinical training ranging from 68 to 118 hours to become competent after initial classroom training. Medical students (2) required 7 shifts to become competent, premedical students (3) 8-16 shifts, while a trainee from an alternative background did not achieve competency. Based on a scribe salary of US$15.91/hour (including 25% on-costs) plus shift loadings, costs were: recruitment and start-up US$3111, education US$1257, administration US$866 and clinical shift costs US$1137 (overall cost US$6317 per competent scribe). Physicians who trained the clinical trainee scribes during shifts did not lose productivity. CONCLUSIONS: Training scribes outside the USA is feasible using an on-line training course and local physicians. It makes economic sense to hire individuals who can work over a long period of time to recoup training costs. TRIAL REGISTRATION NUMBER: ACTRN12615000607572.

Ablation of porcine ligamentum flavum with Ho:YAG, q-switched Ho:YAG, and quadrupled Nd:YAG lasers.

BACKGROUND AND OBJECTIVES: Ligamentum flavum (LF) is a tough, rubbery connective tissue providing a portion of the ligamentous stability to the spinal column, and in its hypertrophied state forms a significant compressive pathology in degenerative spinal stenosis. The interaction of lasers and this biological tissue have not been thoroughly studied. Technological advances improving endoscopic surgical access to the spinal canal makes selective removal of LF using small, flexible tools such as laser-coupled fiber optics increasingly attractive for treatment of debilitating spinal stenosis. Testing was performed to assess the effect of Ho:YAG, Q-switched Ho:YAG, and frequency quadrupled Nd:YAG lasers on samples of porcine LF. The objective was to evaluate the suitability of these lasers for surgical removal of LF. STUDY DESIGN/MATERIALS AND METHODS: LF was resected from porcine spine within 2 hours of sacrifice and stored in saline until immediately prior to laser irradiation, which occurred within an additional 2 hours. The optical absorbance of a sample was measured over the spectral band from 190 to 2,360 nm both before and after dehydration. For the experiments using the Ho:YAG (λ = 2,080 nm, tp = 140 µs, FWHM) and Q-Switched Ho:YAG (λ = 2,080 nm, tp = 260 ns, FWHM) lasers, energy was delivered to the LF through a laser-fiber optic with 600 µm core and NA = 0.39. For the experiment using the frequency quadrupled Nd:YAG laser (λ = 266 nm, tp = 5 ns FWHM), rather than applying the laser energy through a laser-fiber, the energy was focused through an aperture and lens directly onto the LF. Five experiments were conducted to evaluate the effect of the given lasers on LF. First, using the Ho:YAG laser, the single-pulse laser-hole depth versus laser fluence was measured with the laser-fiber in direct contact with the LF (1 g force) and with a standoff distance of 1 mm between the laser-fiber face and the LF. Second, with the LF remaining in situ and the spine bisected along the coronal plane, the surface temperature of the LF was measured with an IR camera during irradiation with the Ho:YAG laser, with and without constant saline flush. Third, the mass loss was measured over the course of 450 Ho:YAG pulses. Fourth, hole depth and temperature were measured over 30 pulses of fixed fluence from the Ho:YAG and Q-Switched Ho:YAG lasers. Fifth, the ablation rate and surface temperature were measured as a function of fluence from the Nd:YAG laser. Several LF staining and hole-depth measurement techniques were also explored. RESULTS: Aside from the expected absorbance peaks corresponding to the water in the LF, the most significant peaks in absorbance were located in the spectral band from 190 to 290 nm and persisted after the tissue was dehydrated. In the first experiment, using the Ho:YAG laser and with the laser-fiber in direct contact with the LF, the lowest single-pulse fluence for which LF was visibly removed was 35 J/cm(2) . Testing was conducted at 6 fluences between 35 and 354 J/cm(2) . Over this range the single-pulse hole depth was shown to be near linear (R(2) = 0.9374, M = 1.6), ranging from 40 to 639 µm (N = 3). For the case where the laser-fiber face was displaced 1 mm from the LF surface, the lowest single-pulse fluence for which tissue was visibly removed was 72 J/cm(2) . Testing was conducted at 4 energy densities between 72 and 180 J/cm(2) . Over this range the single-pulse hole depth was shown to be near linear (R(2) = 0.8951, M = 1.4), ranging from 31 to 220 µm (N = 3). In the second experiment, with LF in situ, constant flushing with room temperature saline was shown to drastically reduce surface temperature during exposure to Ho:YAG at 5 Hz with the laser-fiber in direct contact with the LF. Without saline, over 1 minute of treatment with a per-pulse fluence of 141 mJ/cm(2) , the average maximum surface temperature measured 110°C. With 10 cc's of saline flushed over 1 minute and a per-pulse laser fluence of 212 mJ/cm(2) , the average maximum surface temperature was 35°C. In the third experiment, mass loss was shown to be linear over 450 pulses of 600 mJ from the Ho:YAG laser (212 J/cm(2) , direct contact, N = 4; 108 J/cm(2) , 1 mm standoff, N = 4). With the laser-fiber in direct contact, an average of 53 mg was removed (R(2) = 0.996, M = 0.117) and with 1 mm laser-fiber standoff, an average of 44 mg was removed (R(2) = 0.9988, M = 0.097). In the fourth experiment, 30 pulses of the Ho:YAG and Q-Switched Ho:YAG lasers at 1 mm standoff, and 5 Hz produced similar hole depths for the tested fluences of 9 J/cm(2) (151 and 154 µm, respectively) and 18 J/cm(2) (470 and 442 µm, respectively), though the Ho:YAG laser produced significantly more carbonization around the rim of the laser-hole. The increased carbonization was corroborated by higher measured LF temperature. In all tests with the Ho:YAG and Q-Switched Ho:YAG, an audible photo-acoustic affect coincided with the laser pulse. In the fifth experiment, with the frequency quadrupled Nd:YAG laser at 15 Hz for 450 pulses, ablation depth per pulse was shown to be linear for the fluence range of 0.18 - 0.73 J/cm(2) (R(2) = 0.989, M = 2.4). There was no noticeable photo-acoustic effect nor charring around the rim of the laser-hole. CONCLUSION: The Ho:YAG, Q-Switched Ho:YAG, and frequency quadrupled Nd:YAG lasers were shown to remove ligamentum flavum (LF). A single pulse of the Ho:YAG laser was shown to cause tearing of the tissue and a large zone of necrosis surrounding the laser-hole. Multiple pulses of the Ho:YAG and Q-Switched Ho:YAG lasers caused charring around the rim of the laser-hole, though the extent of charring was more extensive with the Ho:YAG laser. Charring caused by the Ho:YAG laser was shown to be mitigated by continuously flushing the affected LF with saline during irradiation. The Nd:YAG laser was shown to ablate LF with no gross visible indication of thermal damage to surrounding LF.

Radiographic film dosimetry of proton beams for depth-dose constancy check and beam profile measurement.

Radiographic film dosimetry suffers from its energy dependence in proton dosimetry. This study sought to develop a method of measuring proton beams by the film and to evaluate film response to proton beams for the constancy check of depth dose (DD). It also evaluated the film for profile measurements. To achieve this goal, from DDs measured by film and ion chamber (IC), calibration factors (ratios of dose measured by IC to film responses) as a function of depth in a phantom were obtained. These factors imply variable slopes (with proton energy and depth) of linear characteristic curves that relate film response to dose. We derived a calibration method that enables utilization of the factors for acquisition of dose from film density measured at later dates by adapting to a potentially altered processor condition. To test this model, the characteristic curve was obtained by using EDR2 film and in-phantom film dosimetry in parallel with a 149.65 MeV proton beam, using the method. An additional validation of the model was performed by concurrent film and IC measurement perpendicular to the beam at various depths. Beam profile measurements by the film were also evaluated at the center of beam modulation. In order to interpret and ascertain the film dosimetry, Monte Carlos simulation of the beam was performed, calculating the proton fluence spectrum along depths and off-axis distances. By multiplying respective stopping powers to the spectrum, doses to film and water were calculated. The ratio of film dose to water dose was evaluated. Results are as follows. The characteristic curve proved the assumed linearity. The measured DD approached that of IC, but near the end of the spread-out Bragg peak (SOBP), a spurious peak was observed due to the mismatch of distal edge between the calibration and measurement films. The width of SOBP and the proximal edge were both reproducible within a maximum of 5mm; the distal edge was reproducible within 1 mm. At 5 cm depth, the dose was reproducible within 10%. These large discrepancies were identified to have been contributed by film processor uncertainty across a layer of film and the misalignment of film edge to the frontal phantom surface. The deviations could drop from 5 to 2 mm in SOBP and from 10% to 4.5% at 5 cm depth in a well-controlled processor condition(i.e., warm up). In addition to the validation of the calibration method done by the DD measurements, the concurrent film and IC measurement independently validated the model by showing the constancy of depth-dependent calibration factors. For profile measurement, the film showed good agreement with ion chamber measurement. In agreement with the experimental findings, computationally obtained ratio of film dose to water dose assisted understanding of the trend of the film response by revealing relatively large and small variances of the response for DD and beam profile measurements, respectively. Conclusions are as follows. For proton beams, radiographic film proved to offer accurate beam profile measurements. The adaptive calibration method proposed in this study was validated. Using the method, film dosimetry could offer reasonably accurate DD constancy checks, when provided with a well-controlled processor condition. Although the processor warming up can promote a uniform processing across a single layer of the film, the processing remains as a challenge.

Rare Disease Day: Amplifying voices, advocating hope.

Every year on February 28, the global community comes together to observe Rare Disease Day, a day dedicated to raising awareness and understanding for the millions of individuals who live with rare disorders. While individual rare diseases may seem uncommon, their collective impact is significant, affecting the lives of countless families and communities worldwide. This day serves as a crucial platform to amplify the voices of those affected, advocate for increased research and support, and inspire hope for a future where rare diseases can be prevented, diagnosed earlier, and effectively treated.

Global health for rare diseases through primary care.

Rare diseases affect over 300 million people worldwide and are gaining recognition as a global health priority. Their inclusion in the UN Sustainable Development Goals, the UN Resolution on Addressing the Challenges of Persons Living with a Rare Disease, and the anticipated WHO Global Network for Rare Diseases and WHO Resolution on Rare Diseases, which is yet to be announced, emphasise their significance. People with rare diseases often face unmet health needs, including access to screening, diagnosis, therapy, and comprehensive health care. These challenges highlight the need for awareness and targeted interventions, including comprehensive education, especially in primary care. The majority of rare disease research, clinical services, and health systems are addressed with specialist care. WHO Member States have committed to focusing on primary health care in both universal health coverage and health-related Sustainable Development Goals. Recognising this opportunity, the International Rare Diseases Research Consortium (IRDiRC) assembled a global, multistakeholder task force to identify key barriers and opportunities for empowering primary health-care providers in addressing rare disease challenges.

Prediction plays a key role in language development as well as processing.

Although the target article emphasizes the important role of prediction in language use, prediction may well also play a key role in the initial formation of linguistic representations, that is, in language development. We outline the role of prediction in three relevant language-learning domains: transitional probabilities, statistical preemption, and construction learning.

Together4RD position statement on collaboration between European reference networks and industry.

Notwithstanding two decades of policy and legislation in Europe, aimed to foster research and development in rare conditions, only 5-6% of rare diseases have dedicated treatments. Given with the huge number of conditions classed as rare (which is increasing all the time), this equates to major unmet need for patients (over 30 million in the EU alone). Worryingly, the pace of Research and Innovation in Europe is lagging behind other regions of the world, and a seismic shift in the way in which research is planned and delivered is required, in order to remain competitive and-most importantly-bring meaningful, disease-altering treatments to those who desperately need them. The European Reference Networks (ERNs), launched in 2017, hold major potential to alleviate many of these challenges, and more, but only if adequately supported (financially, technically, and via robust policies and infrastructure) to realise that potential: and even then, only if able to forge robust collaborations harnessing the expertise, resources, knowledge and data of all stakeholders involved in rare disease, including Industry. To-date, however, ERN-Industry interactions have been largely limited, for a range of reasons (concerning barriers both tangible and perceived). This Position Statement analyses these barriers, and explains how Together4RD is seeking to move the needle here, by learning from case studies, exploring frameworks for collaboration, and launching pilots to explore how best to plan and deliver multistakeholder interactions addressing real research needs.

Proteomics of brain, CSF, and plasma identifies molecular signatures for distinguishing sporadic and genetic Alzheimer's disease.

Proteomic studies for Alzheimer's disease (AD) are instrumental in identifying AD pathways but often focus on single tissues and sporadic AD cases. Here, we present a proteomic study analyzing 1305 proteins in brain tissue, cerebrospinal fluid (CSF), and plasma from patients with sporadic AD, TREM2 risk variant carriers, patients with autosomal dominant AD (ADAD), and healthy individuals. We identified 8 brain, 40 CSF, and 9 plasma proteins that were altered in individuals with sporadic AD, and we replicated these findings in several external datasets. We identified a proteomic signature that differentiated TREM2 variant carriers from both individuals with sporadic AD and healthy individuals. The proteins associated with sporadic AD were also altered in patients with ADAD, but with a greater effect size. Brain-derived proteins associated with ADAD were also replicated in additional CSF samples. Enrichment analyses highlighted several pathways, including those implicated in AD (calcineurin and Apo E), Parkinson's disease (α-synuclein and LRRK2), and innate immune responses (SHC1, ERK-1, and SPP1). Our findings suggest that combined proteomics across brain tissue, CSF, and plasma can be used to identify markers for sporadic and genetically defined AD.

Patient journey experiences may contribute to improve healthcare for patients with rare endocrine diseases.

Patient journeys are instruments developed by EURORDIS, The Voice of Rare Disease Patients in Europe, to collect patients' experiences; they may identify gaps and areas deserving improvement, as well as elements positively considered by affected persons. As with other patient-reported experiences, they can complete the clinical evaluation and management of a specific disease, improving the often long diagnostic delay, therapy, patient education and access to knowledgeable multidisciplinary teams. This review discusses the utility of such patient-reported experience measures and summarises the experiences of patients with acromegaly, Addison's disease and congenital adrenal hyperplasia from different European countries. Despite rare endocrine diseases being varied and presenting differently, feelings of not having been taken seriously by health professionals, family and friends was a common patient complaint. Empathy and a positive patient-centred environment tend to improve clinical practice by creating a trustworthy and understanding atmosphere, where individual patient needs are considered. Offering access to adequate patient information on their disease, treatments and outcome helps to adapt to living with a chronic disease and what to expect in the future, contemplating the impact of a disease on patients' everyday life, not only clinical outcome but also social, financial, educational, family and leisure issues is desirable; this facilitates more realistic expectancies for patients and can even lead to a reduction in health costs. Patient empowerment with patient-centred approaches to these complex or chronic diseases should be contemplated more and more, not only for the benefit of those affected but also for the entire health system.

Gluten Induces Subtle Histological Changes in Duodenal Mucosa of Patients with Non-Coeliac Gluten Sensitivity: A Multicentre Study.

Background: Histological changes induced by gluten in the duodenal mucosa of patients with non-coeliac gluten sensitivity (NCGS) are poorly defined. Objectives: To evaluate the structural and inflammatory features of NCGS compared to controls and coeliac disease (CeD) with milder enteropathy (Marsh I-II). Methods: Well-oriented biopsies of 262 control cases with normal gastroscopy and histologic findings, 261 CeD, and 175 NCGS biopsies from 9 contributing countries were examined. Villus height (VH, in µm), crypt depth (CrD, in µm), villus-to-crypt ratios (VCR), IELs (intraepithelial lymphocytes/100 enterocytes), and other relevant histological, serologic, and demographic parameters were quantified. Results: The median VH in NCGS was significantly shorter (600, IQR: 400−705) than controls (900, IQR: 667−1112) (p < 0.001). NCGS patients with Marsh I-II had similar VH and VCR to CeD [465 µm (IQR: 390−620) vs. 427 µm (IQR: 348−569, p = 0·176)]. The VCR in NCGS with Marsh 0 was lower than controls (p < 0.001). The median IEL in NCGS with Marsh 0 was higher than controls (23.0 vs. 13.7, p < 0.001). To distinguish Marsh 0 NCGS from controls, an IEL cut-off of 14 showed 79% sensitivity and 55% specificity. IEL densities in Marsh I-II NCGS and CeD groups were similar. Conclusion: NCGS duodenal mucosa exhibits distinctive changes consistent with an intestinal response to luminal antigens, even at the Marsh 0 stage of villus architecture.

Our greatest untapped resource: our patients.

Healthcare is continually evolving to meet the changing needs of twenty-first century populations whilst striving to keeping pace with medical and technological advancements. Patients and clinicians remain the constants in this evolving environment, sitting at the cutting edge of new evidence and innovation and at the coalface of clinical services which need to address the increasingly challenging health priorities we face as a society. Patients and clinicians, positioned centre stage in this changing world, must adjust their relationships and partnerships to reduce the burden of illness and ensure that multifaceted care needs are all properly addressed. In rare diseases, this relationship between patients and professionals demands a new model of care, in which patients are active, valued partners in their own care and function not as 'enlightened self-interested' individuals but as experts by experience. The unique characteristics of rare diseases demand that care evolves beyond multidisciplinary team care to 'Networked-care', in which care is prescribed based upon the body of experience and expertise of a community of experts and patients (who are experts by experience). Healthcare models are being redrawn around a new norm of clinical practice based on true patient-clinical partnerships in care. A partnership with patients, when supported by proper investment, is a collaborative relationship that aligns both the medical and clinical perspectives of professionals with a holistic perspective of patients' life experiences. Such partnerships can (i) ensure that decisions around care and design of services are needs-led, (ii) reduce the fog of uncertainty that surrounds rare diseases, (iii) amplify the success of new discoveries, and (iv) create breakthrough innovations: in these ways, patient-clinical partnerships increase the efficiency and effectiveness of our work and build a more sustainable future for our healthcare services.

Predictors of radiation necrosis in long-term survivors after Gamma Knife stereotactic radiosurgery for brain metastases.

BACKGROUND: The long-term risk of necrosis after radiosurgery for brain metastases is uncertain. We aimed to investigate incidence and predictors of radiation necrosis for individuals with more than 1 year of survival after radiosurgery for brain metastases. METHODS: Patients who had a diagnosis of brain metastases treated between December 2006 and December 2014, who had at least 1 year of survival after first radiosurgery were retrospectively reviewed. Survival was analyzed using the Kaplan-Meier estimator, and the incidence of radiation necrosis was estimated with death or surgical resection as competing risks. Patient and treatment factors associated with radiation necrosis were also analyzed. RESULTS: A total of 198 patients with 732 lesions were analyzed. Thirty-four lesions required salvage radiosurgery and 10 required salvage surgical resection. Median follow-up was 24 months. The estimated median survival for this population was 25.4 months. The estimated per-lesion incidence of radiation necrosis at 4 years was 6.8%. Medical or surgical therapy was required for 60% of necrosis events. Tumor volume and male sex were significant factors associated with radiation necrosis. The per-lesions incidence of necrosis for patients undergoing repeat radiosurgery was 33.3% at 4 years. CONCLUSIONS: In this large series of patients undergoing radiosurgery for brain metastases, patients continued to be at risk for radiation necrosis throughout their first 4 years of survival. Repeat radiosurgery of recurrent lesions greatly exacerbates the risk of radiation necrosis, whereas treatment of larger target volumes increases the risk modestly.

The correlation between vitamin D levels and demographics in patients with gastrointestinal disorders; a cross-sectional study.

AIM: The aim of the present study was to evaluate vitamin D levels, in correlation with age, body mass index (BMI), gender and ethnicity, in patients with gastrointestinal disorders (GID). BACKGROUND: Vitamin D deficiency (VDD) is a global health issue, affecting over 1 billion people. A great body of evidence has shown that it can lead to increased morbidity and mortality. Furthermore, latitude, sedentary lifestyle, limited sunlight exposure, ageing and the presence of comorbidities and chronic illnesses, places patients at an increased risk of VDD. METHODS: 305 consecutive patients, with GID, were assessed for vitamin D levels, using a two-step competitive binding immunoenzymatic assay. Patients were then classified as adequate (50-150nmol/l), insufficient (25-50nmol/l) and deficient (<25nmol/l). RESULTS: 62% of the investigated subjects had low vitamin D levels. From this group, 132 patients (43.3%) had insufficient vitamin D levels, 57 (18.7%) had deficient levels and 116 (38%) had adequate levels. Age was not significantly different in the 3 groups (p=0.29). Interestingly, vitamin D levels were significantly lower in men (39.23±23.62) compared to women (50.68±24.46) (p=0.0001). The BMI was significantly higher in patients with insufficient vitamin D levels. Being of Asian ethnicity had a positive influence on vitamin D levels (B=0.076) (p<0.0001). 71.4% of patients, with IBD, and 60% of patients, with abnormal liver function, had low vitamin D levels. CONCLUSION: VDD has a high prevalence in patients with GID in particular IBD and liver disease in the United Kingdom. Routine vitamin D testing and supplementations in the case of deficiency and suboptimal level of vitamin D for patients with hepatobiliary, pancreatic, kidney, malabsorptive and restrictive diseases/surgeries is recommended.