Stereotactic ablative radiotherapy with or without immunotherapy for early-stage or isolated lung parenchymal recurrent node-negative non-small-cell lung cancer: an open-label, randomised, phase 2 trial.

BACKGROUND: Stereotactic ablative radiotherapy (SABR) is the standard treatment for medically inoperable early-stage non-small-cell lung cancer (NSCLC), but regional or distant relapses, or both, are common. Immunotherapy reduces recurrence and improves survival in people with stage III NSCLC after chemoradiotherapy, but its utility in stage I and II cases is unclear. We therefore conducted a randomised phase 2 trial of SABR alone compared with SABR with immunotherapy (I-SABR) for people with early-stage NSCLC. METHODS: We did an open-label, randomised, phase 2 trial comparing SABR to I-SABR, conducted at three different hospitals in TX, USA. People aged 18 years or older with histologically proven treatment-naive stage IA-IB (tumour size ≤4 cm, N0M0), stage IIA (tumour size ≤5 cm, N0M0), or stage IIB (tumour size >5 cm and ≤7 cm, N0M0) as per the American Joint Committee on Cancer version 8 staging system or isolated parenchymal recurrences (tumour size ≤7 cm) NSCLC (TanyNanyM0 before definitive surgery or chemoradiotherapy) were included in this trial. Participants were randomly assigned (1:1; using the Pocock & Simon method) to receive SABR with or without four cycles of nivolumab (480 mg, once every 4 weeks, with the first dose on the same day as, or within 36 h after, the first SABR fraction). This trial was unmasked. The primary endpoint was 4-year event-free survival (local, regional, or distant recurrence; second primary lung cancer; or death). Analyses were both intention to treat (ITT) and per protocol. This trial is registered with ClinicalTrials.gov (NCT03110978) and is closed to enrolment. FINDINGS: From June 30, 2017, to March 22, 2022, 156 participants were randomly assigned, and 141 participants received assigned therapy. At a median 33 months' follow-up, I-SABR significantly improved 4-year event-free survival from 53% (95% CI 42-67%) with SABR to 77% (66-91%; per-protocol population, hazard ratio [HR] 0·38; 95% CI 0·19-0·75; p=0·0056; ITT population, HR 0·42; 95% CI 0·22-0·80; p=0·0080). There were no grade 3 or higher adverse events associated with SABR. In the I-SABR group, ten participants (15%) had grade 3 immunologial adverse events related to nivolumab; none had grade 3 pneumonitis or grade 4 or higher toxicity. INTERPRETATION: Compared with SABR alone, I-SABR significantly improved event-free survival at 4 years in people with early-stage treatment-naive or lung parenchymal recurrent node-negative NSCLC, with tolerable toxicity. I-SABR could be a treatment option in these participants, but further confirmation from a number of currently accruing phase 3 trials is required. FUNDING: Bristol-Myers Squibb and MD Anderson Cancer Center Alliance, National Cancer Institute at the National Institutes of Health through Cancer Center Core Support Grant and Clinical and Translational Science Award to The University of Texas MD Anderson Cancer Center.

Safety, tolerability, and clinical activity of selinexor in combination with pembrolizumab in treatment of metastatic non-small cell lung cancer.

BACKGROUND: In lung cancer, overexpression of nuclear export proteins can result in inactivation of critical tumor suppressor proteins and cell-cycle regulators. Selective suppression of nuclear export proteins has immunomodulatory activities. Here, clinical safety and early efficacy data are presented on the combination of pembrolizumab and an oral selective nuclear export inhibitor, selinexor, for the treatment of metastatic non-small cell lung cancer (mNSCLC). METHODS: The primary objective of this prospective investigator-initiated study was to determine the safety and tolerability of selinexor in combination with pembrolizumab in patients with mNSCLC. Secondary objectives included determination of objective tumor response rate, disease control rate, and progression-free survival duration. RESULTS: A total of 17 patients were included in the final analysis. Fifteen (88%) received more than two lines of prior systemic therapy and 10 (59%) had prior exposure to anti-PD-1/programmed death-ligand 1 (PD-L1) therapy. The median age was 67.5 years. Ten patients had grade ≥3 adverse events related to selinexor treatment. Responses to treatment occurred in patients who did and did not undergo previous anti-PD-1/PD-L1 therapy and in patients with activating driver mutations. The median overall survival and progression-free survival were 11.4 months (95% CI, 3.4-19.8 months) and 3.0 months (95% CI, 1.7-5.7 months), respectively. The overall response rate was 18% and the 6-month disease control rate was 24%. CONCLUSIONS: Selinexor in combination with pembrolizumab demonstrated promising antitumor activity in patients with mNSCLC, including those who had previously received anti-PD-1/PD-L1 therapy. The therapy-related toxic effects were consistent with the prior safety data for both drugs, and no overlapping toxic effects were observed. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02419495. PLAIN LANGUAGE SUMMARY: New strategies to prevent or reverse resistance to immune checkpoint inhibitors are under investigation. Selective inhibitors of nuclear export proteins, such as selinexor, can induce restoration of tumor-suppressing pathways and induce potent immunomodulatory activities. This article contains the clinical safety and early efficacy data on the combination of pembrolizumab and selinexor in treatment of metastatic non-small cell lung cancer.

Post-traumatic spinal hematoma in diffuse idiopathic skeletal hyperostosis (DISH).

OBJECTIVES: To determine the incidence of spinal hematoma and its relation to neurological deficit after trauma in patients with spinal ankylosis from diffuse idiopathic skeletal hyperostosis (DISH). MATERIALS AND METHODS: A retrospective review of 2256 urgent or emergency MRI referrals over a period of 8 years and nine months revealed 70 DISH patients who underwent CT and MRI scans of the spine. Spinal hematoma was the primary outcome. Additional variables were spinal cord impingement, spinal cord injury (SCI), trauma mechanism, fracture type, spinal canal narrowing, treatment type, and Frankel grades during injury, before and after treatment. Two trauma radiologists reviewed MRI scans blinded to initial reports. RESULTS: Of 70 post-traumatic patients (54 men, median age 73, IQR 66-81) with ankylosis of the spine from DISH, 34 (49%) had spinal epidural hematoma (SEH) and 3 (4%) had spinal subdural hematoma, 47 (67%) had spinal cord impingement, and 43 (61%) had SCI. Ground-level fall (69%) was the most common trauma mechanism. A transverse, AO classification type B spine fracture (39%) through the vertebral body was the most common injury type. Spinal canal narrowing (p < .001) correlated and spinal cord impingement (p = .004) associated with Frankel grade before treatment. Of 34 patients with SEH, one, treated conservatively, developed SCI. CONCLUSIONS: SEH is a common complication after low-energy trauma in patients with spinal ankylosis from DISH. SEH causing spinal cord impingement may progress to SCI if not treated by decompression. CLINICAL RELEVANCE STATEMENT: Low-energy trauma may cause unstable spinal fractures in patients with spinal ankylosis caused by DISH. The diagnosis of spinal cord impingement or injury requires MRI, especially for the exclusion of spinal hematoma requiring surgical evacuation. KEY POINTS: • Spinal epidural hematoma is a common complication in post-traumatic patients with spinal ankylosis from DISH. • Most fractures and associated spinal hematomas in patients with spinal ankylosis from DISH result from low-energy trauma. • Spinal hematoma can cause spinal cord impingement, which may lead to SCI if not treated by decompression.

A Cluster Randomized Trial of Primary Care Practice Redesign to Integrate Behavioral Health for Those Who Need It Most: Patients With Multiple Chronic Conditions.

PURPOSE: Patient outcomes can improve when primary care and behavioral health providers use a collaborative system of care, but integrating these services is difficult. We tested the effectiveness of a practice intervention for improving patient outcomes by enhancing integrated behavioral health (IBH) activities. METHODS: We conducted a pragmatic, cluster randomized controlled trial. The intervention combined practice redesign, quality improvement coaching, provider and staff education, and collaborative learning. At baseline and 2 years, staff at 42 primary care practices completed the Practice Integration Profile (PIP) as a measure of IBH. Adult patients with multiple chronic medical and behavioral conditions completed the Patient-Reported Outcomes Measurement Information System (PROMIS-29) survey. Primary outcomes were the change in 8 PROMIS-29 domain scores. Secondary outcomes included change in level of integration. RESULTS: Intervention assignment had no effect on change in outcomes reported by 2,426 patients who completed both baseline and 2-year surveys. Practices assigned to the intervention improved PIP workflow scores but not PIP total scores. Baseline PIP total score was significantly associated with patient-reported function, independent of intervention. Active practices that completed intervention workbooks (n = 13) improved patient-reported outcomes and practice integration (P ≤ .05) compared with other active practices (n = 7). CONCLUSION: Intervention assignment had no effect on change in patient outcomes; however, we did observe improved patient outcomes among practices that entered the study with greater IBH. We also observed more improvement of integration and patient outcomes among active practices that completed the intervention compared to active practices that did not. Additional research is needed to understand how implementation efforts to enhance IBH can best reach patients.

Loss of Transforming Growth Factor Beta Signaling in Aortic Smooth Muscle Cells Causes Endothelial Dysfunction and Aortic Hypercontractility.

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STEMI: Considerations for Left Main Culprit Lesions.

PURPOSE OF REVIEW: There is a paucity of data regarding the prevalence, clinical characteristics, and outcomes of patients presenting with ST elevation myocardial infarction (STEMI) due to left main (LM) culprit vessel. RECENT FINDINGS: LM culprit STEMI (LMCSTEMI) is an uncommon, but frequently catastrophic event. Prior meta-analyses and registries have described a varying prevalence of LMCSTEMI, associated cardiogenic shock, and in-hospital mortality among those surviving to hospital presentation. These observed clinical discrepancies may be partially attributable to diverse clinical and angiographical subsets among this STEMI population. STEMI due to LM culprit artery disease represents a clinically high-risk subset of patients with substantial in-hospital mortality. In this paper, we summarize the available clinical data pertaining to STEMI with LM culprit, discuss unique ECG characteristics, and discuss contemporary revascularization therapy. We also report the preliminary findings from a contemporary, STEMI database describing clinical characteristics and angiographically defined subsets of LM culprit STEMI.

Ankylosis of the cervical spine increases the incidence of blunt cerebrovascular injury (BCVI) in CTA screening after blunt trauma.

PURPOSE: To examine the incidence, location, and grade of blunt cerebrovascular injury (BCVI), as well as associated strokes in patients with ankylosis of the cervical spine, imaged with CT angiography (CTA) after blunt trauma. The related etiologies of ankylosis had an additional focus. MATERIALS AND METHODS: Altogether of 5867 CTAs of the craniocervical arteries imaged after blunt trauma between October 2011 and March 2020 were manually reviewed for a threshold value of ankylosis of at least three consecutive cervical vertebrae. BCVI was the primary outcome and associated stroke as the secondary outcome. Variables were craniofacial and cervical spine fractures, etiology and levels of ankylosis, traumatic brain injury, spinal hematoma, spinal cord injury, and spinal cord impingement, for which correlations with BCVI were examined. RESULTS: Of the 153 patients with ankylosis and blunt trauma of the cervical spine, 29 had a total of 36 BCVIs, of whom two had anterior and 4 posterior circulation strokes. Most of the BCVIs (n = 32) were in the vertebral arteries. Injuries were graded according to the Biffl scale: 17 grade II, 4 grade III, 14 grade IV, and 1 grade V. A ground-level fall was the most common trauma mechanism. Cervical spine fracture was the only statistically significant predictor for BCVI (OR 7.44). Degenerative spondylosis was the most prevalent etiology for ankylosis. CONCLUSION: Ankylosis of the cervical spine increases the incidence of BCVI up to sevenfold compared to general blunt trauma populations, affecting especially the vertebral arteries.

Costal cartilage fractures in blunt polytrauma patients - a prospective clinical and radiological follow-up study.

PURPOSE: To assess the healing of costal cartilage fractures (CCFX) in patients with blunt polytrauma with follow-up imaging and clinical examination. Effect on physical performance and quality of life (QoL) was also evaluated. METHODS: The study group comprised twenty-one patients with diagnosed CCFX in trauma CT. All the patients underwent MRI, ultrasound, ultra-low-dose CT examinations, and clinical status control. The patients completed QoL questionnaires. Two radiologists evaluated the images regarding fracture union, dislocation, calcifications, and persistent edema at fracture site. An attending trauma surgeon clinically examined the patients, with emphasis on focal tenderness and ribcage mobility. Trauma registry data were accessed to evaluate injury severity and outcome. RESULTS: The patients were imaged at an average of 34.1 months (median 36, range 15.8-57.7) after the initial trauma. In 15 patients (71.4%), CCFX were considered stable on imaging. Cartilage calcifications were seen on healed fracture sites in all the patients. The fracture dislocation had increased in 5 patients (23.8%), and 1 patient (4.8%) showed signs of a non-stable union. Four patients (19.0%) reported persistent symptoms from CCFX. CONCLUSION: Non-union in CCFX is uncommon but may lead to decreased stability and discomfort. Both clinical and radiological examinations play an important part in the post-traumatic evaluation of CCFX. CT and MRI visualize the healing process, while dynamic ultrasound may reveal instability. No significant difference in QoL was detected between patients with radiologically healed and non-healed CCFX. Post-traumatic disability was mostly due to other non-thoracic injuries.

Effect of water temperature on the duration of the internesting interval across sea turtle species.

Sea turtles generally lay several clutches of eggs in a single nesting season. While a negative correlation between water temperatures and the time required between constitutive nesting events (termed the internesting interval) has been previously reported in loggerhead Caretta caretta and green turtles Chelonia mydas, it is not understood whether this relationship remains constant across other sea turtle species. Here, we expanded upon these previous studies on loggerhead and green turtles by using larger sample sizes and including data from species with a wider range of body-sizes; specifically: hawksbill Eretmochelys imbricata, leatherback Dermochelys coriacea, and olive ridley turtles Lepidochelys olivacea. In total, we compiled temperature data from biologgers deployed over internesting intervals on 23 loggerhead, 22 green, 7 hawksbill, 26 leatherback and 11 olive ridley turtles from nesting sites in 8 different countries. The relationship between the duration of the internesting interval and water temperatures in green and loggerhead turtles were statistically similar yet it differed between all other turtle species. Specifically, hawksbill turtles had much longer internesting intervals than green or loggerhead turtles even after controlling for temperature. In addition, both olive ridley and leatherback turtles exhibited thermal independence of internesting intervals presumably due to the large body-size of leatherback turtles and the unique capacity of ridley turtles to delay oviposition. The observed interspecific differences in the relationship between the length of the internesting interval and water temperatures indicate the complex and variable responses that each sea turtle species may exhibit due to environmental fluctuations and climate change.

Telehealth and Public Health Practice in the United States-Before, During, and After the COVID-19 Pandemic.

Telehealth is the use of electronic information and telecommunication technologies to provide care when the patient and the provider are not in the same room at the same time. Telehealth accounted for less than 1% of all Medicare Fee-for-Service outpatient visits in the United States in 2019 but grew to account for 46% of all visits in April 2020. Changes in reimbursement and licensure policies during the COVID-19 pandemic appeared to greatly facilitate this increased use. Telehealth will continue to account for a substantial portion of care provided in the United States and globally. A better understanding of telehealth approaches and their evidence base by public health practitioners may help improve their ability to collaborate with health care organizations to improve population health. The article summarizes the Centers for Disease Control and Prevention's (CDC's) approach to understanding the evidence base for telehealth in public health practice, possible applications for telehealth in public health practice, and CDC's use of telehealth to improve population health.

Isolation and characterization of muscle stem cells, fibro-adipogenic progenitors, and macrophages from human skeletal muscle biopsies.

Animal models clearly illustrate that the maintenance of skeletal muscle mass depends on the function and interaction of a heterogeneous population of resident and infiltrating mononuclear cells. Several lines of evidence suggest that mononuclear cells also play a role in muscle wasting in humans, and targeting these cells may open new treatment options for intervention or prevention in sarcopenia. Methodological and ethical constraints have perturbed exploration of the cellular characteristics and function of mononuclear cells in human skeletal muscle. Thus, investigations of cellular phenotypes often depend on immunohistochemical analysis of small tissue samples obtained by needle biopsies, which do not match the deep phenotyping of mononuclear cells obtained from animal models. Here, we have developed a protocol for fluorescence-activated cell sorting (FACS), based on single-cell RNA-sequencing data, for quantifying and characterizing mononuclear cell populations in human skeletal muscle. Muscle stem cells, fibro-adipogenic progenitors, and two subsets of macrophages (CD11c+/-) are present in needle biopsies in comparable quantities per milligram tissue to open surgical biopsies. We find that direct cell isolation is preferable due to a substantial shift in transcriptome when using preculture before the FACS procedure. Finally, in vitro validation of the cellular phenotype of muscle stem cells, fibro-adipogenic progenitors, and macrophages confirms population-specific traits. This study demonstrates that mononuclear cell populations can be quantified and subsequently analyzed from needle biopsy material and opens the perspective for future clinical studies of cellular mechanisms in muscle wasting.

Trends in Use of Telehealth Among Health Centers During the COVID-19 Pandemic - United States, June 26-November 6, 2020.

Telehealth can facilitate access to care, reduce risk for transmission of SARS-CoV-2 (the virus that causes coronavirus disease 2019 [COVID-19]), conserve scarce medical supplies, and reduce strain on health care capacity and facilities while supporting continuity of care. Health Resources and Services Administration (HRSA)-funded health centers* expanded telehealth† services during the COVID-19 pandemic (1). The Centers for Medicare & Medicaid Services eliminated geographic restrictions and enhanced reimbursement so that telehealth services-enabled health centers could expand telehealth services and continue providing care during the pandemic (2,3). CDC and HRSA analyzed data from 245 health centers that completed a voluntary weekly HRSA Health Center COVID-19 Survey§ for 20 consecutive weeks to describe trends in telehealth use. During the weeks ending June 26-November 6, 2020, the overall percentage of weekly health care visits conducted via telehealth (telehealth visits) decreased by 25%, from 35.8% during the week ending June 26 to 26.9% for the week ending November 6, averaging 30.2% over the study period. Weekly telehealth visits declined when COVID-19 cases were decreasing and plateaued as cases were increasing. Health centers in the South and in rural areas consistently reported the lowest average percentage of weekly telehealth visits over the 20 weeks, compared with health centers in other regions and urban areas. As the COVID-19 pandemic continues, maintaining and expanding telehealth services will be critical to ensuring access to care while limiting exposure to SARS-CoV-2.

Intra-observer agreements in multidisciplinary team assessments of pancreatic cancer patients.

BACKGROUND AND METHODS: Treatment strategies for pancreatic cancer patients are made by a multidisciplinary team (MDT) board. We aimed to assess intra-observer variance at MDT boards. Participating units staged, assessed resectability, and made treatment allocations for the same patients as they did two years earlier. We disseminated clinical information and CT images of pancreatic cancer patients judged by one MDT board to have nonmetastatic pancreatic cancer to the participating units. All units were asked to re-assess the TNM stage, resectability, and treatment allocation for each patient. To assess intra-observer variance, we computed %-agreements for each participating unit, defined as low (<50%), moderate (50%-75%), and high (>75%) agreement. RESULTS: Eighteen patients were re-assessed by six MDT boards. The overall agreement was moderate for TNM-stage (ranging from 50%-70%) and resectability assessment (53%) but low for treatment allocation (46%). Agreement on resectability assessments was low to moderate. Findings were similar but more pronounced for treatment allocation. We observed a shift in treatment strategy towards increasing use of neoadjuvant chemotherapy, particularly in patients with borderline resectable and locally advanced tumors. CONCLUSIONS: We found substantial intra-observer agreement variations across six different MDT boards of 18 pancreatic cancer patients with two years between the first and second assessment.

Shared Language for Shared Work in Population Health.

People working on behalf of population health, community health, or public health often experience confusion or ambiguity in the meaning of these and other common terms-the similarities and differences and how they bear on the tasks and division of labor for care delivery and public health. Shared language must be clear enough to help, not hinder people working together as they ultimately come to mutual understanding of roles, responsibilities, and actions in their joint work. Based on an iterative lexicon development process, the authors developed and propose a definitional framework as an aid to navigating among related population and community health terms. These terms are defined, similarities and differences clarified, and then organized into 3 categories that reflect goals, realities, and ways to get the job done. Goals include (a) health as well-being for persons, (b) population health as that goal expressed in measurable terms for groups, and (c) community health as population health for particular communities of interest, geography, or other defining characteristic-groups with shared identity and particular systemic influences on health. Realities are social determinants as influences, health disparities as effects, and health equity as both a goal and a design principle. Ways to get the job done include health care delivery systems for enrollees and public health in population-based civic activities-with a broad zone of collaboration where streams of effort converge in partnership with served communities. This map of terms can enable people to move forward together in a broad zone of collaboration for health with less confusion, ambiguity, and conflict.

Post-traumatic spinal hematoma in ankylosing spondylitis.

PURPOSE: The purpose of this study is to examine the incidence, location, and magnetic resonance imaging (MRI) features of spinal epidural hematoma (SEH) and spinal subdural hematoma (SSH) in post-traumatic ankylosing spondylitis (AS) patients. METHODS: A total of 2256 consecutive referrals for urgent and emergency MRI scans of the spine over a period of eight years and nine months were manually reviewed for any mentions indicating axial ankylosis and post-traumatic spinal hematoma. We found 164 patients with ankylosed spines complicated by spinal fracture, of whom 32 had AS. Of the 132 excluded patients, 80 had diffuse idiopathic skeletal hyperostosis (DISH). The primary outcome was the presence of spinal hematoma, and the secondary outcome was spinal canal narrowing and spinal cord impingement. Two musculoskeletal radiologists and one fellow in musculoskeletal radiology reviewed the images for the presence of spinal hematoma and related signal characteristics, blinded to one another and initial reports. RESULTS: Of 28 post-traumatic AS patients, 19 had SEHs and five had spinal SSHs. There was a statistically significant difference between Frankel grades before and after surgery in respect of neurological improvement (p = 0.008). Patients who had radiologically proven spinal cord impingement showed more severe neurological deficits (p = 0.012). Hematomas with T1 heterogeneity showed a significantly increased delay (p = 0.047) between injury and imaging, while other signal characteristics were only approximate. CONCLUSIONS: Both SEH and SSH are common complications in post-traumatic AS patients. Patients benefit from surgery, but the relevance of spinal hematoma as a separate factor causing neurological deficit remains unclear.

Utilization of biomarkers as predictors of skeletal muscle mitochondrial content after physiological intervention and in clinical settings.

The measurement of mitochondrial content is essential for bioenergetic research, as it provides a tool to evaluate whether changes in mitochondrial function are strictly due to changes in content or other mechanisms that influence function. In this perspective, we argue that commonly used biomarkers of mitochondrial content may possess limited utility for capturing changes in content with physiological intervention. Moreover, we argue that they may not provide reliable estimates of content in certain pathological situations. Finally, we discuss potential solutions to overcome issues related to the utilization of biomarkers of mitochondrial content. Shedding light on this important issue will hopefully aid conclusions about the mitochondrial structure-function relationship.

Controlling Microarray Feature Spreading and Response Stability on Porous Silicon Platforms by Using Alkene-Terminal Ionic Liquids and UV Hydrosilylation.

In an attempt to develop reversible sensors based on ionic liquid/porous silicon (IL/pSi) platforms, we introduce an approach using task-specific, alkene-terminal ILs (AT-ILs) for direct grafting to the hydrogen-passivated as prepared-pSi (ap-pSi) surface via UV-hydrosilylation to address previous shortcomings associated with IL pattern impermanence (i.e., spread). By employing photoluminescence emission (PLE) and Fourier-transform infrared (FT-IR) imaging measurements, we demonstrate that the covalent grafting of AT-ILs onto the ap-pSi surface via photochemical hydrosilylation not only mitigates such feature spreading but also greatly improves PLE pattern stability. Significantly, we have discovered that, upon hydrosilylation, the resulting contact pin printed IL features remain stable to repeated challenges by toluene vapors, demonstrating the utility of AT-IL hydrosilylation for producing high-fidelity microarray features on pSi toward robust optical sensory microarrays.

Protons in small spaces: Discrete simulations of vesicle acidification.

The lumenal pH of an organelle is one of its defining characteristics and central to its biological function. Experiments have elucidated many of the key pH regulatory elements and how they vary from compartment-to-compartment, and continuum mathematical models have played an important role in understanding how these elements (proton pumps, counter-ion fluxes, membrane potential, buffering capacity, etc.) work together to achieve specific pH setpoints. While continuum models have proven successful in describing ion regulation at the cellular length scale, it is unknown if they are valid at the subcellular level where volumes are small, ion numbers may fluctuate wildly, and biochemical heterogeneity is large. Here, we create a discrete, stochastic (DS) model of vesicular acidification to answer this question. We used this simplified model to analyze pH measurements of isolated vesicles containing single proton pumps and compared these results to solutions from a continuum, ordinary differential equations (ODE)-based model. Both models predict similar parameter estimates for the mean proton pumping rate, membrane permeability, etc., but, as expected, the ODE model fails to report on the fluctuations in the system. The stochastic model predicts that pH fluctuations decrease during acidification, but noise analysis of single-vesicle data confirms our finding that the experimental noise is dominated by the fluorescent dye, and it reveals no insight into the true noise in the proton fluctuations. Finally, we again use the reduced DS model explore the acidification of large, lysosome-like vesicles to determine how stochastic elements, such as variations in proton-pump copy number and cycling between on and off states, impact the pH setpoint and fluctuations around this setpoint.

Orthopaedic metallic artefact reduction algorithm facilitates CT evaluation of the urinary tract after hip prosthesis.

AIM: To examine the improvement in the visualisation of bladder and ureteric pathologies next to a hip prosthesis with metallic artefact reduction for orthopaedic implants (O-MAR). MATERIALS AND METHODS: Thirty-four patients who underwent pelvic computed tomography (CT) for non-prosthesis-related causes were enrolled retrospectively. Portal venous phase scans were reconstructed both with standard iterative reconstruction (ITR) and with O-MAR. The density of the ureters and the bladder was measured at both sides in the plane of the prosthesis. A semi-quantitative score was also used to assess visibility. The R (version 3.4.1) package was used for statistical analysis. RESULTS: The average (µ) density of the 41 prosthesis side ureters was significantly lower on ITR images (µ=-94.76±150.48 [±SD] HU) than on O-MAR images (µ=-13.40±36.37 HU; p<0.0004). The difference between the ITR and O-MAR (µ=-138.62±182.64 versus -35.55±40.21 HU; p<0.0003) was also significant at the prosthesis side of the bladder. The visibility of the prosthesis side ureters was improved: 53.7% was obscured on ITR series compared to 4.9% on O-MAR. The visibility score was also better across all levels (p<0.001) with O-MAR. In four cases (13%), the O-MAR images significantly changed the diagnosis: in two cases ureteric stones, in one case each a bladder stone and a bladder tumour were discovered. CONCLUSIONS: O-MAR reconstruction of CT images significantly improves the visibility of the urinary tract adjacent to metallic hip implants. Thus, O-MAR is essential for detecting ureteric and bladder pathologies in patients with a hip prosthesis.

Positive predictive value of acute and chronic pancreatitis diagnoses in the Danish National Patient Registry: A validation study.

Aims: To examine the validity of the diagnoses of acute and chronic pancreatitis registered in the Danish National Patient Registry. Methods: We identified all patients in the Danish National Patient Registry admitted to two Danish hospitals with acute or chronic pancreatitis from 1996 to 2013. From this population, we randomly sampled 100 patients with acute pancreatitis and 100 patients with chronic pancreatitis. For each cohort, we computed the positive predictive values and associated 95% confidence intervals (CIs) for the discharge diagnosis of acute or chronic pancreatitis using medical records as the gold standard. Results: We identified 2617 patients with acute pancreatitis and 1284 patients with chronic pancreatitis discharged from either of the two hospitals during the study period. Of these, 776 (19.9%) had a diagnosis of both acute and chronic pancreatitis and are thus present in both cohorts. From the 200 sampled patients, a total of 138 (69.0%) medical records were available for review. The positive predictive value for a diagnosis of acute pancreatitis in the Danish National Patient Registry was 97.3% (95% CI 90.5-99.2%) and for chronic pancreatitis 83.1% (95% CI 72.2-90.3%). Conclusions: The validity of diagnoses of acute and chronic pancreatitis registered in the Danish National Patient Registry since 1996 is generally high.