In vivo base editing rescues Hutchinson-Gilford progeria syndrome in mice.

Hutchinson-Gilford progeria syndrome (HGPS or progeria) is typically caused by a dominant-negative C•G-to-T•A mutation (c.1824 C>T; p.G608G) in LMNA, the gene that encodes nuclear lamin A. This mutation causes RNA mis-splicing that produces progerin, a toxic protein that induces rapid ageing and shortens the lifespan of children with progeria to approximately 14 years1-4. Adenine base editors (ABEs) convert targeted A•T base pairs to G•C base pairs with minimal by-products and without requiring double-strand DNA breaks or donor DNA templates5,6. Here we describe the use of an ABE to directly correct the pathogenic HGPS mutation in cultured fibroblasts derived from children with progeria and in a mouse model of HGPS. Lentiviral delivery of the ABE to fibroblasts from children with HGPS resulted in 87-91% correction of the pathogenic allele, mitigation of RNA mis-splicing, reduced levels of progerin and correction of nuclear abnormalities. Unbiased off-target DNA and RNA editing analysis did not detect off-target editing in treated patient-derived fibroblasts. In transgenic mice that are homozygous for the human LMNA c.1824 C>T allele, a single retro-orbital injection of adeno-associated virus 9 (AAV9) encoding the ABE resulted in substantial, durable correction of the pathogenic mutation (around 20-60% across various organs six months after injection), restoration of normal RNA splicing and reduction of progerin protein levels. In vivo base editing rescued the vascular pathology of the mice, preserving vascular smooth muscle cell counts and preventing adventitial fibrosis. A single injection of ABE-expressing AAV9 at postnatal day 14 improved vitality and greatly extended the median lifespan of the mice from 215 to 510 days. These findings demonstrate the potential of in vivo base editing as a possible treatment for HGPS and other genetic diseases by directly correcting their root cause.

The 10,000-year biocultural history of fallow deer and its implications for conservation policy.

Over the last 10,000 y, humans have manipulated fallow deer populations with varying outcomes. Persian fallow deer (Dama mesopotamica) are now endangered. European fallow deer (Dama dama) are globally widespread and are simultaneously considered wild, domestic, endangered, invasive and are even the national animal of Barbuda and Antigua. Despite their close association with people, there is no consensus regarding their natural ranges or the timing and circumstances of their human-mediated translocations and extirpations. Our mitochondrial analyses of modern and archaeological specimens revealed two distinct clades of European fallow deer present in Anatolia and the Balkans. Zooarchaeological evidence suggests these regions were their sole glacial refugia. By combining biomolecular analyses with archaeological and textual evidence, we chart the declining distribution of Persian fallow deer and demonstrate that humans repeatedly translocated European fallow deer, sourced from the most geographically distant populations. Deer taken to Neolithic Chios and Rhodes derived not from nearby Anatolia, but from the Balkans. Though fallow deer were translocated throughout the Mediterranean as part of their association with the Greco-Roman goddesses Artemis and Diana, deer taken to Roman Mallorca were not locally available Dama dama, but Dama mesopotamica. Romans also initially introduced fallow deer to Northern Europe but the species became extinct and was reintroduced in the medieval period, this time from Anatolia. European colonial powers then transported deer populations across the globe. The biocultural histories of fallow deer challenge preconceptions about the divisions between wild and domestic species and provide information that should underpin modern management strategies.

The Clinical Spectrum of Primary Cutaneous CD4+ Small/Medium-Sized Pleomorphic T-Cell Lymphoproliferative Disorder: An Updated Systematic Literature Review and Case Series.

BACKGROUND: Primary cutaneous CD4+ small/medium pleomorphic T-cell lymphoproliferative disorder (SMPLPD) is a provisional entity within the 2016 World Health Organization classification of primary cutaneous lymphomas. The condition is currently classified as a lymphoproliferative disorder to emphasize its benign course and discourage aggressive, systemic treatment modalities. OBJECTIVE: To provide a relevant synthesis for the dermatological practitioner on the prevalence, presentation, and treatment of SMPLPD. METHODS: We conducted an updated systematic literature review and a retrospective chart review of diagnosed cases of SMPLPD from 2 Canadian academic cutaneous lymphoma centers. RESULTS: A total of 23 studies with 136 cases were extracted from the systematic review and 24 patients from our retrospective chart review. SMPLPD proved relatively common accounting for 12.5% of all cutaneous T-cell lymphomas encountered in our cutaneous lymphoma clinics, second in frequency only to mycosis fungoides. The typical clinical presentation was that of an older individual (median age 59 years) with an asymptomatic solitary lesion on their upper extremity. The most common clinical differentials were cutaneous lymphoid hyperplasia, basal cell carcinoma, and lymphoma unspecified. T follicular helper markers were reliably detected. The main treatment modalities were surgical excision, local radiation therapy, and topical or intralesional steroids. Cure was achieved in the vast majority of cases. CONCLUSIONS: SMPLPD is an underdiagnosed T-cell lymphoma with an overtly benign clinical course. The condition has an excellent prognosis and responds well to skin-directed therapies. Practitioners should be aware of this condition to avoid aggressive systemic treatments.

BET bromodomain proteins regulate enhancer function during adipogenesis.

Developmental transitions are guided by master regulatory transcription factors. During adipogenesis, a transcriptional cascade culminates in the expression of PPARγ and C/EBPα, which orchestrate activation of the adipocyte gene expression program. However, the coactivators controlling PPARγ and C/EBPα expression are less well characterized. Here, we show the bromodomain-containing protein, BRD4, regulates transcription of PPARγ and C/EBPα. Analysis of BRD4 chromatin occupancy reveals that induction of adipogenesis in 3T3L1 fibroblasts provokes dynamic redistribution of BRD4 to de novo super-enhancers proximal to genes controlling adipocyte differentiation. Inhibition of the bromodomain and extraterminal domain (BET) family of bromodomain-containing proteins impedes BRD4 occupancy at these de novo enhancers and disrupts transcription of Pparg and Cebpa, thereby blocking adipogenesis. Furthermore, silencing of these BRD4-occupied distal regulatory elements at the Pparg locus by CRISPRi demonstrates a critical role for these enhancers in the control of Pparg gene expression and adipogenesis in 3T3L1s. Together, these data establish BET bromodomain proteins as time- and context-dependent coactivators of the adipocyte cell state transition.

Safety and Efficacy of a Noninvasive 1,060-nm Diode Laser for Fat Reduction of the Flanks.

BACKGROUND: Preliminary reports indicate a hyperthermic diode laser treatment could be a safe and effective method for noninvasive fat reduction using the 1,060-nm wavelength. This wavelength penetrates the skin to heat subcutaneous adipocytes causing cellular disruption, leaving extracellular lipids, and cellular debris to be evacuated naturally by the body. OBJECTIVE: To evaluate the safety and effectiveness of this modality for noninvasive fat reduction of the flanks. MATERIALS AND METHODS: Forty-nine subjects received single laser treatment to 1 flank. Ultrasound images were taken at baseline, follow-up at 6 and 12 weeks after treatment. High-resolution photographs were taken at baseline and 12 weeks after treatment and then evaluated by independent reviewers. Adverse events recorded at all visits. Subjects completed a satisfaction questionnaire at the conclusion of the trial. RESULTS: Ultrasound images showed statistically significant (p < .001) average fat reduction of 2.6 ± 1.1 mm. Reviewers correctly ordered photographs 90.3% of the time. Ninety-six percentage of subjects rated that they were satisfied. Noted side effects were transient mild to moderate tenderness which subsided within 1 to 3 weeks; no serious adverse events were reported. CONCLUSION: The hyperthermic 1,060-nm diode laser treatment used in this study was safe and effective for noninvasive fat reduction of the flank.

Safety and Efficacy of a Non-Invasive 1060 nm Diode Laser for Fat Reduction of the Abdomen.

BACKGROUND: Changes in temperature are known to produce apoptosis in adipocytes. This study examines the use of a non-invasive treatment that applies 1060 nm laser energy transcutaneously to hyperthermically induce disruption of fat cells in the abdomen. METHODS: Thirty-five subjects received application of 1060 nm laser on the abdomen for fat reduction. Ultrasound images and high-resolution two-dimensional photography were recorded at baseline, 6 weeks, and 12 weeks post treatment. Subjects maintained a stable diet and exercise routine throughout the course of the study. Weight was recorded at baseline and each follow-up visit. Three board certified dermatologists were trained as blinded evaluators and tasked with identifying before and after photographs from randomized, paired baseline, and 12-week photographs. Ultrasound images were used to measure the fat thickness change from baseline at 6 and 12 weeks. Level of patient satisfaction was graded at 12 weeks using a 6 point Likert scale. REULTS: 23% of subjects were Fitzpatrick IV-VI. Blinded evaluators correctly identified the post-treatment photograph 95% of the time (88%, 97%, and 100%). Mean reduction in fat layer thickness from baseline was statistically significant (P less than 0.001) at both 6 weeks (1.5 +/-1.23 mm) and 12 weeks (2.65 +/-1.41 mm). Mean weight change was +0.1 lb. Side effects were mild to moderate including edema, tenderness, and induration mostly resolving within 1-3 weeks post treatment. No serious adverse events were reported. CONCLUSION: 1060 nm based laser treatment can consistently reduce the fat contour in the abdomen with an excellent safety profile in all skin types. The study met all three of its prospectively defined endpoints of success.

J Drugs Dermatol. 2018;17(1):106-112.

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Older Adults' Casino Gambling Behavior and Their Attitudes Toward New Casino Development.

Research on new casinos typically focuses upon their impact on the community, rather than on specific at-risk groups. This research study explores the impact of the opening of a new casino on attitudes of older adult casino patrons, especially those at particular risk of having gambling problems. Results demonstrate that over 80% of older adult casino patrons would not change their attitudes toward gambling or expect to increase their gambling as a result of the opening of a new casino. However, older adults with problem gambling issues are more likely to indicate they would visit a casino more, spend more time at a casino, and gamble more as a result of the opening of a new casino. In addition, older adults with signs of a gambling problem are more likely to say the opening of a new casino would change their opinions of gambling in general or casino gambling.

Polarization enhanced wide-field imaging for evaluating dermal changes caused by non-ablative fractional laser treatment.

BACKGROUND AND OBJECTIVE: Laser non-ablative fractional treatment (NAFT) is an important part of armamentarium of modern dermatology. Recently, such treatments have become available in at-home setting due to advent of self-application NAFT devices. Safety and clinical efficacy of NAFT are well established in multiple studies. Less information is available on morphological and functional changes in tissue occurring as a result of NAFT. Polarization-enhanced multispectral wide-field imaging device allows for in vivo real time visualization of dermal structures. The objective of this study is to use this imaging modality to monitor early effects of the home-use NAFT on collagen networks. MATERIALS AND METHODS: Eight subjects (skin types I-III) used a commercially available NAFT device (wavelength 1410 nm, energy per pulse up to 15 mJ) to treat peri-orbital wrinkles in standard recommended mode, that is daily, for a period of two weeks. In each session, subjects applied a pre-treatment gel to the peri-orbital areas and then used the device, delivering 8-10 applications to each side of the face without overlap. Subjects were asked to use the highest device setting. Cross-polarized 440 nm wide-field images were acquired from peri-orbital areas before and two weeks after the onset of the treatment regimen. Wide-field images were normalized and thresholded to a level of 40% brightness to emphasize collagen structure. Collagen content was quantitatively determined from thresholded collagen images. Improvement in collagen content at two weeks of daily treatments was assessed. RESULTS: Eight subjects (age 24-53 years) completed the study. Cross-polarized 440 nm wide-field images clearly delineated collagen networks. Quantitative assessment of collagen images revealed statistically significant (P < 0.05) improvement of collagen content at a time point of two weeks. Seven out of eight subjects showed varying degree of improvement. The increase of collagen content in responders ranged from 1-26%, with the mean improvement of 11%. Subjects in their early 40s showed the best improvement in comparison to younger and older age groups. CONCLUSIONS: Polarization-enhanced multispectral wide-field reflectance imaging method is a suitable technique for noninvasive in vivo assessment of dermal structures. Post-treatment images, taken three days after the last treatment session, demonstrate that non-ablative fractional treatment resulted in increased dermal collagen content as measured by the polarization-enhanced technique as early as two weeks post onset of the treatments. However, further studies with a larger number of subjects and longer treatment period are required to determine the optimal regimen and how long the results will last.

Acute suppression of lower limb spasm by sacral afferent stimulation for people with spinal cord injury: A pilot study.

Lower limb spasm and spasticity may develop following spinal cord injury (SCI), causing hyper-excitability and increased tone, which can impact function and quality of life. Pharmaceutical interventions for spasticity may cause unwanted side effects such as drowsiness and weakness. Invasive and non-invasive electrical stimulation has been shown to reduce spasticity without these side effects. The aim of this study was to investigate the effect of sacral afferent stimulation (SAS), through surface electrical stimulation of the dorsal genital nerve (N = 7), and through implanted electrodes on the sacral afferent nerve roots, on lower limb spasm and spasticity (N = 2). Provoked spasms were interrupted with conditional SAS, where stimulation commenced following a provoked spasm, or unconditional stimulation, which was applied continuously. Conditionally and unconditionally applied SAS was shown to suppress acute provoked spasms in people with SCI. There was a statistically significant reduction in area under the curve of quadriceps electromyography during acute spasm with SAS compared to a control spasm. These results show that SAS may provide a safe, low-cost method of reducing acute spasm and spasticity in people living with SCI. SAS through implanted electrodes may also provide an additional function to sacral nerve stimulation devices.

The Continuing Impact of the COVID-19 Pandemic on Diabetic Retinopathy Screenings.

PURPOSE: This retrospective observational study of health claims data seeks to quantify the prolonged impact of the COVID-19 pandemic on DR screening rates in central Massachusetts. METHODS: Retrospective claims data from the UMass Memorial Managed Care Network were collected for the years of 2018-2022. Comprehensive and DR screening exams were identified using CPT codes for patients with diabetes. Data were derived from claims submitted by the UMass Memorial Managed Care network to four insurance programs via CPT billing code for comprehensive and DR screening exams for patients with diabetes. Over one million claims for the years 01/2018-05/2022 were collected. RESULTS: We found a significant decrease in unadjusted DR screening rates in the post-lockdown period compared to the pre-COVID-19 period (p < 0.001). Bivariate analysis revealed a 15.1% decrease in weekly DR screenings during post-lockdown (RR = 0.849, 95% CI = 0.811, 0.888). After adjusting for seasonal variation, the mean weekly DR screening rate was 12% lower in the post-lockdown period, with a 95% CI of 6.1% to 17.5% decrease (Adjusted RR = 0.880, 95% CI = 0.825, 0.939 Stratified analysis based on patient status revealed a significant decrease in adjusted DR screening rates for established patients post-lockdown compared to pre-pandemic (p < 0.0001), while no significant difference was observed for new patients (p > 0.05). CONCLUSION: The impact of COVID-19 on DR screening and treatment rates persisted even after the resumption of non-essential care services, with a discrepancy between new and established patients. Future research should work to identify and overcome the barriers to DR screening.

Horse to human: Streptococcus equi septicemia presenting as endogenous endophthalmitis.

Purpose: To present a rarely reported systemic infection with streptococcus equi subspecies zooepidemicus (streptococcus equi), transmitted from a horse, and to describe successful treatment when complicated by endogenous endophthalmitis. Observations: We diagnosed suspected streptococcus equi septicemia presenting as loss of vision in the right eye of an otherwise healthy polo player/horse trainer. He received immediate intravenous antibiotics and three vitrectomies with two intravitreal antibiotic injections during the first week, to cure infection and subsequent retinal detachment. Blood and initial vitreous cultures rapidly grew streptococcus equi. The septicemia was quickly controlled by systemic antibiotics without developing commonly seen and often fatal meningitis. The right eye recovered 20/30 visual acuity three months post infection. Conclusions: Presentation of this rare septicemia as endogenous endophthalmitis illustrates the potentially lifesaving role of early diagnosis by the ophthalmologist. Immediate and recurrent vitrectomy in conjunction with intravitreal and systemic antibiotic therapy resulted in recovery of near normal vision, whereas less timely and interventional treatments have failed heretofore.

Definition of Implanted Neurological Device Abandonment: A Systematic Review and Consensus Statement.

Importance: Establishing a formal definition for neurological device abandonment has the potential to reduce or to prevent the occurrence of this abandonment. Objective: To perform a systematic review of the literature and develop an expert consensus definition for neurological device abandonment. Evidence Review: After a Royal Society Summit on Neural Interfaces (September 13-14, 2023), a systematic English language review using PubMed was undertaken to investigate extant definitions of neurological device abandonment. Articles were reviewed for relevance to neurological device abandonment in the setting of deep brain, vagal nerve, and spinal cord stimulation. This review was followed by the convening of an expert consensus group of physicians, scientists, ethicists, and stakeholders. The group summarized findings, added subject matter experience, and applied relevant ethics concepts to propose a current operational definition of neurological device abandonment. Data collection, study, and consensus development were done between September 13, 2023, and February 1, 2024. Findings: The PubMed search revealed 734 total articles, and after review, 7 articles were found to address neurological device abandonment. The expert consensus group addressed findings as germane to neurological device abandonment and added personal experience and additional relevant peer-reviewed articles, addressed stakeholders' respective responsibilities, and operationally defined abandonment in the context of implantable neurotechnological devices. The group further addressed whether clinical trial failure or shelving of devices would constitute or be associated with abandonment as defined. Referential to these domains and dimensions, the group proposed a standardized definition for abandonment of active implantable neurotechnological devices. Conclusions and Relevance: This study's consensus statement suggests that the definition for neurological device abandonment should entail failure to provide fundamental aspects of patient consent; fulfill reasonable responsibility for medical, technical, or financial support prior to the end of the device's labeled lifetime; and address any or all immediate needs that may result in safety concerns or device ineffectiveness and that the definition of abandonment associated with the failure of a research trial should be contingent on specific circumstances.

Patient Experience With Resident Versus Staff Physicians: Results From a Cross-Sectional Patient Survey From Canadian Family Medicine Residencies.

BACKGROUND AND OBJECTIVES: We compared experiences of patients who reported usually being seen by a resident with those usually seen by a staff physician. METHODS: We analyzed responses to a patient experience survey distributed at 13 family medicine teaching practices affiliated with the University of Toronto between May and June 2020. We analyzed responses to seven questions pertaining to timely access, continuity, and patient-centeredness. We compared responses between two types of usual primary care clinicians and calculated odds ratios before and after adjustment for patient characteristics. RESULTS: We analyzed data from 6,545 unique surveys; 18.6% reported their usual clinician was a resident physician. Resident patients were more likely to be older, born outside of Canada, report a high school education or less, and report having difficulty making ends meet. Compared to patients of staff physicians, patients of resident physicians had lower odds of being able to see their preferred primary care clinician and lower odds of getting nonurgent care in a reasonable time. They also had lower odds of reporting patient-centered care, but we found no significant differences in whether the time for an urgent appointment was about right or whether accessing care after hours was easy. CONCLUSIONS: In our setting, patients who reported usually seeing resident physicians had worse continuity of care and timeliness for nonurgent care than patients who reported usually seeing staff physicians despite resident patients being older, sicker, and having a lower socioeconomic position. Postgraduate training programs need to test models to support access and continuity for resident patient panels.

Biochemical progression free and overall survival among Black men with stage IV prostate cancer in South Africa: Results from a prospective cohort study.

BACKGROUND: Men of African descent are disproportionately affected by prostate cancer (PCa), and many have metastatic disease at presentation. In South Africa (SA), androgen deprivation therapy (ADT) is the first-line treatment for stage IV PCa. OBJECTIVE: To identify predictors of overall survival (OS) in Black South African men with stage IV PCa treated with ADT. DESIGN, SETTING, AND PARTICIPANTS: Men diagnosed with prostate cancer (3/22/2016-10/30/2020) at Chris Hani Baragwanath Academic Hospital in Soweto, Johannesburg, were recruited for the Men of African Descent with Cancer of the Prostate study. We included men with newly diagnosed stage IV PCa treated with ADT who had a prostate-specific antigen (PSA) level drawn prior to initiation of ADT and had ≥1 PSA drawn ≥12 weeks after ADT start. OUTCOMES MEASURES AND STATISTICAL ANALYSIS: We used Kaplan-Meier statistics to estimate OS and Cox regression models to identify predictors of OS. RESULTS AND LIMITATIONS: Of the 1097 men diagnosed with prostate cancer, we included 153 men with stage IV PCa who received ADT and met PSA requirements. The median age was 68.0 years (interquartile range 64-73 years). Median OS from time of ADT initiation was 3.39 years (95% confidence interval (CI): 3.14%-noncalculable), while biochemical progression-free survival was 2.36 years (95% CI: 2.03%-3.73%). Biochemical progression (HR 3.52, 95% CI: 1.85%-6.70%), PSA nadir level >4 ng/mL (HR 3.77, 95% CI: 1.86%-7.62%), alkaline phosphatase level at diagnosis >150 IU/dL (HR 3.09, 95% CI: 1.64%-5.83%), and hemoglobin at diagnosis <13.5 g/dL (HR 2.90, 95% CI: 1.28%-6.56%) were associated with worse OS. CONCLUSIONS: In this study, we identified factors associated with poor OS among Black South African men with stage IV PCa treated with ADT. These factors may be useful in identifying patients for upfront treatment escalation, including the use of docetaxel chemotherapy or escalation of therapy at the time of biochemical progression. PATIENT SUMMARY: In this study, we found that high alkaline phosphatase level, anemia at diagnosis, and high PSA nadir after initiation of androgen deprivation therapy are associated with worse overall survival among Black South African men treated with androgen deprivation therapy for metastatic prostate cancer.

Heterogeneous genetic architectures of prostate cancer susceptibility in sub-Saharan Africa.

Men of African descent have the highest prostate cancer incidence and mortality rates, yet the genetic basis of prostate cancer in African men has been understudied. We used genomic data from 3,963 cases and 3,509 controls from Ghana, Nigeria, Senegal, South Africa and Uganda to infer ancestry-specific genetic architectures and fine-map disease associations. Fifteen independent associations at 8q24.21, 6q22.1 and 11q13.3 reached genome-wide significance, including four new associations. Intriguingly, multiple lead associations are private alleles, a pattern arising from recent mutations and the out-of-Africa bottleneck. These African-specific alleles contribute to haplotypes with odds ratios above 2.4. We found that the genetic architecture of prostate cancer differs across Africa, with effect size differences contributing more to this heterogeneity than allele frequency differences. Population genetic analyses reveal that African prostate cancer associations are largely governed by neutral evolution. Collectively, our findings emphasize the utility of conducting genetic studies that use diverse populations.

Combined hepatocellular and cholangiocarcinoma (biphenotypic) tumors: imaging features and diagnostic accuracy of contrast-enhanced CT and MRI.

OBJECTIVE: The purpose of this study was to evaluate the diagnostic accuracy of preoperative imaging for diagnosis of combined hepatocellular cholangiocarcinoma tumors and to evaluate the clinical and imaging features and demographics of patients presenting to our institution with such tumors. MATERIALS AND METHODS: From January 2001 to January 2011, 29 patients presented with pathologically proven combined hepatocellular cholangiocarcinoma tumors to our institution. A retrospective review of the imaging studies, clinical data, and demographic information in these patients was conducted. Two radiologists with 6 and 18 years of experience reviewed the imaging studies of patients with combined hepatocellular cholangiocarcinoma tumors and matched control cases of hepatocellular carcinoma (HCC) (n = 15) and cholangiocarcinoma (n = 18). The reviewers were blinded to the pathologic diagnosis. Imaging features on contrast-enhanced MRI and CT with the suggested final diagnosis were recorded. RESULTS: The demographics of our patient population were similar to other reported U.S. populations, with cirrhosis and hepatitis present in a minority of patients. The imaging features of combined hepatocellular cholangiocarcinoma tumors overlapped with those of HCC and cholangiocarcinoma. The correct diagnosis of combined hepatocellular cholangiocarcinoma tumors was made in a minority of cases by either radiologist, with misdiagnosis more often leading to suggestion of cholangiocarcinoma than HCC. Sensitivities and specificities for diagnosis of combined hepatocellular cholangiocarcinoma tumors ranged from 33% to 34% and 81% to 100%, respectively. CONCLUSION: Preoperative diagnosis of combined hepatocellular cholangiocarcinoma tumors on the basis of imaging features is accurate in the minority of cases. Tumor markers and risk factors may help improve accuracy; however, in the absence of classic imaging features and supportive information for HCC or cholangiocarcinoma, biopsy should be considered for confirmation of diagnosis.

Role of multi-layer tissue composition of musculoskeletal extremities for prediction of in vivo surface indentation response and layer deformations.

Emergent mechanics of musculoskeletal extremities (surface indentation stiffness and tissue deformation characteristics) depend on the underlying composition and mechanics of each soft tissue layer (i.e. skin, fat, and muscle). Limited experimental studies have been performed to explore the layer specific relationships that contribute to the surface indentation response. The goal of this study was to examine through statistical modeling how the soft tissue architecture contributed to the aggregate mechanical surface response across 8 different sites of the upper and lower extremities. A publicly available dataset was used to examine the relationship of soft tissue thickness (fat and muscle) to bulk tissue surface compliance. Models required only initial tissue layer thicknesses, making them usable in the future with only a static ultrasound image. Two physics inspired models (series of linear springs), which allowed reduced statistical representations (combined locations and location specific), were explored to determine the best predictability of surface compliance and later individual layer deformations. When considering the predictability of the experimental surface compliance, the physics inspired combined locations model showed an improvement over the location specific model (percent difference of 25.4 +/- 27.9% and 29.7 +/- 31.8% for the combined locations and location specific models, respectively). While the statistical models presented in this study show that tissue compliance relies on the individual layer thicknesses, it is clear that there are other variables that need to be accounted for to improve the model. In addition, the individual layer deformations of fat and muscle tissues can be predicted reasonably well with the physics inspired models, however additional parameters may improve the robustness of the model outcomes, specifically in regard to capturing subject specificity.

Analyzing differences between spatial exposure estimation methods: A case study of outdoor food and beverage advertising in London, Canada.

Exposure assessment in the context of mobility-oriented health research often is challenged by the type of spatial measurement technique used to estimate exposures to environmental features. The purpose of this study is to compare smartphone global positioning system (GPS), shortest network path mobility, and buffer-based approaches in estimating exposure to outdoor food and beverage advertising among a sample of 154 teenagers involved in the SmartAPPetite study during 2018 in London, Ontario, Canada. Participants were asked to report their home postal code, age, gender identity, ethnicity, and number of purchases they had made at a retail food outlet in the past month. During the same time period, a mobile phone application was used to log their mobility and specifically record when a participant was in close proximity to outdoor advertising. The results of negative binomial regression modelling reveal significant differences in estimates of advertising exposure, and the relationship to self-reported purchasing. Spatial exposure estimation methods showed differences across regression models, with the buffer and observed GPS approaches delivering the best fitting models, depending on the type of retail food outlet. There is a clear need for more robust research of spatial exposure measurement techniques in the context of mobility and food (information) environment research.

Tracking the British agricultural revolution through the isotopic analysis of dated parchment.

Between the sixteenth and nineteenth century, British agriculture underwent a 'revolutionary' transformation. Yet despite over a century of research and the recognised centrality of agricultural developments to industrialisation and population growth, the character or chronology of any 'revolution' during this period remains contentious. Enquiry has been hampered by the fragmented and locally specific nature of historic accounts and the broad dating of early-modern zooarchaeological assemblages. To address this, we conducted stable isotope analysis on 658 legal documents written on sheepskin parchment; a unique biological resource that records the day, month and year of use (AD 1499 to 1969). We find these provide a high temporal resolution analysis of changing agricultural practices and episodes of disease. Most significantly, they suggest that if an 'Agricultural Revolution' occurred in livestock management, it did so from the mid-nineteenth century, in the aftermath of the Napoleonic Wars.

Ocular immunosuppressive microenvironment and novel drug delivery for control of uveitis.

Ocular immune privilege is a phenomenon described by Peter Medawar in relation to the indefinite survival of the placement of foreign tissue grafts into the eye. Several mechanisms have been described that contribute to ocular immune privilege, such as a blood-ocular barrier and lack of lymphatics in the eye, the production of immune-suppressing molecules inside the ocular microenvironment, and the induction of systemic regulatory immunity against antigens found in the eye. Because ocular immune privilege is not absolute, failure of it can result in uveitis. Uveitis is a group of inflammatory disorders that can lead to vision loss if not treated properly. The current uveitis treatments involve the use of immunosuppressive and anti-inflammatory medications. Researching mechanisms of ocular immune privilege and the development of novel treatments for uveitis is ongoing. This review discusses mechanisms of ocular immune privilege, followed by an overview of uveitis treatments and ongoing clinical trials.