Boundary Layer Behaviour in Circular EHL contacts in the Elastic-Piezoviscous Regime

The solution of elastohydrodynamically lubricated contacts at high loads and/or low speeds can be described as a Hertzian pressure with inlet and outlet boundary layers: zones where significant pressure flow occurs. For the soft lubrication regime (elastic-isoviscous), a self-similar solution exists in the boundary layers satisfying localized equations. In this paper, the boundary layer behaviour in the elastic-piezoviscous regime is investigated. The lengthscale of the boundary layers and the scaling of pressure and film thickness are expressed in non-dimensional parameters. The boundary layer width scales as 1/M−−√ (equivalent to λ¯3/8 ), the maximum pressure difference relative to the Hertzian solution as 1/M−−√3 (equivalent to λ¯1/4 ) and the film thickness as 1/M−−√16 (equivalent to λ¯3/64 ) with M the Moes non-dimensional load and λ¯ a dimensionless speed parameter. The Moes dimensionless lubricant parameter L was fixed. These scalings differ from the isoviscous-elastic (soft lubrication) regime. With increasing load (decreasing speed), the solution exhibits an increasing degree of rotational symmetry. The pressure varies less than 10 % over an angle less than 45 degrees from the lubricant entrainment direction. The results provide additional fundamental understanding of the nature of elastohydrodynamic lubrication and give physical rationale to the finding of roughness deformation depending on the “inlet length”. The findings may contribute to more efficient numerical solutions and to improved semi-analytical prediction methods for engineering based on physically correct asymptotic behaviour

Senile Systemic Amyloidosis: Clinical Features at Presentation and Outcome

Background Cardiac amyloidosis is a fatal disease whose prognosis and treatment rely on identification of the amyloid type. In our aging population transthyretin amyloidosis (ATTRwt) is common and must be differentiated from other amyloid types. We report the clinical presentation, natural history, and prognostic features of ATTRwt compared with cardiac‐isolated AL amyloidosis and calculate the probability of disease diagnosis of ATTRwt from baseline factors. Methods and Results All patients with biopsy‐proven ATTRwt (102 cases) and isolated cardiac AL (36 cases) seen from 2002 to 2011 at the UK National Amyloidosis Center were included. Median survival from the onset of symptoms was 6.07 years in the ATTRwt group and 1.7 years in the AL group. Positive troponin, a pacemaker, and increasing New York Heart Association (NYHA) class were associated with worse survival in ATTRwt patients on univariate analysis. All patients with isolated cardiac AL and 24.1% of patients with ATTRwt had evidence of a plasma cell dyscrasia. Older age and lower N‐terminal pro‐B‐type natriuretic peptide (NT pro‐BNP) were factors significantly associated with ATTRwt. Patients aged 70 years and younger with an NT pro‐BNP <183 pmol/L were more likely to have ATTRwt, as were patients older than 70 years with an NT pro‐BNP <1420 pmol/L. Conclusions Factors at baseline associated with a worse outcome in ATTRwt are positive troponin T, a pacemaker, and NYHA class IV symptoms. The age of the patient at diagnosis and NT pro‐BNP level can aid in distinguishing ATTRwt from AL amyloidosis

Design of experiment (DoE)-driven in vitro and in vivo uptake studies of exosomes for pancreatic cancer delivery enabled by copper-free click chemistry-based labelling

Exosomes (Exo)-based therapy holds promise for treatment of lethal pancreatic cancer (PC). Limited understanding of key factors affecting Exo uptake in PC cells restricts better design of Exo-based therapy. This work aims to study the uptake properties of different Exo by PC cells. Exo from pancreatic carcinoma, melanoma and non-cancer cell lines were isolated and characterised for yield, size, morphology and exosomal marker expression. Isolated Exo were fluorescently labelled using a novel in-house developed method based on copper-free click chemistry to enable intracellular tracking and uptake quantification in cells. Important factors influencing Exo uptake were initially predicted by Design of Experiments (DoE) approach to facilitate subsequent actual experimental investigations. Uptake of all Exo types by PC cells (PANC-1) showed time- and dose-dependence as predicted by the DoE model. PANC-1 cell-derived exosomes (PANC-1 Exo) showed significantly higher uptake in PANC-1 cells than that of other Exo types at the longest incubation time and highest Exo dose. In vivo biodistribution studies in subcutaneous tumour-bearing mice similarly showed favoured accumulation of PANC-1 Exo in self-tissue (i.e. PANC-1 tumour mass) over the more vascularised melanoma (B16-F10) tumours, suggesting intrinsic tropism of PC-derived Exo for their parent cells. This study provides a simple, universal and reliable surface modification approach via click chemistry for in vitro and in vivo exosome uptake studies and can serve as a basis for a rationalised design approach for pre-clinical Exo cancer therapies

Suprachiasmatic VIP neurons are required for normal circadian rhythmicity and comprised of molecularly distinct subpopulations

The hypothalamic suprachiasmatic (SCN) clock contains several neurochemically defined cell groups that contribute to the genesis of circadian rhythms. Using cell-specific and genetically targeted approaches we have confirmed an indispensable role for vasoactive intestinal polypeptide-expressing SCN (SCN(VIP)) neurons, including their molecular clock, in generating the mammalian locomotor activity (LMA) circadian rhythm. Optogenetic-assisted circuit mapping revealed functional, di-synaptic connectivity between SCN(VIP) neurons and dorsomedial hypothalamic neurons, providing a circuit substrate by which SCN(VIP) neurons may regulate LMA rhythms. In vivo photometry revealed that while SCN(VIP) neurons are acutely responsive to light, their activity is otherwise behavioral state invariant. Single-nuclei RNA-sequencing revealed that SCN(VIP) neurons comprise two transcriptionally distinct subtypes, including putative pacemaker and non-pacemaker populations. Altogether, our work establishes necessity of SCN(VIP) neurons for the LMA circadian rhythm, elucidates organization of circadian outflow from and modulatory input to SCN(VIP) cells, and demonstrates a subpopulation-level molecular heterogeneity that suggests distinct functions for specific SCN(VIP) subtypes

Variations in national availability of waivered buprenorphine prescribers by racial and ethnic composition of zip codes

Background Opioid overdose remains a public health crisis in diverse communities. Between 2019 and 2020, there was an almost 40% increase in drug fatalities primarily due to opioid analogues of both stimulants and opioids. Medications for opioid use disorder (MOUD; e.g., buprenorphine) are effective, evidence-based treatments that can be delivered in office-based primary care settings. We investigated disparities in the proportion of national prescribers who have obtained a waiver issued to prescribe MOUD by demographic characteristics. Methods Data for the secondary data analyses were obtained from the Drug Enforcement Administration that maintains data on waivered MOUD prescribers across the US. Proportion of waivered prescribers were examined by ZIP code, race and ethnicity composition, socioeconomic status, insurance, and urban–rural designation using generalized linear mixed effects models. Results Compared with predominantly Non-Hispanic White ZIP codes, other racially and ethnically diverse areas had a higher proportion of waivered buprenorphine prescribers. Differences in prescriber availability between predominant racial group was dependent on rurality based on the interaction found in our fitted model. In metropolitan areas, we found that predominantly Non-Hispanic White ZIP codes had a lower rate of waivered prescribers compared to predominantly Black/African American ZIP codes. Conclusions Our findings suggest that among AI/AN and Black/African American neighborhoods, availability of waivered prescribers may not be a primary barrier. However, availability of waivered prescribers and prescribing might potentially be an obstacle for Hispanic/Latinx and rural communities. Additional research to determine factors related to improving MOUD availability among diverse communities therefore remains vital to advancing health equity

Intermittent versus Continuous Androgen Deprivation in Prostate Cancer

BackgroundCastration resistance occurs in most patients with metastatic hormone-sensitive prostate cancer who are receiving androgen-deprivation therapy. Replacing androgens before progression of the disease is hypothesized to prolong androgen dependence.MethodsMen with newly diagnosed, metastatic, hormone-sensitive prostate cancer, a performance status of 0 to 2, and a prostate-specific antigen (PSA) level of 5 ng per milliliter or higher received a luteinizing hormone-releasing hormone analogue and an antiandrogen agent for 7 months. We then randomly assigned patients in whom the PSA level fell to 4 ng per milliliter or lower to continuous or intermittent androgen deprivation, with patients stratified according to prior or no prior hormonal therapy, performance status, and extent of disease (minimal or extensive). The coprimary objectives were to assess whether intermittent therapy was noninferior to continuous therapy with respect to survival, with a one-sided test with an upper boundary of the hazard ratio of 1.20, and whether quality of life differed between the groups 3 months after randomization.ResultsA total of 3040 patients were enrolled, of whom 1535 were included in the analysis: 765 randomly assigned to continuous androgen deprivation and 770 assigned to intermittent androgen deprivation. The median follow-up period was 9.8 years. Median survival was 5.8 years in the continuous-therapy group and 5.1 years in the intermittent-therapy group (hazard ratio for death with intermittent therapy, 1.10; 90% confidence interval, 0.99 to 1.23). Intermittent therapy was associated with better erectile function and mental health (P&lt;0.001 and P=0.003, respectively) at month 3 but not thereafter. There were no significant differences between the groups in the number of treatment-related high-grade adverse events.ConclusionsOur findings were statistically inconclusive. In patients with metastatic hormone-sensitive prostate cancer, the confidence interval for survival exceeded the upper boundary for noninferiority, suggesting that we cannot rule out a 20% greater risk of death with intermittent therapy than with continuous therapy, but too few events occurred to rule out significant inferiority of intermittent therapy. Intermittent therapy resulted in small improvements in quality of life. (Funded by the National Cancer Institute and others; ClinicalTrials.gov number, NCT00002651.)