Atomic clocks occupy a unique position in measurement science, exhibiting higher accuracy than any other measurement standard and underpinning six out of seven base units in the SI system. By ...exploiting higher resonance frequencies, optical atomic clocks now achieve greater stability and lower frequency uncertainty than existing primary standards. Here, we report frequency ratios of the \(^{27}\)Al\(^+\), \(^{171}\)Yb and \(^{87}\)Sr optical clocks in Boulder, Colorado, measured across an optical network spanned by both fiber and free-space links. These ratios have been evaluated with measurement uncertainties between \(6\times10^{-18}\) and \(8\times10^{-18}\), making them the most accurate reported measurements of frequency ratios to date. This represents a critical step towards redefinition of the SI second and future applications such as relativistic geodesy and tests of fundamental physics.
Despite seasonal cholera outbreaks in Bangladesh, little is known about the relationship between environmental conditions and cholera cases. We seek to develop a predictive model for cholera ...outbreaks in Bangladesh based on environmental predictors. To do this, we estimate the contribution of environmental variables, such as water depth and water temperature, to cholera outbreaks in the context of a disease transmission model. We implement a method which simultaneously accounts for disease dynamics and environmental variables in a Susceptible-Infected-Recovered-Susceptible (SIRS) model. The entire system is treated as a continuous-time hidden Markov model, where the hidden Markov states are the numbers of people who are susceptible, infected, or recovered at each time point, and the observed states are the numbers of cholera cases reported. We use a Bayesian framework to fit this hidden SIRS model, implementing particle Markov chain Monte Carlo methods to sample from the posterior distribution of the environmental and transmission parameters given the observed data. We test this method using both simulation and data from Mathbaria, Bangladesh. Parameter estimates are used to make short-term predictions that capture the formation and decline of epidemic peaks. We demonstrate that our model can successfully predict an increase in the number of infected individuals in the population weeks before the observed number of cholera cases increases, which could allow for early notification of an epidemic and timely allocation of resources.
In October 2019, Novartis launched brolucizumab, a single-chain variable fragment molecule targeting vascular endothelial growth factor A, for the treatment of neovascular age-related macular ...degeneration. In 2020, rare cases of retinal vasculitis and/or retinal vascular occlusion (RV/RO) were reported, often during the first few months after treatment initiation, consistent with a possible immunologic pathobiology. This finding was inconsistent with preclinical studies in cynomolgus monkeys that demonstrated no drug-related intraocular inflammation, or RV/RO, despite the presence of preexisting and treatment-emergent antidrug antibodies (ADAs) in some animals. In this study, the immune response against brolucizumab in humans was assessed using samples from clinical trials and clinical practice. In the brolucizumab-naïve population, anti-brolucizumab ADA responses were detected before any treatment, which was supported by the finding that healthy donors can harbor brolucizumab-specific B cells. This suggested prior exposure of the immune system to proteins with structural similarity. Experiments on samples showed that naïve and brolucizumab-treated ADA-positive patients developed a class-switched, high-affinity immune response, with several linear epitopes being recognized by ADAs. Only patients with RV/RO showed a meaningful T cell response upon recall with brolucizumab. Further studies in cynomolgus monkeys preimmunized against brolucizumab with adjuvant followed by intravitreal brolucizumab challenge demonstrated that high ADA titers were required to generate ocular inflammation and vasculitis/vascular thrombosis, comparable to RV/RO in humans. Immunogenicity therefore seems to be a prerequisite to develop RV/RO. However, because only 2.1% of patients with ADA develop RV/RO, additional factors must play a role in the development of RV/RO.
Immunogenicity against intravitreally administered brolucizumab has been previously described and associated with cases of severe intraocular inflammation, including retinal vasculitis/retinal ...vascular occlusion (RV/RO). The presence of antidrug antibodies (ADAs) in these patients led to the initial hypothesis that immune complexes could be key mediators. Although the formation of ADAs and immune complexes may be a prerequisite, other factors likely contribute to some patients having RV/RO, whereas the vast majority do not. To identify and characterize the mechanistic drivers underlying the immunogenicity of brolucizumab and the consequence of subsequent ADA-induced immune complex formation, a translational approach was performed to bridge physicochemical characterization, structural modeling, sequence analysis, immunological assays, and a quantitative systems pharmacology model that mimics physiological conditions within the eye. This approach revealed that multiple factors contributed to the increased immunogenic potential of brolucizumab, including a linear epitope shared with bacteria, non-natural surfaces due to the single-chain variable fragment format, and non-native drug species that may form over prolonged time in the eye. Consideration of intraocular drug pharmacology and disease state in a quantitative systems pharmacology model suggested that immune complexes could form at immunologically relevant concentrations modulated by dose intensity. Assays using circulating immune cells from treated patients or treatment-naïve healthy volunteers revealed the capacity of immune complexes to trigger cellular responses such as enhanced antigen presentation, platelet aggregation, endothelial cell activation, and cytokine release. Together, these studies informed a mechanistic understanding of the clinically observed immunogenicity of brolucizumab and associated cases of RV/RO.
Background
Some Canadians have limited access to longitudinal primary care, despite its known advantages for population health. Current initiatives to transform primary care aim to increase access to ...team-based primary care clinics. However, many regions lack a reliable method to enumerate clinics, limiting estimates of clinical capacity and ongoing access gaps. A region-based complete clinic list is needed to effectively describe clinic characteristics and to compare primary care outcomes at the clinic level.
Objective
The objective of this study is to show how publicly available data sources, including the provincial physician license registry, can be used to generate a verifiable, region-wide list of primary care clinics in British Columbia, Canada, using a process named the Clinic List Algorithm (CLA).
Methods
The CLA has 10 steps: (1) collect data sets, (2) develop clinic inclusion and exclusion criteria, (3) process data sets, (4) consolidate data sets, (5) transform from list of physicians to initial list of clinics, (6) add additional metadata, (7) create working lists, (8) verify working lists, (9) consolidate working lists, and (10) adjust processing steps based on learnings.
Results
The College of Physicians and Surgeons of British Columbia Registry contained 13,726 physicians, at 2915 unique addresses, 6942 (50.58%) of whom were family physicians (FPs) licensed to practice in British Columbia. The CLA identified 1239 addresses where primary care was delivered by 4262 (61.39%) FPs. Of the included addresses, 84.50% (n=1047) were in urban locations, and there was a median of 2 (IQR 2-4, range 1-23) FPs at each unique address.
Conclusions
The CLA provides a region-wide description of primary care clinics that improves on simple counts of primary care providers or self-report lists. It identifies the number and location of primary care clinics and excludes primary care providers who are likely not providing community-based primary care. Such information may be useful for estimates of capacity of primary care, as well as for policy planning and research in regions engaged in primary care evaluation or transformation.
Abstract only
Introduction:
It is estimated that by 2020 there will be 2.6 million nonagenarians and 135,000 centenarians in the United States. The in-hospital management and disposition of these ...patients remain poorly defined.
Hypothesis:
We describe in-hospital management and disposition of patients over the age of 90 years presenting with an acute coronary syndrome (ACS) at a tertiary medical center.
Methods:
All patients admitted between January 1, 2008 to December 31, 2012 with the diagnosis of an ACS and are over the age of 90 were included in this study. Demographic, clinical variables, in-hospital treatment, and post-hospital disposition were reviewed from medical records. The use of aspirin (ASA), beta-blockers, statins, ACEI/ARB, clopidogrel and aggressive versus conservative management were recorded.
Results:
109 patients (13.9% males) were included. Demographics and clinical variables were as follows: Prior CAD 63.3%, prior MI 25.7%, renal insufficiency 33%, HT 80.7%, hyperlipidemia 45%, DM 23.9%, heart failure 30.3%, dementia 15.6%, smoking history 21.1%, and atrial fibrillation 22%. Patients were admitted from home 50.9%, nursing home/assisted living 35.2%, transfer from a local cath lab 12% and from primary care physician’s office 1.2%. ACS symptoms consisted of UA 23.9%, NSTEMI 65.4%, STEMI 11%. Coronary intervention was performed in 43.5%. Conservative management was driven by: dementia 4.6%, patient or family wishes 34.2%, physician 13%, non-treatable disease 4.6%. Pharmacologic management on discharge included ASA 82.1%, beta blockers 72%, statins 41.1%, ACEI 31.5%, ARB 8.3%, clopidogrel 52.4%. In-hospital mortality was 8.4% (cardiac related 7.5%) and length of hospital stay was 4.8 ± 4 days. Patients were discharged to home with visiting nurse (VN) support 30.1%, without VN 7.8%, to a family member’s home 4.9%, nursing home 29.1%, skilled nursing/rehabilitation 15.5%, and hospice 5.8%.
Conclusions:
In-hospital mortality rates of patients over the age of 90 is acceptable. Frequently these patients are treated with PCI. Conservative management is mostly guided by the patient and family wishes. Unfortunately, these patients remain markedly undertreated with standard post MI or UA drugs. Less than half of these patients returned home.
