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Abstract Oral Janus kinase inhibitors (JAKi), a class of advanced targeted systemic therapy, have demonstrated efficacy and safety in the treatment of moderate-to-severe atopic dermatitis (AD). Like other small molecules, oral JAKi have the potential for off-target effects including laboratory-related adverse events (AEs). Product labels for oral JAKi recommend an initial laboratory assessment and follow-up 4–12 weeks later to monitor for potential changes, based on evidence from clinical trials across therapeutic indications for oral JAKi, which may not reflect a population of moderate-to-severe AD patients typically seen in routine clinical practice. To address this gap, a panel of eight dermatologists with clinical and research experience with oral JAKi for the management of AD conducted a targeted review of the literature focused on key laboratory-related AEs associated with oral JAKi in the moderate-to-severe AD population. Based on the synthesis of evidence and informed opinion, a set of best practice statements related to fundamental standards of care and consensus recommendations on laboratory monitoring were suggested, and level of agreement was ascertained using a Likert scale from 0 to 100. There was a high level of agreement on three of the four suggested recommendations related to assessment and monitoring of key laboratory parameters and to dose reduction or switching in response to laboratory changes; there was a lower level of agreement related to the frequency of ongoing laboratory monitoring. Appropriate patient selection and laboratory assessment is an important strategy to mitigate the potential risks associated with oral JAKi when treating AD.

Abstract Introduction An expert panel of Canadian dermatologists was assembled to develop consensus statements regarding the current landscape of topical therapies for plaque psoriasis and the place in therapy of the recently approved fixed-dose combination halobetasol propionate (HP)/tazarotene (TAZ) lotion (HP/TAZ) in the treatment algorithm for plaque psoriasis. Method A modified nominal group technique, which combined both independent and group input from the expert panel, was used to develop the consensus statements. The expert panel completed surveys to elicit their independent views on the current landscape of topical therapies for plaque psoriasis in Canada. The first expert panel session was held to discuss the existing body of literature and develop draft consensus statements about topical therapies and the place in therapy of HP/TAZ. Independent feedback on the draft consensus statements was solicited from expert panel members prior to another expert panel session where the amended consensus statements were further discussed, edited and, finally, voted on. Results The expert panel reached consensus on 20 statements. Conclusion Expert panel members agreed, based on the existing body of literature, that there is a place in therapy for HP/TAZ to address several current unmet treatment needs of patients with plaque psoriasis. Studies have shown that HP/TAZ is an effective and safe first-line treatment for moderate-to-severe plaque psoriasis. Due to its cosmetically pleasing vehicle and once-daily administration, HP/TAZ may improve patient acceptance and treatment adherence.

It is crucial to increase the resilience of the global food production and distribution systems against the growing concerns relating to factors that could cause global catastrophic infrastructure losses, such as nuclear war or a worldwide pandemic. Currently, such an event would result in the global loss of industry, including the ability to drill and refine crude oil. In such an event, the existing above-ground reserves of diesel and gasoline are likely to still be intact but would only be able to power the production and transportation of food between 158 days and 481 days with 80% confidence, where the mean is 195 days at current rates. This paper investigates a novel group of interventions in relation to the scenario of providing food under these conditions. It was found that by using a plausible combination of wood gasification, increasing vehicle utilisation rate, and reducing food consumption, the stockpile duration could increase to between 382 days and 1501 days with 80% confidence, where the mean is 757 days. This is an improvement in mean duration by a factor of 3.9. It was discovered that diesel is the limiting fuel in all scenarios due to wood gas only being a partial replacement for diesel fuel and also because of the prevalence of diesel engines in both the agricultural and trucking industries. A sensitivity analysis was completed identifying that reducing food consumption to minimum levels was the most effective method to prolong diesel reserves. The other factors that benefited from extending fuel reserves in terms of their effectiveness are reducing the lag time before gasification devices are installed, increasing the rate at which gasification devices are installed, and increasing the agricultural equipment utilisation rate.

A refined analytical model of spatially resolved diffuse reflectance with small source-detector separations (SDSs) for the in vivo skin studies is proposed. Compared to the conventional model developed by Farrell et al., it accounts for the limited acceptance angle of the detector fiber. The refined model is validated in the wide range of optical parameters by Monte Carlo simulations of skin diffuse reflectance at SDSs of units of mm. Cases of uniform dermis and two-layered epidermis-dermis structures are studied. Higher accuracy of the refined model compared to the conventional one is demonstrated in the separate, constraint-free reconstruction of absorption and reduced scattering spectra of uniform dermis from the Monte Carlo simulated data. In the case of epidermis-dermis geometry, the recovered values of reduced scattering in dermis are overestimated and the recovered values of absorption are underestimated for both analytical models. Presumably, in the presence of a thin mismatched topical layer, only the effective attenuation coefficient of the bottom layer can be accurately recovered using a diffusion theory-based analytical model while separate reconstruction of absorption and reduced scattering fails due to the inapplicability of the method of images. These findings require implementation of more sophisticated models of light transfer in inhomogeneous media in the recovery algorithms.

IntroductionHidradenitis suppurativa (HS) is a chronic, immune-mediated skin condition characterized by inflammatory lesions that can cause pain, impaired physical activity, and reduced quality of life. This study evaluated the efficacy and safety of risankizumab, a humanized immunoglobulin G1 monoclonal antibody that specifically inhibits interleukin 23 by binding to its p19 subunit, for the treatment of HS.MethodsThis phase II multicenter, randomized, placebo-controlled, double-blind study investigated the efficacy and safety of risankizumab in patients with moderate-to-severe HS. Patients were randomized 1:1:1 to receive subcutaneous risankizumab 180 mg; risankizumab 360 mg; or placebo at weeks 0, 1, 2, 4, and 12. Patients initially randomized to placebo received blinded risankizumab 360 mg at weeks 16, 17, and 18; patients initially randomized to risankizumab received blinded matching placebo at the same time points. From weeks 20-60, all patients received open-label risankizumab 360 mg every 8 weeks. The primary endpoint was the achievement of HS Clinical Response (HiSCR) at week 16. Safety was assessed by monitoring of treatment-emergent adverse events (TEAEs).ResultsA total of 243 patients were randomized (risankizumab 180 mg, n = 80; risankizumab 360 mg, n = 81; placebo, n = 82). HiSCR was achieved by 46.8% of patients with risankizumab 180 mg, 43.4% with risankizumab 360 mg, and 41.5% with placebo at week 16. The primary endpoint was not met, and the study was terminated early. Incidence of TEAEs, severe TEAEs, TEAEs considered possibly related to study drug, and TEAEs leading to discontinuation of study drug were generally low and comparable across treatment groups.ConclusionRisankizumab does not appear to be an efficacious treatment for moderate-to-severe HS. Future studies to understand the complex molecular mechanisms underlying HS pathogenesis and develop improved therapies are warranted.Trial registrationClinicalTrials.gov identifier: NCT03926169.

This is a review of Foundations of Real-World Economics, 3rd edition, by John Komlos (Routledge, 2023)

Abstract Archaeological evidence suggests that the population dynamics of Mid-Holocene (Late Mesolithic to Initial Bronze Age, ca. 7000–3000 BCE) Europe are characterized by recurrent booms and busts of regional settlement and occupation density. These boom-bust patterns are documented in the temporal distribution of 14C dates and in archaeological settlement data from regional studies. We test two competing hypotheses attempting to explain these dynamics: climate forcing and social dynamics leading to inter-group conflict. Using the framework of spatially-explicit agent-based models, we translated these hypotheses into a suite of explicit computational models, derived quantitative predictions for population fluctuations, and compared these predictions to data. We demonstrate that climate variation during the European Mid-Holocene is unable to explain the quantitative features (average periodicities and amplitudes) of observed boom-bust dynamics. In contrast, scenarios with social dynamics encompassing density-dependent conflict produce population patterns with time scales and amplitudes similar to those observed in the data. These results suggest that social processes, including violent conflict, played a crucial role in the shaping of population dynamics of European Mid-Holocene societies.

Abstract Background Obesity is associated with an increased risk of multiple conditions, ranging from heart disease to cancer. However, there are few predictive models for these outcomes that have been developed specifically for people with overweight/obesity. Objective To develop predictive models for obesity‐related complications in patients with overweight and obesity. Methods Electronic health record data of adults with body mass index 25–80 kg/m2 treated in primary care practices between 2000 and 2019 were utilized to develop and evaluate predictive models for nine long‐term clinical outcomes using a) Lasso‐Cox models and b) a machine‐learning method random survival forests (RSF). Models were trained on a training dataset and evaluated on a test dataset over 100 replicates. Parsimonious models of

Abstract Background Data entry errors are common in clinical research databases. Omitted data are of particular concern because they are more common than erroneously inserted data and therefore could potentially affect research findings. However, few affordable strategies for their prevention are available. Methods We have conducted a prospective observational study of the effect of a novel tool called "Summary Page" on the frequency of correction of omitted data errors in a radiation oncology research database between July 2008 and March 2009. "Summary Page" was implemented as an optionally accessed screen in the database that visually integrates key fields in the record. We assessed the frequency of omitted data on the example of the Date of Relapse field. We considered the data in this field to be omitted for all records that had empty Date of Relapse field and evidence of relapse elsewhere in the record. Results A total of 1,156 records were updated and 200 new records were entered in the database over the study period. "Summary Page" was accessed for 44% of all updated records and for 69% of newly entered records. Frequency of correction of the omitted date of cancer relapse was six-fold higher in records for which "Summary Page" was accessed (p = 0.0003). Conclusions "Summary Page" was strongly associated with an increased frequency of correction of omitted data errors. Further, controlled, studies are needed to confirm this finding and elucidate its mechanism of action.

Abstract Background Home blood pressure (BP) is closely linked to patient outcomes. However, the prevalence of its documentation has not been examined. The objective of this study was to analyze the prevalence and factors affecting documentation of home BP in routine clinical care. Methods A retrospective study of 142,973 encounters of 9,840 hypertensive patients with diabetes from 2000 to 2005 was performed. The prevalence of recorded home BP and the factors associated with its documentation were analyzed. We assessed validity of home BP information by comparing the difference between home and office BP to previously published prospective studies. Results Home BP was documented in narrative notes for 2.08% of encounters where any blood pressure was recorded and negligibly in structured data (EMR flowsheets). Systolic and diastolic home BP in narrative notes were lower than office BP readings by 9.6 and 2.5 mm Hg, respectively (p < 0.0001 for both), consistent with prospective data. Probability of home BP documentation increased by 23.0% for each 10 mm Hg of office systolic BP (p < 0.0001), by 6.2% for each $10,000 in median income of zip code (p = 0.0055), and by 17.7% for each decade in the patient's age (p < 0.0001). Conclusions Home BP readings provide a valid representation of the patient's condition, yet are seldom documented despite their potential utility in both patient care and research. Strong association between higher patient income and home BP documentation suggests that the cost of the monitors may be a limiting factor; reimbursement of home BP monitoring expenses should be pursued.

Abstract Introduction Hidradenitis suppurativa (HS) is a chronic, immune-mediated skin condition characterized by inflammatory lesions that can cause pain, impaired physical activity, and reduced quality of life. This study evaluated the efficacy and safety of risankizumab, a humanized immunoglobulin G1 monoclonal antibody that specifically inhibits interleukin 23 by binding to its p19 subunit, for the treatment of HS. Methods This phase II multicenter, randomized, placebo-controlled, double-blind study investigated the efficacy and safety of risankizumab in patients with moderate-to-severe HS. Patients were randomized 1:1:1 to receive subcutaneous risankizumab 180 mg; risankizumab 360 mg; or placebo at weeks 0, 1, 2, 4, and 12. Patients initially randomized to placebo received blinded risankizumab 360 mg at weeks 16, 17, and 18; patients initially randomized to risankizumab received blinded matching placebo at the same time points. From weeks 20–60, all patients received open-label risankizumab 360 mg every 8 weeks. The primary endpoint was the achievement of HS Clinical Response (HiSCR) at week 16. Safety was assessed by monitoring of treatment-emergent adverse events (TEAEs). Results A total of 243 patients were randomized (risankizumab 180 mg, n = 80; risankizumab 360 mg, n = 81; placebo, n = 82). HiSCR was achieved by 46.8% of patients with risankizumab 180 mg, 43.4% with risankizumab 360 mg, and 41.5% with placebo at week 16. The primary endpoint was not met, and the study was terminated early. Incidence of TEAEs, severe TEAEs, TEAEs considered possibly related to study drug, and TEAEs leading to discontinuation of study drug were generally low and comparable across treatment groups. Conclusion Risankizumab does not appear to be an efficacious treatment for moderate-to-severe HS. Future studies to understand the complex molecular mechanisms underlying HS pathogenesis and develop improved therapies are warranted. Trial Registration ClinicalTrials.gov identifier: NCT03926169.

Abstract Background Patients with treated solid tumours (TSTs) are a highly heterogeneous population at an increased risk for malignancy compared with the general population. When treating psoriasis in patients with a history of TSTs, clinicians are concerned about the immunosuppressive nature of psoriasis therapies, the possibility of augmenting cancer recurrence/progression, and infectious complications. No direct, high-level evidence exists to address these concerns. Objectives We aim to provide a structured framework supporting healthcare professional and patient discussions on the risks and benefits of systemic psoriasis therapy in patients with previously TSTs. Our goal was to address the clinically important question, “In patients with TSTs, does therapy with systemic agents used for psoriasis increase the risk of malignancy or malignancy recurrence?” Methods We implemented an inference-based approach relying on indirect evidence when direct clinical trial and real-world data were absent. We reviewed indirect evidence supporting inferences on the status of immune function in patients with TSTs. Recommendations on systemic psoriasis therapies in patients with TSTs were derived using an inferential heuristic. Results We identified five indirect indicators of iatrogenic immunosuppression informed by largely independent bodies of evidence: (1) overall survival, (2) rate of malignancies with psoriasis and systemic psoriasis therapies, (3) rate of infections with psoriasis and systemic psoriasis therapies, (4) common disease biochemical pathways for solid tumours and systemic psoriasis therapies, and (5) solid organ transplant outcomes. On the basis of review of the totality of this data, we provided inference-based conclusions and ascribed level of support for each statement. Conclusions Prior to considering new therapies for psoriasis, an understanding of cancer prognosis should be addressed. Patients with TSTs and a good cancer prognosis will have similar outcomes to non-TST patients when treated with systemic psoriasis therapies. For patients with TSTs and a poor cancer prognosis, the quality-of-life benefits of treating psoriasis may outweigh the theoretical risks.

Abstract Background Body mass index (BMI) will be a reportable health measure in the United States (US) through implementation of Healthcare Effectiveness Data and Information Set (HEDIS) guidelines. We evaluated current documentation of BMI, and documentation and control of associated risk factors by BMI category, based on electronic health records from a 12-clinic primary care network. Methods We conducted a cross-sectional analysis of 79,947 active network patients greater than 18 years of age seen between 7/05 - 12/06. We defined BMI category as normal weight (NW, 18-24.9 kg/m2), overweight (OW, 25-29.9), and obese (OB, ≥ 30). We measured documentation (yes/no) and control (above/below) of the following three risk factors: blood pressure (BP) ≤130/≤85 mmHg, low-density lipoprotein (LDL) ≤130 mg/dL (3.367 mmol/L), and fasting glucose Results BMI was documented in 48,376 patients (61%, range 34-94%), distributed as 30% OB, 34% OW, and 36% NW. Documentation of all three risk factors was higher in obesity (OB = 58%, OW = 54%, NW = 41%, p for trend Conclusions In a large primary care network BMI documentation has been incomplete and for patients with BMI measured, risk factor control has been poorer in obese patients compared with NW, even in those with obesity and CVD or diabetes. Better knowledge of BMI could provide an opportunity for improved quality in obesity care.

In the original publication [...]

This report describes the current canonical time-series dataset named “Equinox2020,” a subset of Seshat: Global History Databank data for a well-curated list of polities and variables available on the Seshat Data Browser. The report provides an introduction to the methods and procedures of the Seshat project relating to the curation and release of the Equinox2020 dataset.

A review of Escape from Rome: The Failure of Empire and the Road to Prosperity by Walter Scheidel (Princeton University Press, 2019)

Abstract Background Breast cancer neoadjuvant chemotherapy (NACT) allows for assessing tumor sensitivity to systemic treatment, planning adjuvant treatment and follow-up. However, a sufficiently large number of patients fail to achieve the desired level of pathological tumor response while optimal early response assessment methods have not been established now. In our study, we simultaneously assessed the early chemotherapy-induced changes in the tumor volume by ultrasound (US), the tumor oxygenation by diffuse optical spectroscopy imaging (DOSI), and the state of the tumor vascular bed by Doppler US to elaborate the predictive criteria of breast tumor response to treatment. Methods A total of 133 patients with a confirmed diagnosis of invasive breast cancer stage II to III admitted to NACT following definitive breast surgery were enrolled, of those 103 were included in the final analysis. Tumor oxygenation by DOSI, tumor volume by US, and tumor vascularization by Doppler US were determined before the first and second cycle of NACT. After NACT completion, patients underwent surgery followed by pathological examination and assessment of the pathological tumor response. On the basis of these, data regression predictive models were created. Results We observed changes in all three parameters 3 weeks after the start of the treatment. However, a high predictive potential for early assessment of tumor sensitivity to NACT demonstrated only the level of oxygenation, ΔStO2, (ρ = 0.802, p ≤ 0.01). The regression model predicts the tumor response with a high probability of a correct conclusion (89.3%). The “Tumor volume” model and the “Vascularization index” model did not accurately predict the absence of a pathological tumor response to treatment (60.9% and 58.7%, respectively), while predicting a positive response to treatment was relatively better (78.9% and 75.4%, respectively). Conclusions Diffuse optical spectroscopy imaging appeared to be a robust tool for early predicting breast cancer response to chemotherapy. It may help identify patients who need additional molecular genetic study of the tumor in order to find the source of resistance to treatment, as well as to correct the treatment regimen.