User's manual for the sisyphus simulation environment

Journal ArticleThis report describes how to create and simulate a design with Sisyphus. Inasmuch as Sisyphus is written in Symbolics-Lisp, some familiarity with both Lisp and with Symbolics computers is presumed. In addition, the concepts presented here presume an acquaintance with [3]. First, a disclaimer ? this report is neither a user's manual nor a reference manual, but rather a combination of the two. As such, it is neither a s detailed as a reference manual, nor as conversational as a tutorial. Further, this report describes yet another hardware description language and, in this author's humble opinion, there are already far too many HDLs and hence very little justification for writing more. To quote from the eminent numerician C.W. Gear's Forsythe award lecture [1]

Closing the Loop on Morphogenesis: A Mathematical Model of Morphogenesis by Closed-Loop Reaction-Diffusion

Morphogenesis, the establishment and repair of emergent complex anatomy by groups of cells, is a fascinating and biomedically-relevant problem. One of its most fascinating aspects is that a developing embryo can reliably recover from disturbances, such as splitting into twins. While this reliability implies some type of goal-seeking error minimization over a morphogenic field, there are many gaps with respect to detailed, constructive models of such a process being used to implement the collective intelligence of cellular swarms. We describe a closed-loop negative-feedback system for creating reaction-diffusion (RD) patterns with high reliability. It uses a cellular automaton to characterize a morphogen pattern, then compares it to a goal and adjusts accordingly, providing a framework for modeling anatomical homeostasis and robust generation of target morphologies. Specifically, we create a RD pattern with N repetitions, where N is easily changeable. Furthermore, the individual repetitions of the RD pattern can be easily stretched or shrunk under genetic control to create, e.g., some morphological features larger than others. Finally, the cellular automaton uses a computation wave that scans the morphogen pattern unidirectionally to characterize the features that the negative feedback then controls. By taking advantage of a prior process asymmetrically establishing planar polarity (e.g., head vs. tail), our automaton is greatly simplified. This work contributes to the exciting effort of understanding design principles of morphological computation, which can be used to understand evolved developmental mechanisms, manipulate them in regenerative medicine settings, or embed a degree of synthetic intelligence into novel bioengineered constructs.Comment: 20 pages, 3 tables, 5 figure

Adiposity and weight change in mid-life in relation to healthy survival after age 70 in women: prospective cohort study

Objective: To examine the hypothesis that mid-life adiposity is associated with a reduced probability of maintaining an optimal health status among those who survive to older ages. Design: Prospective cohort study. Setting: The Nurses’ Health Study, United States. Participants: 17 065 women who survived until at least the age of 70, provided information on occurrence of chronic disease, cognitive function, physical function, and mental health at older ages, and were free from major chronic diseases at mid-life (mean age was 50 at baseline in 1976). Main outcome measures: Healthy survival to age 70 and over was defined as having no history of 11 major chronic diseases and having no substantial cognitive, physical, or mental limitations. Results: Of the women who survived until at least age 70, 1686 (9.9%) met our criteria for healthy survival. Increased body mass index (BMI) at baseline was significantly associated with linearly reduced odds of healthy survival compared with usual survival, after adjustment for various lifestyle and dietary variables (P<0.001 for trend). Compared with lean women (BMI 18.5-22.9), obese women (BMI ≥30) had 79% lower odds of healthy survival (odds ratio 0.21, 95% confidence interval 0.15 to 0.29). In addition, the more weight gained from age 18 until mid-life, the less likely was healthy survival after the age of 70. The lowest odds of healthy survival were among women who were overweight (BMI ≥25) at age 18 and gained ≥10 kg weight (0.18, 0.09 to 0.36), relative to women who were lean (BMI 18.5-22.9) and maintained a stable weight. Conclusions: These data provide evidence that adiposity in mid-life is strongly related to a reduced probability of healthy survival among women who live to older ages, and emphasise the importance of maintaining a healthy weight from early adulthood

Serious Illness and End‐of‐Life Treatments for Nurses Compared with the General Population

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/151285/1/jgs16044.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/151285/2/jgs16044_am.pd

Hormonal replacement therapy, prothrombotic mutations and the risk of venous thrombosis

Hormone replacement therapy (HRT) increases the risk of venous thrombosis. We investigated whether this risk is affected by carriership of hereditary prothrombotic abnormalities. Therefore, we determined the two most common prothrombotic mutations, factor V Leiden and prothrombin 20210A in women who participated in a case-control study on venous thrombosis. Relative risks were expressed as odds ratios (OR) with 95% confidence intervals (CI95). Among 7 7 women aged 45-64 years with a first venous thrombosis, 51% were receiving HRT at the time of thrombosis, compared with 24% of control women (OR = 3.3, CI95 1.8-5.8). Among the patients, 23% had a prothrombotic defect, versus 7% among the control women (OR = 3.8, CI95 1.7- 8.5). Women who had factor V Leiden and used HRT had a 15-fold increased risk (OR = 15.5, CI95 3.1-77), which exceeded the expected joint odds ratio of 6.1 (under an additive model). We conclude that the thrombotic risk of HRT may particularly affect women with prothrombotic mutations. Efforts to avoid HRT in women with increased risk of thrombosis are advisable

Glucose absorption during continuous ambulatory peritoneal dialysis

Glucose absorption during continuous ambulatory peritoneal dialysis. Patients undergoing continuous ambulatory peritoneal dialysis (CAPD) are exposed to a continuous infusion of glucose via their peritoneal cavity. We performed studies to quantitate the amount of energy derived from dialysate glucose. Net glucose absorption averaged 182 ± (SD) 61 g/day in 19 studies with a dialysate dextrose concentration of 1.5 or 4.25 g/dl. The amount of glucose absorbed per liter of dialysate (y) varied with the concentration of glucose in dialysate (x), (y = 11.3x - 10.9, r = 0.96), The amount of glucose absorbed per day during a given dialysis regimen was constant. Energy intake from dialysate glucose was 8.4 ± 2.8 kcal/kg of body wt per day, or 12 to 34% of total energy intake. This additional energy may contribute to the anabolic effect reported during CAPD. The ability to vary glucose absorption by altering the dialysate glucose concentration may prove a useful tool to modify energy intake.Absorption de glucose au cours de la dialyse péritonéale continue ambulatoire. Les malades soumis à la dialyse péritonéale continue ambulatoire (CAPD) sont exposés à une administration continue de glucose via leur cavité péritonéale. La quantité d'énergie qui dérive du glucose du dialysat a été quantifiée. L'absorption nette de glucose est en moyenne de 182 ± (SD) 61 g/jour au cours de 19 études avec un dialysat contenant du dextrose, 1,5 ou 4,25 g/dl. La quantité de glucose absorbée par litre de dialysat (y) varie avec la concentration de glucose dans le dialysat (x), (y = 11,3x - 10,9, r = 0,96). La quantité de glucose absorbée par jour pour un type donné de dialyse a été constante. L'entrée d'énergie à partir du glucose du dialysat était de 8,4 ± 2,8 kcal/kg de poids par jour, soit 12 à 34% de l'entrée totale d'énergie. Cette énergie supplémentaire peut contribuer à l'effet anabolique rapporté au cours de CAPD. La possibilité de faire varier l'absorption de glucose en modifiant la concentration de glucose dans le dialysat peut être un moyen utile pour influencer l'entrée d'énergie

Association of body mass index and waist circumference with successful ageing: 16 year follow-up of the Whitehall II study

Objective: We examined whether midlife body mass index (BMI) and waist circumference (WC) predict successful ageing. Design and Methods BMI/WC were assessed in 4869 persons (mean age 51.2, range 42–63 in 1991/93) and survival and successful ageing (alive, no chronic disease at age >60 years, not in the worst age- and sex-standardized quintile of cognitive, physical, respiratory, and cardiovascular, and mental health) ascertained over a 16-year follow-up, analysed using logistic regression adjusted for socio-demographic factors and health behaviours. Results: 507 participants died, 1008 met the criteria for successful ageing. Those with BMI≥30 kg/m2 had lower odds of successful ageing (Odds Ratio (OR)=0.37; 95% Confidence Interval (CI): 0.27, 0.50) and survival (OR=0.55; 95% CI: 0.41, 0.74) compared to BMI between 18.5–25 kg/m2. Those with a large waist circumference (≥102/88 cm in men/women) had lower odds of successful ageing (OR=0.41; 95% CI: 0.31, 0.54) and survival (OR=0.57; 95% CI: 0.44, 0.73) compared to those with a small waist (<94/80 cm in men/women). Analysis with finer categories showed lower odds of successful ageing starting at BMI ≥23.5 kg/m2 and waist circumference 82/68 cm in men/women. Conclusions: Optimal midlife BMI and waist circumference for successful ageing might be substantially below the current thresholds used to define obesity

Migraine and Cognitive Decline Among Women: Prospective Cohort Study

Objective: To evaluate the association between migraine and cognitive decline among women. Design Prospective cohort study. Setting Women’s Health Study, United States. Participants 6349 women aged 65 or older enrolled in the Women’s Health Study who provided information about migraine status at baseline and participated in cognitive testing during follow-up. Participants were classified into four groups: no history of migraine, migraine with aura, migraine without aura, and past history of migraine (reports of migraine history but no migraine in the year prior to baseline). Main outcome measures Cognitive testing was carried out at two year intervals up to three times using the telephone interview for cognitive status, immediate and delayed recall trials of the east Boston memory test, delayed recall trial of the telephone interview for cognitive status 10 word list, and a category fluency test. All tests were combined into a global cognitive score, and tests assessing verbal memory were combined to create a verbal memory score. Results: Of the 6349 women, 853 (13.4%) reported any migraine; of these, 195 (22.9%) reported migraine with aura, 248 (29.1%) migraine without aura, and 410 (48.1%) a past history of migraine. Compared with women with no history of migraine, those who experienced migraine with or without aura or had a past history of migraine did not have significantly different rates of cognitive decline in any of the cognitive scores: values for the rate of change of the global cognitive score between baseline and the last observation ranged from −0.01 (SE 0.04) for past history of migraine to 0.08 (SE 0.04) for migraine with aura when compared with women without any history of migraine. Women who experienced migraine were also not at increased risk of substantial cognitive decline (worst 10% of the distribution of decline). When compared with women without a history of migraine, the relative risks for the global score ranged from 0.77 (95% confidence interval 0.46 to 1.28) for women with migraine without aura to 1.17 (0.84 to 1.63) for women with a past history of migraine. Conclusion: In this prospective cohort of women, migraine status was not associated with faster rates of cognitive decline

Treatment of parvovirus B19 viremia to facilitate kidney transplantation in a patient with collapsing glomerulopathy.

Collapsing glomerulopathy (CG) is a severe form of glomerulopathy which results in nephrotic syndrome and often ensues in rapid progression to end-stage kidney disease (ESKD). Although most commonly a result of HIV infection, other conditions such as parvovirus B19 (PB19) infection have been associated with CG. We present a case of an 18-year-old male with CG associated with PB19 infection who was heterozygous for APOL1 G1 and G2 genetic variants. In an attempt to treat, he was started on intravenous immunoglobulin (IVIg), however rapidly progressed to ESKD. During workup for a living donor kidney transplant he was found to have persistent low-grade PB19 viremia. Despite having no major immunodeficiency and given subsequent courses of IVIg, viremia continued to persist. In a final attempt to eradicate the PB19 we began treatment with cidofovir, an antiviral agent with in vitro efficacy against PB19. Subsequent to initiation of cidofovir, PB19 viremia slowly cleared after which he received a living unrelated kidney transplant. The patient had an early cellular rejection treated with rabbit antithymocyte globulin after which he recovered kidney function without signs of recurrent CG. Our case report suggests efficacy of IVIg and cidofovir for persistent PB19 infection in ESKD to allow subsequent transplantation, while minimizing the risk of recurrent CG

Closing the loop on morphogenesis: a mathematical model of morphogenesis by closed-loop reaction-diffusion

Morphogenesis, the establishment and repair of emergent complex anatomy by groups of cells, is a fascinating and biomedically-relevant problem. One of its most fascinating aspects is that a developing embryo can reliably recover from disturbances, such as splitting into twins. While this reliability implies some type of goal-seeking error minimization over a morphogenic field, there are many gaps with respect to detailed, constructive models of such a process. A common way to achieve reliability is negative feedback, which requires characterizing the existing body shape to create an error signal–but measuring properties of a shape may not be simple. We show how cells communicating in a wave-like pattern could analyze properties of the current body shape. We then describe a closed-loop negative-feedback system for creating reaction-diffusion (RD) patterns with high reliability. Specifically, we use a wave to count the number of peaks in a RD pattern, letting us use a negative-feedback controller to create a pattern with N repetitions, where N can be altered over a wide range. Furthermore, the individual repetitions of the RD pattern can be easily stretched or shrunk under genetic control to create, e.g., some morphological features larger than others. This work contributes to the exciting effort of understanding design principles of morphological computation, which can be used to understand evolved developmental mechanisms, manipulate them in regenerative-medicine settings, or engineer novel synthetic morphology constructs with desired robust behavior