Characterizing physiological and symptomatic variation in menstrual cycles using self-tracked mobile health data

The menstrual cycle is a key indicator of overall health for women of reproductive age. Previously, menstruation was primarily studied through survey results; however, as menstrual tracking mobile apps become more widely adopted, they provide an increasingly large, content-rich source of menstrual health experiences and behaviors over time. By exploring a database of user-tracked observations from the Clue app by BioWink of over 378,000 users and 4.9 million natural cycles, we show that self-reported menstrual tracker data can reveal statistically significant relationships between per-person cycle length variability and self-reported qualitative symptoms. A concern for self-tracked data is that they reflect not only physiological behaviors, but also the engagement dynamics of app users. To mitigate such potential artifacts, we develop a procedure to exclude cycles lacking user engagement, thereby allowing us to better distinguish true menstrual patterns from tracking anomalies. We uncover that women located at different ends of the menstrual variability spectrum, based on the consistency of their cycle length statistics, exhibit statistically significant differences in their cycle characteristics and symptom tracking patterns. We also find that cycle and period length statistics are stationary over the app usage timeline across the variability spectrum. The symptoms that we identify as showing statistically significant association with timing data can be useful to clinicians and users for predicting cycle variability from symptoms or as potential health indicators for conditions like endometriosis. Our findings showcase the potential of longitudinal, high-resolution self-tracked data to improve understanding of menstruation and women's health as a whole.Comment: The Supplementary Information for this work, as well as the code required for data pre-processing and producing results is available in https://github.com/iurteaga/menstrual_cycle_analysi

Recognizing normal reproductive biology: A comparative analysis of variability in menstrual cycle biomarkers in German and Bolivian women

The idealized “normal” menstrual cycle typically comprises a coordinated ebb and flow of hormones over a 28-day span with ovulation invariably shown at the midpoint. It's a pretty picture—but rare. Systematic studies have debunked the myth that cycles occur regularly about every 28 days. However, assumptions persist regarding the extent and normalcy of variation in other cycle biomarkers. The processes of judging which phenotypic variants are “normal” is context dependent. In everyday life, normal is that which is most commonly seen. In biomedicine normal is often defined as an arbitrarily bounded portion of the phenotype's distribution about its statistical mean. Standards thus defined in one population are problematic when applied to other populations; population specific standards may also be suspect. Rather, recognizing normal female reproductive biology in diverse human populations requires specific knowledge of proximate mechanisms and functional context. Such efforts should be grounded in an empirical assessment of phenotypic variability. We tested hypotheses regarding cycle biomarker variability in women from a wealthy industrialized population (Germany) and a resource-limited rural agropastoral population (Bolivia). Ovulatory cycles in both samples displayed marked but nonetheless comparable variability in all cycle biomarkers and similar means/medians for cycle and phase lengths. Notably, cycle and phase lengths are poor predictors of mid-luteal progesterone concentrations. These patterns suggest that global and local statistical criteria for “normal” cycles would be difficult to define. A more productive approach involves elucidating the causes of natural variation in ovarian cycling and its consequences for reproductive success and women's health

The AE4 transporter mediates kidney acid-base sensing

The kidney plays a key role in the correction of systemic acid-base imbalances. Central for this regulation are the intercalated cells in the distal nephron, which secrete acid or base into the urine. How these cells sense acid-base disturbances is a long-standing question. Intercalated cells exclusively express the Na$^{+}$-dependent Cl$^{−}$/HCO$_{3}$$^{−}$ exchanger AE4 (Slc4a9). Here we show that AE4-deficient mice exhibit a major dysregulation of acid-base balance. By combining molecular, imaging, biochemical and integrative approaches, we demonstrate that AE4-deficient mice are unable to sense and appropriately correct metabolic alkalosis and acidosis. Mechanistically, a lack of adaptive base secretion via the Cl$^{−}$/HCO$_{3}$$^{−}$ exchanger pendrin (Slc26a4) is the key cellular cause of this derailment. Our findings identify AE4 as an essential part of the renal sensing mechanism for changes in acid-base status

Sailing into a dilemma : an economic and legal analysis of an EU trading scheme for maritime emissions

On the basis of a joint economic and legal analysis, we evaluate the effects of a “regional” (European) emission trading scheme aiming at reducing emissions of international shipping. The focus lies on the question which share of emissions from maritime transport activities to and from the EU can and should be included in such a system. Our findings suggest that the attempt to implement an EU maritime ETS runs into a dilemma. It is not possible to design a system that achieves emission reductions in a cost efficient manner and is compatible with international law

Disruption of vascular Ca2+-activated chloride currents lowers blood pressure

High blood pressure is the leading risk factor for death worldwide. One of the hallmarks is a rise of peripheral vascular resistance, which largely depends on arteriole tone. Ca2+-activated chloride currents (CaCCs) in vascular smooth muscle cells (VSMCs) are candidates for increasing vascular contractility. We analyzed the vascular tree and identified substantial CaCCs in VSMCs of the aorta and carotid arteries. CaCCs were small or absent in VSMCs of medium-sized vessels such as mesenteric arteries and larger retinal arterioles. In small vessels of the retina, brain, and skeletal muscle, where contractile intermediate cells or pericytes gradually replace VSMCs, CaCCs were particularly large. Targeted disruption of the calcium-activated chloride channel TMEM16A, also known as ANO1, in VSMCs, intermediate cells, and pericytes eliminated CaCCs in all vessels studied. Mice lacking vascular TMEM16A had lower systemic blood pressure and a decreased hypertensive response following vasoconstrictor treatment. There was no difference in contractility of medium-sized mesenteric arteries; however, responsiveness of the aorta and small retinal arterioles to the vasoconstriction-inducing drug U46619 was reduced. TMEM16A also was required for peripheral blood vessel contractility, as the response to U46619 was attenuated in isolated perfused hind limbs from mutant mice. Out data suggest that TMEM16A plays a general role in arteriolar and capillary blood flow and is a promising target for the treatment of hypertension

Side effects and the need for secrecy: characterising discontinuation of modern contraception and its causes in Ethiopia using mixed methods

Background: Contraceptive discontinuation is a major barrier to reducing global unmet needs for family planning, but the reasons why women discontinue contraception are poorly understood. Here we use data from Ethiopia to investigate (i) the magnitude of contraceptive discontinuation in 2005-2011, (ii) how the risk of discontinuation varies with method type and education level and (iii) the barriers to continuation. Our main hypothesis is that contraceptive discontinuation is driven by the experience of physiological side-effects associated with the use of hormonal contraception, rather than a lack of formal education. Methods: We used a mixed methods explanatory sequential design to explain the quantitative results in more details through the qualitative data. First, we analysed quantitative data from the 2011 Ethiopian Demographic and Health Survey to study patterns of contraceptive discontinuation and method choice using multilevel multiprocess models. Second, we conducted semi-structured interviews and focus group discussions in the 3 most populated regions of Ethiopia with individuals of reproductive age and health professionals. Results: The analysis of EDHS data shows that the rate of discontinuation has not reduced in the period 2005-2011 and remains high. Discontinuation mainly takes the form of abandonment, and is a function of method type, age and wealth but not of educational level. Interviews with women and health professionals reveal that the experience of debilitating physiological side effects, the need for secrecy and poverty are important barriers to continuation. Conclusions: Our findings together suggest that physiological and social side-effects of contraceptive use, not a lack of formal education, are the root causes of contraceptive abandonment in Ethiopia. </p

Role of serum S100B and PET-CT in follow-up of patients with cutaneous melanoma

<p>Abstract</p> <p>Background</p> <p>Increased level of serum S100B can serve as a marker of metastatic spread in patients with cutaneous melanoma (CM). In patients with elevated S100 B and/or clinical signs of disease progression PET-CT scan is a valuable tool for discovering metastases and planning treatment.</p> <p>The aims of this study were to determine whether regular measurements of serum S100B are a useful tool for discovering patients with CM metastases and to evaluate the diagnostic value of PET-CT during the follow-up.</p> <p>Methods</p> <p>From September 2007 to February 2010, 115 CM patients included in regular follow up at the Institute of Oncology Ljubljana were appointed to PET-CT. There were 82 (71.3%) patients with clinical signs of disease progression and 33 (28.7%) asymptomatic patients with two subsequent elevated values of S100B. Sensitivity, specificity, positive and negative predictive value (PPV, NPV) of S100B and PET-CT were calculated using standard procedures.</p> <p>Results</p> <p>Disease progression was confirmed in 81.7% of patients (in 86.5% of patients with clinical signs of disease progression and in 69.7% of asymptomatic patients with elevated S100B). Sensitivity, specificity, PPV and NPV of S100B was 33.8%, 90.9%, 96.0% and 17.5% in patients with clinical signs of disease progression. In 20.0% of patients increased serum S100B was the only sign of disease progression. Sensitivity and PPV of S100 in this group of patients were 100.0% and 69.7%.</p> <p>With PET-CT disease progression was diagnosed in 84.2% of symptomatic patients and in 72.7% of asymptomatic patients with elevated S100B. The sensitivity, specificity, PPV and NPV of PET-CT for symptomatic patients was 98.5%, 90.9%, 98.5% and 90.9% and 100%, 90.0%, 95.8% and 100% for asymptomatic patients with elevated S100.</p> <p>Conclusions</p> <p>Measurements of serum S100B during regular follow-up of patients with CM are a useful tool for discovering disease progression in asymptomatic patients. The value of its use increases if measurements are followed by extended whole body PET-CT.</p

Childhood socioeconomic position and objectively measured physical capability levels in adulthood: a systematic review and meta-analysis

&lt;p&gt;&lt;b&gt;Background:&lt;/b&gt; Grip strength, walking speed, chair rising and standing balance time are objective measures of physical capability that characterise current health and predict survival in older populations. Socioeconomic position (SEP) in childhood may influence the peak level of physical capability achieved in early adulthood, thereby affecting levels in later adulthood. We have undertaken a systematic review with meta-analyses to test the hypothesis that adverse childhood SEP is associated with lower levels of objectively measured physical capability in adulthood.&lt;/p&gt; &lt;p&gt;&lt;b&gt;Methods and Findings:&lt;/b&gt; Relevant studies published by May 2010 were identified through literature searches using EMBASE and MEDLINE. Unpublished results were obtained from study investigators. Results were provided by all study investigators in a standard format and pooled using random-effects meta-analyses. 19 studies were included in the review. Total sample sizes in meta-analyses ranged from N = 17,215 for chair rise time to N = 1,061,855 for grip strength. Although heterogeneity was detected, there was consistent evidence in age adjusted models that lower childhood SEP was associated with modest reductions in physical capability levels in adulthood: comparing the lowest with the highest childhood SEP there was a reduction in grip strength of 0.13 standard deviations (95% CI: 0.06, 0.21), a reduction in mean walking speed of 0.07 m/s (0.05, 0.10), an increase in mean chair rise time of 6% (4%, 8%) and an odds ratio of an inability to balance for 5s of 1.26 (1.02, 1.55). Adjustment for the potential mediating factors, adult SEP and body size attenuated associations greatly. However, despite this attenuation, for walking speed and chair rise time, there was still evidence of moderate associations.&lt;/p&gt; &lt;p&gt;&lt;b&gt;Conclusions:&lt;/b&gt; Policies targeting socioeconomic inequalities in childhood may have additional benefits in promoting the maintenance of independence in later life.&lt;/p&gt

Towards Protein Crystallization as a Process Step in Downstream Processing of Therapeutic Antibodies: Screening and Optimization at Microbatch Scale

Crystallization conditions of an intact monoclonal IgG4 (immunoglobulin G, subclass 4) antibody were established in vapor diffusion mode by sparse matrix screening and subsequent optimization. The procedure was transferred to microbatch conditions and a phase diagram was built showing surprisingly low solubility of the antibody at equilibrium. With up-scaling to process scale in mind, purification efficiency of the crystallization step was investigated. Added model protein contaminants were excluded from the crystals to more than 95%. No measurable loss of Fc-binding activity was observed in the crystallized and redissolved antibody. Conditions could be adapted to crystallize the antibody directly from concentrated and diafiltrated cell culture supernatant, showing purification efficiency similar to that of Protein A chromatography. We conclude that crystallization has the potential to be included in downstream processing as a low-cost purification or formulation step

Neurochemical Architecture of the Central Complex Related to Its Function in the Control of Grasshopper Acoustic Communication

The central complex selects and coordinates the species- and situation-specific song production in acoustically communicating grasshoppers. Control of sound production is mediated by several neurotransmitters and modulators, their receptors and intracellular signaling pathways. It has previously been shown that muscarinic cholinergic excitation in the central complex promotes sound production whereas both GABA and nitric oxide/cyclic GMP signaling suppress its performance. The present immunocytochemical and pharmacological study investigates the question whether GABA and nitric oxide mediate inhibition of sound production independently. Muscarinic ACh receptors are expressed by columnar output neurons of the central complex that innervate the lower division of the central body and terminate in the lateral accessory lobes. GABAergic tangential neurons that innervate the lower division of the central body arborize in close proximity of columnar neurons and thus may directly inhibit these central complex output neurons. A subset of these GABAergic tangential neurons accumulates cyclic GMP following the release of nitric oxide from neurites in the upper division of the central body. While sound production stimulated by muscarine injection into the central complex is suppressed by co-application of sodium nitroprusside, picrotoxin-stimulated singing was not affected by co-application of this nitric oxide donor, indicating that nitric oxide mediated inhibition requires functional GABA signaling. Hence, grasshopper sound production is controlled by processing of information in the lower division of the central body which is subject to modulation by nitric oxide released from neurons in the upper division