The Relationship between Gastrointestinal Health,Micronutrient Concentrations,and Autoimmunity: A Focus on the Thyroid

Currently, there is a lack of understanding of why many patients with thyroid dysfunction remain symptomatic despite being biochemically euthyroid. Gastrointestinal (GI) health is imperative for absorption of thyroid-specific nutrients as well as thyroid function directly. This comprehensive narrative review describes the impact of what the authors have conceptualized as the “nutrient–GI–thyroid axis”. Compelling evidence reveals how gastrointestinal health could be seen as the epicenter of thyroid-related care given that: (1) GI conditions can lower thyroid-specific nutrients; (2) GI care can improve status of thyroid-specific nutrients; (3) GI conditions are at least 45 times more common than hypothyroidism; (4) GI care can resolve symptoms thought to be from thyroid dysfunction; and (5) GI health can affect thyroid autoimmunity. A new appreciation for GI health could be the missing link to better nutrient status, thyroid status, and clinical care for those with thyroid dysfunction.     

Acceleration of peripheral nerve regeneration after crush injury in rat

It the sciatic nerve of a rat is crushed in the thigh, axons from the proximal side of the crush will regenerate so that the toe-spreading reflex becomes observable again after 10.4 +/- 1.7 (mean +/- S.D.) days. If the nerve is electrically stimulated for 0.25-1.0 h at the crush site, just after the crush occurs, the toe-spreading reflex first becomes observable 4.14 +/- 1.6 (mean +/- S.D.) days after the crush. Stimulation is most effective if delivered immediately after the crush but can be delayed up to an hour and still cause significantly faster regeneration. This phenomenon could be useful in clinical management of crushed peripheral nerves.     

Proteomic and postproteomic characterization of keratan sulfate-glycanated isoforms of thyroglobulin and transferrin uniquely elaborated by papillary thyroid carcinomas

Previous studies have suggested that surface components of papillary thyroid carcinoma (PTC) cells may be aberrantly glycanated, but the precise nature of these molecules has not been unveiled nor documented to be of clinical relevance. A monoclonal antibody was raised against a unique keratan sulfate (KS) determinant and used to differentially screen benign and malignant thyroid tissue for the expression of components carrying these moieties. In a total of 349 cases of benign and malignant thyroid lesions, 100% of the 115 PTC cases examined (including various histological subtypes) were found to contain KS-bearing molecules, whereas these were virtually absent from benign tissues and other thyroid tumors, with the exception of 21% of the follicular carcinoma cases analyzed. A composite immunoaffinity chromatography, immunochemistry, and mass spectrometric approach revealed that the PTC-specific KS-bearing macromolecules were unique glycoforms of thyroglobulin and transferrin. Combined, reciprocal immunoprecipitation and Western blotting further indicated that the former glycoform predominated and that most of the transferrin produced by PTC was glycanated with KS moieties. Fluorescent keratanase II-based fingerprinting of the KS moieties bound to these isoforms further demonstrated several PTC-specific peculiarities: 1) that a considerable portion of the moieties was covalently attached via a novel core protein linkage structure; 2) they had an unusual extended average length; 3) an unusual relative ratio of highly sulfated disaccharides terminating with alpha (2-3)-linked N-acetylneuraminic acid capping residues; and 4) a novel unidentified oligosaccharide moiety at the nonreducing terminus. Comparative analysis of the relative distribution of transferrin in benign versus PTC tissues highlighted a marked malignancy-associated abundance of the molecule, with a >75% frequency in expression in PTC. These findings demonstrate that PTC cells synthesize unique post-translationally modified thyroglobulin and transferrin variants in situ that may be directly exploitable for diagnosis, through histological and noninvasive cytological procedures; for devising novel strategies for antibody-guided imaging of this tumor in vivo; and for postsurgery follow-up of PTC patients.     

Short leucine-rich glycoproteins of the extracellular matrix display diverse patterns of complement interaction and activation

The extracellular matrix consists of structural macromolecules and other proteins with regulatory functions. An important family of the latter class of molecules found in most tissues is the small leucine-rich repeat proteins (SLRPs). We have previously shown that the SLRP fibromodulin binds directly to C1q and activates the classical pathway of complement. In the present study we further examine the interactions between SLRPs and complement. Osteoadherin, like fibromodulin, binds C1q and activates the classical pathway strongly while moderate activation is seen in the terminal pathway. This can be explained by the interaction of fibromodulin and osteoadherin with factor H, a major soluble inhibitor of complement. Also, chondroadherin was found to bind C1q and activate complement, albeit to a lesser extent. Chondroadherin also binds factor H. We confirm published data showing that biglycan and decorin bind C1q but do not activate complement. In this study a similar pattern is seen for lumican although its affinity for C1q is lower than for biglycan and decorin. Furthermore, using electron microscopy and radiolabeled SLRPs, we demonstrate two different classes of SLRP binding sites on C1q, to head and stalk respectively, where only binding to the head appears to be activating. We propose a role for SLRPs in the regulation of complement activation in diseases involving the extracellular matrix, particularly those characterized by chronic inflammation such as rheumatoid arthritis, atherosclerosis, osteoarthritis and chronic obstructive lung disease.     

Mask wearing in community settings reduces SARS-CoV-2 transmission

The effectiveness of mask wearing at controlling severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission has been unclear. While masks are known to substantially reduce disease transmission in healthcare settings [D. K. Chu et al., Lancet 395, 1973–1987 (2020); J. Howard et al., Proc. Natl. Acad. Sci. U.S.A. 118, e2014564118 (2021); Y. Cheng et al., Science eabg6296 (2021)], studies in community settings report inconsistent results [H. M. Ollila et al., medRxiv (2020); J. Brainard et al., Eurosurveillance 25, 2000725 (2020); T. Jefferson et al., Cochrane Database Syst. Rev. 11, {"type":"entrez-nucleotide","attrs":{"text":"CD006207","term_id":"30322945","term_text":"CD006207"}}CD006207 (2020)]. Most such studies focus on how masks impact transmission, by analyzing how effective government mask mandates are. However, we find that widespread voluntary mask wearing, and other data limitations, make mandate effectiveness a poor proxy for mask-wearing effectiveness. We directly analyze the effect of mask wearing on SARS-CoV-2 transmission, drawing on several datasets covering 92 regions on six continents, including the largest survey of wearing behavior (n= 20 million) [F. Kreuter et al., https://gisumd.github.io/COVID-19-API-Documentation (2020)]. Using a Bayesian hierarchical model, we estimate the effect of mask wearing on transmission, by linking reported wearing levels to reported cases in each region, while adjusting for mobility and nonpharmaceutical interventions (NPIs), such as bans on large gatherings. Our estimates imply that the mean observed level of mask wearing corresponds to a 19% decrease in the reproduction number R. We also assess the robustness of our results in 60 tests spanning 20 sensitivity analyses. In light of these results, policy makers can effectively reduce transmission by intervening to increase mask wearing.

Face masks are one of the most prominent interventions against COVID-19, with very high uptake in most countries (1). However, global mask wearing fell substantially in 2021, even in countries with low vaccination rates (Fig. 1). Given ongoing epidemics, establishing the effectiveness of mask wearing in community settings is critical. The following sections review past work on the effectiveness of mask wearing in different settings and at different scales.Open in a separate windowFig. 1.Reported mask wearing in countries with <40% of population fully vaccinated, as of 1 October 2021 [wearing from the UMD/Facebook survey (1); vaccinations from ref. 2]. The y axis is the proportion who reported that, over the last week, they wore masks most or all of the time in public spaces.In the context of healthcare, N95 masks (as defined by ref. 3) work well when worn properly by trained users—reducing transmission of coronaviruses including severe acute respiratory coronavirus syndrome 2 (SARS-CoV-2) by at least half (4, 5). Cheng et al. (6) find that ideal surgical masking (7, 8) of a noninfected person corresponds to a 65 to 75% reduction in their risk of COVID-19.However, the effect of mask wearing in small-scale community settings is more difficult to detect.In particular, four meta-analyses have summarized studies on respiratory infections, conducted in community settings (4, 9–11). They estimate mean decreases in infection risk between 4% and 15% for surgical masks, but with large uncertainty: Individual results ranged from a 7% increase in infection risk to a 61% decrease in infection risk. In addition, few of these studies are randomized controlled trials (RCTs), and those that are RCTs have considerable issues: Bungaard et al. (12) found a small, nonsignificant reduction in infection risk. Abaluck et al. (13), found a significant, 8.6% decrease in symptomatic seropositivity linked to mask wearing. However, limitations of the study included a requirement for unblinded participants to self-report symptoms before testing, use of an antibody test with a very low 5 d sensitivity, and unclear generalization from the specific context (rural villages in Bangladesh).We focus on the effects of mask wearing or mandates (i.e., legal requirements to wear a mask) on transmission in large connected populations. To study mask impacts on transmission, many studies use the timing of mask mandates as a proxy for sharp changes in the level of mask wearing. Some such studies have inferred limited or inconclusive effects in cross-country analyses (14) and within-country studies (15), while others find cross-country evidence that mask mandates and recommendations lead to decreased transmission and mortality (16, 17).Other analyses provide evidence for reduced case growth following subnational mandates within countries such as the United States (18–20) and Germany (21). A potential explanation for the inconsistency and uncertainty of these results is that data on national mandate timing may be poorly suited for analyzing the effects of mask wearing on transmission.Epidemiological studies often use government mask mandates as a proxy for mask wearing. However, the existing literature on the relationship between mandates and actual levels of mask wearing has shown surprisingly weak effects. For example, studying US states, ref. 22 failed to find a statistically significant relationship between mandates and subsequent wearing, while other studies found postmandate increases in wearing of just 13% (23) and 23% (24). Betsch et al. (25) find a ∼40% increase in wearing after local mandates in Germany, but no other study finds a comparably large increase. Given that the link between mandates and wearing is surprisingly weak, it is likely that the link between mandates and transmission is difficult to detect. Three additional factors lead us to suspect that a link between mandates and transmission would be difficult to detect. First, introducing a mandate is a coarse, one-off event that necessarily loses signal by not tracking day-to-day changes in mask wearing. We also have fewer data on mandates: Less than half of the regions we study enforced any mandate during the study period. Second, past studies treat mandates as a binary on/off intervention that is fully implemented at a single point in time. However, modeling the effect of mandates as an instantaneous change in the reproduction number or mortality fails to capture changes in wearing behavior following the announcement of a mandate but before its enforcement (21). Nor does it account for gradual change in behavior after the implementation of a mandate. Finally, the circumstances of mandate policies are highly heterogeneous, both in terms of the preexisting level of voluntary wearing at the time of implementation and in terms of how exactly they are defined, enforced, and complied with. Consequently, averaging the international effect of mandates based on coarse data is unlikely to provide a useful summary of heterogeneous mandate effects. Importantly, these arguments point to the link between mandates and transmission being difficult to detect, not that it is absent.Because of these difficulties in studying the effect of mandates, we instead focus on estimating the effect of mask wearing on transmission, using a large (n = 19.97 million) global survey of self-reported mask wearing (1). Two other studies estimate mask effectiveness from self-reports: In their study of 24 countries, Aravindakshan et al. (26) use YouGov wearing data to infer an overall 3.9 to 10% relative decrease in case growth rate from whole population mask wearing. Rader et al. (22) study US states using a novel SurveyMonkey wearing dataset to infer a ∼10% decrease in transmission between the lowest and highest empirical quartiles of wearing (a 50 to 75% increase in wearing). Rader et al. use data limited to 12 US states during June–July 2020. Our data are richer: We study 56 countries on six continents, and our inferential analyses span May–September 2020.Our analysis goes further than past work in the quality of wearing data—100 times the sample size, with random sampling and poststratification—the geographical scope, the use of a semimechanistic infection model, the incorporation of uncertainty into epidemiological parameters, and the robustness of our results (59 sensitivity tests). See

Neuroanatomical Correlates of Skin Conductance Orienting in Normal Humans: A Magnetic Resonance Imaging Study

Although little is known about the neuroanatomical basis of skin conductance orienting in intact normal humans, the limited literature on animals and humans with neurological and clinical disorders implicate prefrontal, temporal/amygdala, and pons brain areas in mediating skin conductance orienting. This study relates area of these structures using magnetic resonance imaging techniques to skin conductance orienting responses in 17 normal humans in order to test hypotheses that larger area of these excitatory structures will be associated with more orienting responses. Left and right hand skin conductance orienting was significantly associated with left and right prefrontal area (r = .44-.60), area of the pons (r = .43-.54), and left but not right temporal/amygdala area (r = .47-.53). No relationships were observed with areas thought to be unrelated to skin conductance activity (cerebellum, nonfrontal cortical area), medial prefrontal cortex, or the third ventricle. This appears to be the first study relating brain structure to skin conductance orienting in intact normal humans. Although preliminary at the present time, these results implicate prefrontal, pons, and temporal/amygdala areas in the mediation of skin conductance orienting in normal humans.     

Comparison of Three Different FDA-Approved Plasma HIV-1 RNA Assay Platforms Confirms the Virologic Failure Endpoint of 200 Copies per Milliliter Despite Improved Assay Sensitivity

Discrepancies between HIV-1 RNA results assayed by different FDA-approved platforms have been reported. Plasma samples collected from 332 randomly selected clinical trial participants during the second year of antiretroviral treatment were assayed with three FDA-approved platforms: UltraSensitive Roche Amplicor Monitor, v1.5 (Monitor), the Abbott RealTime HIV-1 test on the m2000 system (Abbott), and the Roche TaqMan HIV-1 test, v2.0 (TaqMan). Samples from 61 additional participants with confirmed HIV-1 RNA levels of >50 copies/ml during trial follow-up were also included. Endpoints were HIV-1 RNA quantification of ≤50 copies/ml versus >50 copies/ml at an individual-sample level (primary) and determination of confirmed virologic failure (VF) from longitudinal samples. A total of 389 participants had results obtained from all assays on at least one sample (median = 6). Proportions of results of >50 copies/ml were 19% (Monitor), 22% (TaqMan), and 25% (Abbott). Despite indication of strong agreement (Cohen''s kappa, 0.76 to 0.82), Abbott was more likely to detect HIV-1 RNA levels of >50 copies/ml than Monitor (matched-pair odds ratio [mOR] = 4.2; modified Obuchowski P < 0.001) and TaqMan (mOR = 2.1; P < 0.001); TaqMan was more likely than Monitor (mOR = 2.6; P < 0.001). Despite strong agreement in classifying VF across assay comparisons (kappa, 0.75 to 0.92), at a 50-copies/ml threshold, differences in the probability of VF classification (in the same direction as primary) were apparent (all McNemar''s P < 0.007). At a 200-copies/ml VF threshold, no differences between assays were apparent (all P > 0.13). Despite strong agreement among assays, significant differences were observed with respect to detecting HIV-1 RNA levels of >50 copies/ml and identifying VF at the 50-copies/ml threshold. This has important implications for the definition of VF in clinical trials and clinical practice.     

Infrared skin damage thresholds from 1940-nm continuous-wave laser exposures

A series of experiments are conducted in vivo using Yucatan mini-pigs (Sus scrofa domestica) to determine thermal damage thresholds to the skin from 1940-nm continuous-wave thulium fiber laser irradiation. Experiments employ exposure durations from 10 ms to 10 s and beam diameters of approximately 4.8 to 18 mm. Thermal imagery data provide a time-dependent surface temperature response from the laser. A damage endpoint of minimally visible effect is employed to determine threshold for damage at 1 and 24 h postexposure. Predicted thermal response and damage thresholds are compared with a numerical model of optical-thermal interaction. Results are compared with current exposure limits for laser safety. It is concluded that exposure limits should be based on data representative of large-beam exposures, where effects of radial diffusion are minimized for longer-duration damage thresholds.     

Reduced cardiac stiffness following exercise is associated with preserved myocardial collagen characteristics in the rat

We determined whether the increment in cardiac end-diastolic compliance (a reduced diastolic stiffness constant) following endurance training is related to alterations in myocardial collagen characteristics. Sixteen weeks of habitual exercise (Ex) in rats, which produced left ventricular (LV) hypertrophy (LVH) [LV weight in g: Ex=1.01 (0.04), sedentary control?=?0.89 (0.04); P<0.05], resulted in a reduced LV end-diastolic (LVED) chamber stiffness [slope of the linearised LVED pressure versus LVED internal diameter relation in kPa?·?mm^?1: Ex=0.67 (0.03), control=0.80 (0.03); P<0.05]. The increased LVED chamber distensibility was associated with an attenuated myocardial stiffness [slope of the linearised LVED stress versus strain relation in g?·?cm^?2; Ex=15 (3), control=25?(2); P<0.05]. Although LV total collagen content (mg) was increased in the exercised rats [Ex=5.0?(0.3), control=4.1 (0.2); P<0.05], this was a reflection of the presence of LVH, as the myocardial collagen concentration (μg?·?mg^?1 LV wet weight) was unaltered [Ex=4.9 (0.2), control=4.6 (0.2)]. Furthermore, habitual exercise did not influence the percentage of myocardial collagen extracted following cyanogen bromide digestion (an index of collagen cross-linking), [i.e. Ex=38 (3), control=38 (3)], nor the proportion of myocardial collagen phenotypes I and III [I/III; Ex=3.04 (0.20), control=2.85 (0.22)]. In conclusion, exercise-induced increments in end-diastolic myocardial distensibility are unlikely to be a consequence of alterations in the properties of myocardial collagen.