Re-evaluating John Snow's 1856 south London study.

John Snow, the London doctor who studied cholera in the 1840s and 1850s, argued in Snow (1856) that water exerted an "overwhelming influence" on mortality in a region of south London during the 1854 outbreak. In a paper re-assessing Snow's analysis, Koch and Denike (2006) claim that "Snow made not merely minor arithmetic errors but more importantly critical, conceptual mistakes that adversely affected his results." The claim of errors and mistakes is incorrect and due to a misreading or misunderstanding of Snow's data and analysis. Koch and Denike apply an inappropriate statistical test to Snow's original data (and do so incorrectly). More importantly, due to the misreading of the historical record they alter the underlying primary-source data, rendering their results invalid. Analysis of the data following Snow's approach but with modern statistical tools strongly supports Snow's claim for the primacy of water in accounting for variation in cholera mortality.

Refinement of an ovine-based immunoglobulin therapy against SARS-CoV-2, with comparison of whole IgG versus F(ab')2 fragments.

The development of new therapies against SARS-CoV-2 is required to extend the toolkit of intervention strategies to combat the global pandemic. In this study, hyperimmune plasma from sheep immunised with whole spike SARS-CoV-2 recombinant protein has been used to generate candidate products. In addition to purified IgG, we have refined candidate therapies by removing non-specific IgG via affinity binding along with fragmentation to eliminate the Fc region to create F(ab')2 fragments. These preparations were evaluated for in vitro activity and demonstrated to be strongly neutralising against a range of SARS-CoV-2 strains, including Omicron B2.2. In addition, their protection against disease manifestations and viral loads were assessed using a hamster SARS-CoV-2 infection model. Results demonstrated protective effects of both IgG and F(ab')2, with the latter requiring sequential dosing to maintain in vivo activity due to rapid clearance from the circulation.

Spirituality of Science: Implications for Meaning, Well-Being, and Learning.

Scientists often refer to spiritual experiences with science. This research addresses this unique component of science attitudes-spirituality of science: feelings of meaning, awe, and connection derived through scientific ideas. Three studies (N = 1,197) examined individual differences in Spirituality of Science (SoS) and its benefits for well-being, meaning, and learning. Spirituality of Science was related to belief in science, but unlike other science attitudes, spirituality of science was also associated with trait awe and general spirituality (Study 1). spirituality of science also predicted meaning in life and emotional well-being in a group of atheists and agnostics, showing that scientific sources of spirituality can provide similar psychological benefits as religious spirituality (Study 2). Finally, Spirituality of Science predicted stronger engagement and recall of scientific information (Study 3). Results provide support for an experience of spirituality related to science, with benefits for meaning, well-being, and learning.

Focused ultrasound neuromodulation of the spleen activates an anti-inflammatory response in humans.

Focused ultrasound stimulation (FUS) activates mechanosensitive ion channels and is emerging as a method of noninvasive neuromodulation. In preclinical studies, FUS of the spleen (sFUS) activates an anti-inflammatory neural pathway which suppresses acute and chronic inflammation. However, the relevance of sFUS for regulating inflammatory responses in humans is unknown. Here, we used a modified diagnostic ultrasound imaging system to target the spleen of healthy human subjects with 3 min of continuously swept or stationary focused pulsed ultrasound, delivered at three different energy levels within allowable safety exposure limits. Potential anti-inflammatory effects of sFUS were assessed by measuring sFUS-elicited changes in endotoxin-induced tumor necrosis factor (TNF) production in whole blood samples from insonified subjects. We found that stimulation with either continuously swept or focused pulsed ultrasound has an anti-inflammatory effect: sFUS lowers TNF production for >2 h, with TNF returning to baseline by 24 h following sFUS. This response is independent of anatomical target (i.e., spleen hilum or parenchyma) or ultrasound energy level. No clinical, biochemical, or hematological parameters are adversely impacted. This is the first demonstration that sFUS suppresses the normal inflammatory response in humans, with potential implications for noninvasive bioelectronic therapy of inflammatory disorders.

Thiocarbazate building blocks enable the construction of azapeptides for rapid development of therapeutic candidates.

Peptides, polymers of amino acids, comprise a vital and expanding therapeutic approach. Their rapid degradation by proteases, however, represents a major limitation to their therapeutic utility and chemical modifications to native peptides have been employed to mitigate this weakness. Herein, we describe functionalized thiocarbazate scaffolds as precursors of aza-amino acids, that, upon activation, can be integrated in a peptide sequence to generate azapeptides using conventional peptide synthetic methods. This methodology facilitates peptide editing-replacing targeted amino acid(s) with aza-amino acid(s) within a peptide-to form azapeptides with preferred therapeutic characteristics (extending half-life/bioavailability, while at the same time typically preserving structural features and biological activities). We demonstrate the convenience of this azapeptide synthesis platform in two well-studied peptides with short half-lives: FSSE/P5779, a tetrapeptide inhibitor of HMGB1/MD-2/TLR4 complex formation, and bradykinin, a nine-residue vasoactive peptide. This bench-stable thiocarbazate platform offers a robust and universal approach to optimize peptide-based therapeutics.

Origin and Development of Cervical Dentin Hypersensitivity and Noncarious Cervical Lesions: Literature Review.

This article reports on published literature for causative factors of cervical dentin hypersensitivity and noncarious cervical lesions. The author conducted an exhaustive literary review of both conditions to examine etiologic co-factors involved for these dental findings. Previous literature found that these two conditions arise from combinations of dental stress distant from occlusal contacts, biocorrosion, and possibly friction. It is impossible to separate these three factors for the modern dentate human due to masticatory function and tooth contact when swallowing. The author concludes that in vivo study is needed to clarify the roles that etiologic factors play in the development of this type of dental pain and/or noncarious lesions. The clinical significance of this review is that a dental and medical history and active etiologic factors need to be uncovered for cervical dentin hypersensitivity with resulting noncarious cervical lesions. The successful clinician needs to determine causative factors, if possible, prior to treatment.

Stimulation of the hepatoportal nerve plexus with focused ultrasound restores glucose homoeostasis in diabetic mice, rats and swine.

Peripheral neurons that sense glucose relay signals of glucose availability to integrative clusters of neurons in the brain. However, the roles of such signalling pathways in the maintenance of glucose homoeostasis and their contribution to disease are unknown. Here we show that the selective activation of the nerve plexus of the hepatic portal system via peripheral focused ultrasound stimulation (pFUS) improves glucose homoeostasis in mice and rats with insulin-resistant diabetes and in swine subject to hyperinsulinemic-euglycaemic clamps. pFUS modulated the activity of sensory projections to the hypothalamus, altered the concentrations of metabolism-regulating neurotransmitters, and enhanced glucose tolerance and utilization in the three species, whereas physical transection or chemical blocking of the liver-brain nerve pathway abolished the effect of pFUS on glucose tolerance. Longitudinal multi-omic profiling of metabolic tissues from the treated animals confirmed pFUS-induced modifications of key metabolic functions in liver, pancreas, muscle, adipose, kidney and intestinal tissues. Non-invasive ultrasound activation of afferent autonomic nerves may represent a non-pharmacologic therapy for the restoration of glucose homoeostasis in type-2 diabetes and other metabolic diseases.

Impedance Planimetry and the Changing Paradigm of Esophageal Dysphagia.

OBJECTIVES: Patients presenting with dysphagia can encounter a pathway to therapy and relief that is expensive and frustrating. High resolution impedance planimetry (HRIP) is a new mechanism for enhancing and possibly hastening that process. A balloon with integrated pressure sensors is utilized to measure luminal geometry and pressure by volume-controlled distention. Esophagogastric junction (EGJ) distensibility and body contractility are assessed at the time of other endoscopic procedures. Here we describe a single-center experience utilizing HRIP in the endoscopic evaluation of patients presenting with dysphagia. METHODS: A prospectively maintained registry of patients undergoing impedance planimetry assessments at an academic medical center was queried for demographics, procedural details, and patient-reported outcomes. RESULTS: Data was reviewed for 122 procedures performed by two providers. HRIP was performed in 63 (52%) patients for initial dysphagia assessment, 36 (30%) for follow-up assessment, and 20 (16%) as a procedural adjunct at the time of other planned procedures. HRIP contractile response was characterized as normal in 36%, absent in 32%, and diminished/disorganized in 14%. These results motivated clinical planning for surgical referral in 7 (5%) patients, 31 (26%) additional testing, and 82 (68%) continued medical management and follow-up. DISCUSSION: HRIP is an emerging endoscopic modality which can streamline diagnostic work-up and therapeutic planning for patients with symptomatic dysphagia. Using functional esophageal assessment at the time of other diagnostic and therapeutic procedures, HRIP may expedite care and lead to improved patient satisfaction and clinical outcomes.

In Doubt and Disbelief: How Mrdjenovich 2018 Misunderstands the (Non)Religion-Health Relationship.

The article, "Religiously/Spiritually Involved, but in Doubt or Disbelief-Why? Healthy?" (Mrdjenovich in J Relig Health. https://doi.org/10.1007/s10943-018-0711-2 , 2018) addressed why subsets of Nones would engage in religious activities. While the subject matter of Mrdjenovich's work is important and understudied, several problematic conclusions about the nonreligion-health field were drawn. We provide constructive criticisms of Mrdjenovich's methodologies, conclusions, and characterizations of the nonreligion-health field, and offer several solutions to the problems identified.

Targeted peripheral focused ultrasound stimulation attenuates obesity-induced metabolic and inflammatory dysfunctions.

Obesity, a growing health concern, is associated with an increased risk of morbidity and mortality. Chronic low-grade inflammation is implicated in obesity-driven metabolic complications. Peripheral focused ultrasound stimulation (pFUS) is an emerging non-invasive technology that modulates inflammation. Here, we reasoned that focused ultrasound stimulation of the liver may alleviate obesity-related inflammation and other comorbidities. After 8 weeks on a high-fat high-carbohydrate "Western" diet, C57BL/6J mice were subjected to either sham stimulation or focused ultrasound stimulation at the porta hepatis. Daily liver-focused ultrasound stimulation for 8 weeks significantly decreased body weight, circulating lipids and mitigated dysregulation of adipokines. In addition, liver-focused ultrasound stimulation significantly reduced hepatic cytokine levels and leukocyte infiltration. Our findings demonstrate the efficacy of hepatic focused ultrasound for alleviating obesity and obesity-associated complications in mice. These findings suggest a previously unrecognized potential of hepatic focused ultrasound as a possible novel noninvasive approach in the context of obesity.

The psychology of nonbelievers.

Contrary to some conceptualizations, nonbelievers are more than simply those scoring low on religiosity scales. They seem to be characterized by analytic, flexible, and open-minded social-cognitive attributes, although this may interact with sociocultural levels of religiosity. This paper demonstrates that nonbelief, at least in the West, tends to coincide with specific worldviews, namely valuing rationality and science, as well as humanistic and liberal values. Furthermore, nonbelievers seem to parallel believers in various indicators of health. Finally, as all ideologists, nonbelievers may hold prejudicial attitudes toward groups perceived as threatening their (secular) worldviews, although this has some limits. Global increases in secularity make the nascent psychological study of nonbelievers and nonreligious worldviews an important research programme.

Nonspecific wrist pain in pediatric patients: A systematic review.

Determining the cause of wrist pain is a challenge for clinicians due to the complex biomechanical characteristics of the multiple articulations which comprise the wrist, and the intricacies of the soft tissue supporting them. Patients presenting with wrist pain can be diagnosed by obtaining a detailed history, physical examination and radiographic images. For some patients, a diagnosis remains elusive even after a complete appropriate work up, and the pain may persist following conservative management. The aim of this systematic review was to analyze the effect that psychosocial factors have on the development chronic idiopathic wrist pain in children and adolescents.

DMSO-mediated curing of several yeast prion variants involves Hsp104 expression and protein solubilization, and is decreased in several autophagy related gene (atg) mutants.

Chaperones and autophagy are components of the protein quality control system that contribute to the management of proteins that are misfolded and aggregated. Here, we use yeast prions, which are self-perpetuating aggregating proteins, as a means to understand how these protein quality control systems influence aggregate loss. Chaperones, such as Hsp104, fragment prion aggregates to generate more prion seeds for propagation. While much is known about the role of chaperones, little is known about how other quality control systems contribute to prion propagation. We show that the aprotic solvent dimethyl sulfoxide (DMSO) cures a range of [PSI+] prion variants, which are related to several misfolded aggregated conformations of the Sup35 protein. Our studies show that DMSO-mediated curing is quicker and more efficient than guanidine hydrochloride, a prion curing agent that inactivates the Hsp104 chaperone. Instead, DMSO appears to induce Hsp104 expression. Using the yTRAP system, a recently developed transcriptional reporting system for tracking protein solubility, we found that DMSO also rapidly induces the accumulation of soluble Sup35 protein, suggesting a potential link between Hsp104 expression and disassembly of Sup35 from the prion aggregate. However, DMSO-mediated curing appears to also be associated with other quality control systems. While the induction of autophagy alone does not lead to curing, we found that DMSO-mediated curing is dramatically impaired in autophagy related (atg) gene mutants, suggesting that other factors influence this DMSO mechanism of curing. Our data suggest that DMSO-mediated curing is not simply dependent upon Hsp104 overexpression alone, but may further depend upon other aspects of proteostasis.

Author Correction: Noninvasive sub-organ ultrasound stimulation for targeted neuromodulation.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Respiratory Support during Bronchiolitis Due to One Virus versus More Than One Virus: An Observational Study.

Bronchiolitis is common during infancy and frequently leads to pediatric intensive care unit (PICU) admission. This study aimed to determine if there is a difference in the duration of respiratory support when bronchiolitis is due to one virus or more than one virus. This is a retrospective, observational study of cases admitted to PICU with confirmed bronchiolitis. There were 306 cases analyzed, 70% (215/306) were infected by a single virus and 30% (91/306) were infected with more than one virus. Both groups had similar duration of respiratory support and PICU length of stay (LOS). Hospital LOS was longer for the group with more than one virus.

Distributed Acoustic Sensing of Strain at Earth Tide Frequencies.

The solid Earth strains in response to the gravitational pull from the Moon, Sun, and other planetary bodies. Measuring the flexure of geologic material in response to these Earth tides provides information about the geomechanical properties of rock and sediment. Such measurements are particularly useful for understanding dilation of faults and fractures in competent rock. A new approach to measuring earth tides using fiber optic distributed acoustic sensing (DAS) is presented here. DAS was originally designed to record acoustic vibration through the measurement of dynamic strain on a fiber optic cable. Here, laboratory experiments demonstrate that oscillating strain can be measured with DAS in the microHertz frequency range, corresponding to half-day (M2) lunar tidal cycles. Although the magnitude of strain measured in the laboratory is larger than what would be expected due to earth tides, a clear signal at half-day period was extracted from the data. With the increased signal-to-noise expected from quiet field applications and improvements to DAS using engineered fiber, earth tides could potentially be measured in deep boreholes with DAS. Because of the distributed nature of the sensor (0.25 m measurement interval over kilometres), fractures could be simultaneously located and evaluated. Such measurements would provide valuable information regarding the placement and stiffness of open fractures in bedrock. Characterization of bedrock fractures is an important goal for multiple subsurface operations such as petroleum extraction, geothermal energy recovery, and geologic carbon sequestration.

Noninvasive sub-organ ultrasound stimulation for targeted neuromodulation.

Tools for noninvasively modulating neural signaling in peripheral organs will advance the study of nerves and their effect on homeostasis and disease. Herein, we demonstrate a noninvasive method to modulate specific signaling pathways within organs using ultrasound (U/S). U/S is first applied to spleen to modulate the cholinergic anti-inflammatory pathway (CAP), and US stimulation is shown to reduce cytokine response to endotoxin to the same levels as implant-based vagus nerve stimulation (VNS). Next, hepatic U/S stimulation is shown to modulate pathways that regulate blood glucose and is as effective as VNS in suppressing the hyperglycemic effect of endotoxin exposure. This response to hepatic U/S is only found when targeting specific sub-organ locations known to contain glucose sensory neurons, and both molecular (i.e. neurotransmitter concentration and cFOS expression) and neuroimaging results indicate US induced signaling to metabolism-related hypothalamic sub-nuclei. These data demonstrate that U/S stimulation within organs provides a new method for site-selective neuromodulation to regulate specific physiological functions.

Immunization Elicits Antigen-Specific Antibody Sequestration in Dorsal Root Ganglia Sensory Neurons.

The immune and nervous systems are two major organ systems responsible for host defense and memory. Both systems achieve memory and learning that can be retained, retrieved, and utilized for decades. Here, we report the surprising discovery that peripheral sensory neurons of the dorsal root ganglia (DRGs) of immunized mice contain antigen-specific antibodies. Using a combination of rigorous molecular genetic analyses, transgenic mice, and adoptive transfer experiments, we demonstrate that DRGs do not synthesize these antigen-specific antibodies, but rather sequester primarily IgG1 subtype antibodies. As revealed by RNA-seq and targeted quantitative PCR (qPCR), dorsal root ganglion (DRG) sensory neurons harvested from either naïve or immunized mice lack enzymes (i.e., RAG1, RAG2, AID, or UNG) required for generating antibody diversity and, therefore, cannot make antibodies. Additionally, transgenic mice that express a reporter fluorescent protein under the control of Igγ1 constant region fail to express Ighg1 transcripts in DRG sensory neurons. Furthermore, neural sequestration of antibodies occurs in mice rendered deficient in neuronal Rag2, but antibody sequestration is not observed in DRG sensory neurons isolated from mice that lack mature B cells [e.g., Rag1 knock out (KO) or µMT mice]. Finally, adoptive transfer of Rag1-deficient bone marrow (BM) into wild-type (WT) mice or WT BM into Rag1 KO mice revealed that antibody sequestration was observed in DRG sensory neurons of chimeric mice with WT BM but not with Rag1-deficient BM. Together, these results indicate that DRG sensory neurons sequester and retain antigen-specific antibodies released by antibody-secreting plasma cells. Coupling this work with previous studies implicating DRG sensory neurons in regulating antigen trafficking during immunization raises the interesting possibility that the nervous system collaborates with the immune system to regulate antigen-mediated responses.

A literature review and hypothesis for the etiologies of cervical and root caries.

The presence of endogenous acids from bacteria acting on a suitable substrate combined with sources of exogenous biocorrosives such as exogenous acids and proteolytic enzymes in areas of stress concentration are hypothesized to lead to the development and progression of cervical and root caries (RC). Quantifying the effects of each of the mechanisms (stress and biocorrosion) is a daunting task to investigate since so many factors are involved at various times in the etiology of noncarious cervical lesions (NCCLs), cervical caries (CC), and RC. Frictional action of the tongue has a cleansing effect and lingual serous saliva, which has a high flow rate buffering capacity from bicarbonates seem to account for the paucity of lingual NCCLs, cervical, and RC in these areas of teeth. Future studies are indicated to determine the effects of stress and biocorrosion and their factors in the etiology of CC and RC. CLINICAL SIGNIFICANCE: This manuscript presents hypothetical and literary information that the combined effects of stress concentration and biocorrosion contribute to the formation as well as progression of cervical and root caries.