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Peripheral neuropathy (PN) is a prevalent and debilitating complication of obesity, prediabetes, and type 2 diabetes, which remains poorly understood and lacks disease-modifying therapies. Fortunately, diet and/or exercise have emerged as effective treatment strategies for PN. Here, we examined the impact of caloric restriction (CR) and high-intensity interval training (HIIT) interventions, alone or combined (HIIT-CR), on metabolic and PN outcomes in high-fat diet (HFD) mice. HFD feeding alone resulted in obesity, impaired glucose tolerance, and PN. Peripheral nerves isolated from these mice also developed insulin resistance (IR). CR and HIIT-CR, but not HIIT alone, improved HFD-induced metabolic dysfunction. However, all interventions improved PN to similar extents. When examining the underlying neuroprotective mechanisms in whole nerves, we found that CR and HIIT-CR activate the fuel-sensing enzyme AMPK. We then performed complimentary in vitro work in Schwann cells, the glia of peripheral nerves. Treating primary Schwann cells with the saturated fatty acid palmitate to mimic prediabetic conditions caused IR, which was reversed by the AMPK activator, AICAR. Together, these results enhance our understanding of PN pathogenesis, the differential mechanisms by which diet and exercise may improve PN, and Schwann cell-specific contributions to nerve insulin signaling and PN progression. Article Highlights: Diet and exercise are recommended for treating peripheral neuropathy in prediabetes. To identify the optimal regimen and the underlying neuroprotective mechanisms, we compared the effects of caloric restriction (CR), high-intensity interval training (HIIT), and their combination (HIIT-CR), on metabolic and neuropathy outcomes following high-fat diet feeding. While all interventions improved neuropathy, CR and HIIT-CR, but not HIIT alone, improved metabolic profiles and promoted insulin sensitivity in peripheral nerves of high-fat diet–fed mice. In vitro, palmitate-treated Schwann cells developed insulin resistance, which was reversed by AMPK activation. CR, alone or combined with HIIT, ameliorates neuropathy by restoring nerve insulin sensitivity. [ABSTRACT FROM AUTHOR]

aiman,3 Jenny Ahlstrom,4 Margaret Yung,5 Kathleen L Deering,5 Victoria Kulbokas,5 Joshua L Feldman,6 Erika Kline,6 Noa Biran71Janssen Scientific Affairs LLC, Titusville, NJ, USA; 2Duke Cancer Institute, Duke University School of Medicine, Durham, NC, USA; 3Cleveland Clinic, Taussig Cancer Institute, Cleveland, OH, USA; 4HealthTree Foundation, Draper, UT, USA; 5EPI-Q Inc, Chicago, IL, USA; 6Inspire Insights, Arlington, VA, USA; 7Hackensack Meridian Health, John Theurer Cancer Center, Hackensack, NJ, USA Correspondence: Lisa Dwyer Orr, Janssen Scientific Affairs LLC, Titusville, NJ, USA, Tel +1 561 290-9901, Email [email protected] Introduction: Treatment decision-making for multiple myeloma (MM) is complex. Individuals involved in decision-making may value treatment attributes differently based on their role as a patient, care partner, or physician. This study describes those attributes, and what is most important by role. Methods: We conducted a cross-sectional online survey with consenting adult patients with MM, MM care partners, and physicians treating MM. Respondents were recruited from US panels (Inspire and M3 Global Research) between September and December 2022. Survey items were informed by a targeted literature review, qualitative interviews, and a steering committee comprising clinical experts, a patient advocate, patient, and care partner. Descriptive statistics were generated and reported in aggregate. Results: Email invitations were sent to 8071 Inspire members interested in or posting about MM. Of these, 4427 viewed the invitation, 941 responded, and 156 patients and care partners completed the survey (17% of respondents). For physicians, 5588 were invited via Email by M3 Global Research, with 761 viewing the invitation, 214 accessing the survey link, and 137 completing the survey (64% of respondents). Duration of response, side effects, and patients' quality-of-life (QoL) were the top three treatment attributes selected across the three cohorts; alignment of these attributes was consistent among patients regardless of disease severity. Separately, patients rated QoL and the amount of caregiving needed during/after treatment as the most important factors for future treatment decisions. If more effective MM treatments were offered, care partners were more willing to assume greater family burden (77%) compared to patients (49%), and patients were more accepting of potential serious side effects (50%) than were care partners (34%). Conclusion: Patients with MM, care partners, and physicians consider and value various treatment decision-making factors. Recognizing and addressing these differences is critical to meeting patients' preferences, needs, and optimizing patient outcomes. [ABSTRACT FROM AUTHOR]

The Urban Water Atlas for Europe constitutes an original overview of Urban Water Management in Europe, explain- ing and illustrating water in an unprecedented way and reflecting how water, the essence of life, flows through the arteries of our cities. Leading experts in water sciences and technologies, together with climate change researchers, have joined artists and children in order to show how thirsty our cities really are and how we can cope with their growing demand for the most precious resource of our planet. The result is the first major publication of the Sci- ence and Knowledge Service of the European Commission, the JRC, which within a movement stemming from its Sci-Art Programme seeks to explore the important opportunities arising from the cross-fertilisation between science and art. The Atlas itself establishes the benchmark for over 40 cities, both European and from farther afield, in 30 different countries, in a manner which permits a vast range of municipalities to confront one of the greatest global challenges by employing local solutions in order to ensure a supply of water for all. It contains 95 scientific indicators and parameters, over 700 graphs, original illustrations and never seen before photographs and combines the work of 40 contributors from 22 organisations. Yet, the true value of this publication lies in the process of ensuring thatthe underlying scientific knowledge is available for societal uptake. The resolving of conflicts which stem from an exclusive self-understanding of traditional natural sciences, the difficulty to communicate the purpose of technological solutions and the challenge to engage in peer-to-peer discussion between the sciences, politics and the citizen constitute worthy lessons for both environmental experts and their social science counterparts.

Breathing is a well-described, vital and surprisingly complex behaviour, with behavioural and physiological outputs that are easy to directly measure. Key neural elements for generating breathing pattern are distinct, compact and form a network amenable to detailed interrogation, promising the imminent discovery of molecular, cellular, synaptic and network mechanisms that give rise to the behaviour. Coupled oscillatory microcircuits make up the rhythmic core of the breathing network. Primary among these is the preBötzinger Complex (preBötC), which is composed of excitatory rhythmogenic interneurons and excitatory and inhibitory pattern-forming interneurons that together produce the essential periodic drive for inspiration. The preBötC coordinates all phases of the breathing cycle, coordinates breathing with orofacial behaviours and strongly influences, and is influenced by, emotion and cognition. Here, we review progress towards cracking the inner workings of this vital core.

The preBötzinger Complex (preBötC), a compact medullary region essential for generating normal breathing rhythm and pattern, is the kernel of the breathing central pattern generator (CPG). Excitatory preBötC neurons in rats project to major breathing-related brainstem regions. Here, we provide a brainstem connectivity map in mice for both excitatory and inhibitory preBötC neurons. Using a genetic strategy to label preBötC neurons, we confirmed extensive projections of preBötC excitatory neurons within the brainstem breathing CPG including the contralateral preBötC, Bötzinger Complex (BötC), ventral respiratory group, nucleus of the solitary tract, parahypoglossal nucleus, parafacial region (RTN/pFRG or alternatively, pFL /pFV ), parabrachial and Kölliker-Füse nuclei, as well as major projections to the midbrain periaqueductal gray. Interestingly, preBötC inhibitory projections paralleled the excitatory projections. Moreover, we examined overlapping projections in the pons in detail and found that they targeted the same neurons. We further explored the direct anatomical link between the preBötC and suprapontine brain regions that may govern emotion and other complex behaviors that can affect or be affected by breathing. Forebrain efferent projections were sparse and restricted to specific nuclei within the thalamus and hypothalamus, with processes rarely observed in cortex, basal ganglia, or other limbic regions, e.g., amygdala or hippocampus. We conclude that the preBötC sends direct, presumably inspiratory-modulated, excitatory and inhibitory projections in parallel to distinct targets throughout the brain that generate and modulate breathing pattern and/or coordinate breathing with other behaviors, physiology, cognition, or emotional state.

Recently, based on functional differences, we subdivided neurons juxtaposed to the facial nucleus into two distinct populations, the parafacial ventral and lateral regions, i.e., pFV and pFL. Little is known about the composition of these regions, i.e., are they homogenous or heterogeneous populations? Here, we manipulated their excitability in spontaneously breathing vagotomized urethane anesthetized adult rats to further characterize their role in breathing. In the pFL, disinhibition or excitation decreased breathing frequency (f) with a concomitant increase of tidal volume (VT), and induced active expiration; in contrast, reducing excitation had no effect. This result is congruent with pFL neurons constituting a conditional expiratory oscillator comprised of a functionally homogeneous set of excitatory neurons that are tonically suppressed at rest. In the pFV, disinhibition increased f with a presumptive reflexive decrease in VT; excitation increased f, VT and sigh rate; reducing excitation decreased VT with a presumptive reflexive increase in f. Therefore, the pFV, has multiple functional roles that require further parcellation. Interestingly, while hyperpolarization of the pFV reduces ongoing expiratory activity, no perturbation of pFV excitability induced active expiration. Thus, while the pFV can affect ongoing expiratory activity, presumably generated by the pFL, it does not appear capable of directly inducing active expiration. We conclude that the pFL contains neurons that can initiate, modulate, and sustain active expiration, whereas the pFV contains subpopulations of neurons that differentially affect various aspects of breathing pattern, including but not limited to modulation of ongoing expiratory activity.

Flood hazard mapping in the United States (US) is deeply tied to the National Flood Insurance Program (NFIP). Consequently, publicly available flood maps provide essential information for insurance purposes, but they do not necessarily provide relevant information for non-insurance aspects of flood risk management (FRM) such as public education and emergency planning. Recent calls for flood hazard maps that support a wider variety of FRM tasks highlight the need to deepen our understanding about the factors that make flood maps useful and understandable for local end users. In this study, social scientists and engineers explore opportunities for improving the utility and relevance of flood hazard maps through the co-production of maps responsive to end users' FRM needs. Specifically, two-dimensional flood modeling produced a set of baseline hazard maps for stakeholders of the Tijuana River valley, US, and Los Laureles Canyon in Tijuana, Mexico. Focus groups with natural resource managers, city planners, emergency managers, academia, non-profit, and community leaders refined the baseline hazard maps by triggering additional modeling scenarios and map revisions. Several important end user preferences emerged, such as (1) legends that frame flood intensity both qualitatively and quantitatively, and (2) flood scenario descriptions that report flood magnitude in terms of rainfall, streamflow, and its relation to an historic event. Regarding desired hazard map content, end users' requests revealed general consistency with mapping needs reported in European studies and guidelines published in Australia. However, requested map content that is not commonly produced included (1) standing water depths following the flood, (2) the erosive potential of flowing water, and (3) pluvial flood hazards, or flooding caused directly by rainfall. We conclude that the relevance and utility of commonly produced flood hazard maps can be most improved by illustrating pluvial flood hazards and by using concrete reference points to describe flooding scenarios rather than exceedance probabilities or frequencies.

Maternal smoking with obligatory nicotine inhalation is associated with preterm delivery, low birth weight, fetal growth retardation and developmental defects. We tested the hypothesis that cigarette smoking-relevant nicotine inhalation during pregnancy impairs cardiovascular function and uterine hemodynamics with consequential fetal ischemia. Pregnant rats exposed to episodic inhaled nicotine via a novel lung alveolar region-targeted aerosol method produced nicotine pharmacokinetics resembling cigarette smoking in humans. This clinically relevant nicotine aerosol inhalation (NAI) induced transient reduction and irregular fluctuations in uterine artery blood flow associated with cardiac arrhythmia and high magnitude irregular fluctuations of systemic blood pressure. The arrhythmia included sinoatrial (SA) block, sinus arrest, 2° and 3° atrioventricular (A-V) block and supraventricular escape rhythm. These effects were blocked by the nicotinic acetylcholine receptor (nAChR) antagonist mecamylamine. Resection of the ovarian nerve, which innervates uterine blood vessels, counteracted the NAI-induced reduction in uterine blood flow. We suggest that the rapid rise pattern of arterial blood nicotine concentration stimulates and then desensitizes autonomic nAChRs leading to disruptions of cardiac function as well as systemic and uterine hemodynamics that reduces uteroplacental blood flow, a mechanism underlying maternal smoking-associated pregnancy complications and developmental disorders. These findings challenge the safety of pure nicotine inhalation, i.e., E-cigarettes.

Abstract. Flood hazard mapping in the United States (US) is deeply tied to the National Flood Insurance Program (NFIP). Consequently, publicly available flood maps provide essential information for insurance purposes, but do not necessarily provide relevant information for non-insurance aspects of flood risk management (FRM) such as public education and emergency planning. Recent calls for flood hazard maps that support a wider variety of FRM tasks highlight the need to deepen our understanding about the factors that make flood maps useful and understandable for local end-users. In this study, social scientists and engineers explore opportunities for improving the utility and relevance of flood hazard maps through the co-production of maps responsive to end-users' FRM needs. Specifically, two-dimensional flood modeling produced a set of baseline hazard maps for stakeholders of the Tijuana River Valley, US, and Los Laureles Canyon in Tijuana, Mexico. Focus groups with natural resource managers, city planners, emergency managers, academia, non-profit, and community leaders refined the baseline hazard maps by triggering additional modeling scenarios and map revisions. Several important end-user preferences emerged, such as (1) legends that frame flood intensity both qualitatively and quantitatively, and (2) flood scenario descriptions that report flood magnitude in terms of rainfall, streamflow, and its relation to an historic event. Regarding desired hazard map content, end-users' requests revealed general consistency with mapping needs reported in European studies and guidelines published in Australia. However, requested map content that is not commonly produced included: (1) standing water depths following the flood, (2) the erosive potential of flowing water, and (3) pluvial flood hazards, or flooding caused directly by rainfall. We conclude that the relevance and utility of commonly produced flood hazard maps can be most improved by illustrating pluvial flood hazards and by using concrete reference points to describe flooding scenarios rather than exceedance probabilities or frequencies.

Slow, controlled breathing has been used for centuries to promote mental calming, and it is used clinically to suppress excessive arousal such as panic attacks. However, the physiological and neural basis of the relationship between breathing and higher-order brain activity is unknown. We found a neuronal subpopulation in the mouse preBötzinger complex (preBötC), the primary breathing rhythm generator, which regulates the balance between calm and arousal behaviors. Conditional, bilateral genetic ablation of the ~175 Cdh9/Dbx1 double-positive preBötC neurons in adult mice left breathing intact but increased calm behaviors and decreased time in aroused states. These neurons project to, synapse on, and positively regulate noradrenergic neurons in the locus coeruleus, a brain center implicated in attention, arousal, and panic that projects throughout the brain.

OBJECTIVE: To determine bidirectional associations between the timing of chronic diabetes complications (CDCs) and mental health disorders (MHDs) in individuals with type 1 or type 2 diabetes. RESEARCH DESIGN AND METHODS: We used a nationally representative health care claims database to identify matched individuals with type 1 or 2 diabetes or without diabetes using a propensity score quasirandomization technique stratified by age (0–19, 20–39, 40–59, and ≥60 years). CDCs and MHDs were identified using ICD-9/10 codes. We fit Cox proportional hazards models with time-varying diagnoses of CDCs or MHDs to investigate their association with the hazard of developing MHDs or CDCs, respectively. RESULTS: From 2001 to 2018, a total of 553,552 individuals were included (44,735 with type 1 diabetes, 152,187 with type 2 diabetes, and 356,630 without diabetes). We found that having a CDC increased the hazard of developing an MHD (hazard ratio [HR] 1.9–2.9; P < 0.05, with higher HRs in older age strata), and having an MHD increased the hazard of developing a CDC (HR 1.4–2.5; P < 0.05, with the highest HR in age stratum 0–19 years). In those aged <60 years, individuals with type 1 diabetes were more likely to have CDCs, whereas individuals with type 2 diabetes were more likely to have MHDs. However, the relationship between CDCs and MHDs in either direction was not affected by diabetes type (P > 0.05 for interaction effects). CONCLUSIONS: We found a consistent bidirectional association between CDCs and MHDs across the life span, highlighting the important relationship between CDCs and MHDs. Prevention and treatment of either comorbidity may help reduce the risk of developing the other. [ABSTRACT FROM AUTHOR]

OBJECTIVE: Diabetic peripheral neuropathy (DPN) is common; however, the features and burden of neuropathic pain (NP) in type 1 diabetes (T1D) are poorly understood. We evaluated the incidence of first occurrence, annual prevalence, remission, and risk factors for NP during long-term follow-up of participants with T1D. RESEARCH DESIGN AND METHODS: The Michigan Neuropathy Screening Instrument (MNSI) was administered annually (1994–2020) for 1,324 participants in the Epidemiology of Diabetes Interventions and Complications (EDIC) study. NP with clinical signs of DPN (NP DPN+) was defined according to self-reported NP plus an examination score >2, while NP without clinical signs of DPN (NP DPN−) was defined according to self-reported NP and an examination score ≤2. RESULTS: At EDIC year 1, median age for participants was 36 years (interquartile range 30, 41), diabetes duration 13 years (10, 18), and HbA1c 7.9% (7.2, 8.9). At year 26 (median diabetes duration 39 years), cumulative incidence of NP was 57%, regardless of concomitant clinical signs of DPN (36% NP DPN+ vs. 46% NP DPN−). NP prevalence was 20% at 26 years (11% NP DPN+ and 9% NP DPN−), suggesting frequent remission. Annualized remission rates were similar regardless of pain medication use. In addition to HbA1c, female sex was associated with NP DPN−. CONCLUSIONS: NP incidence in T1D was high and frequently occurred in the absence of clinical signs of neuropathy, as assessed with the MNSI. Pain remission was not explained by pain medication use. Effective clinical strategies for identification and management are needed. [ABSTRACT FROM AUTHOR]