Increases in 'deaths of despair' during the COVID-19 pandemic in the United States and the United Kingdom.

OBJECTIVES: The COVID-19 pandemic significantly impacted mental health, health-related behaviours such as drinking and illicit drug use and the accessibility of health and social care services. How these pandemic shocks affected 'despair'-related mortality in different countries is less clear. This study uses public data to compare deaths from alcohol, drugs and suicide in the United States and the United Kingdom to identify similarities or differences in the impact of the pandemic on important non-COVID causes of death across countries and to consider the public health implications of these trends. STUDY DESIGN AND METHODS: Data were taken from publicly available mortality figures for England and Wales, Northern Ireland, Scotland and the United States of America, 2001-2021, and analysed descriptively through age-standardised and age-specific mortality rates from suicide, alcohol and drug use. RESULTS: Alcohol-specific deaths increased in all countries between 2019 and 2021, most notably in the United States and, to a lesser extent, England and Wales. Suicide rates did not increase markedly during the pandemic in any of the included nations. Drug-related mortality rates rose dramatically over the same period in the United States but not in other nations. CONCLUSIONS: Mortality from 'deaths of despair' during the pandemic has displayed divergent trends between causes and countries. Concerns about increases in deaths by suicide appear to have been unfounded, whereas deaths due to alcohol have risen across the United Kingdom and in the United States and across almost all age groups. Scotland and the United States had similarly high levels of drug-related deaths pre-pandemic, but the differing trends during the pandemic highlight the different underlying causes of these drug death epidemics and the importance of tailoring policy responses to these specific contexts.

Determination of the

We report the first measurement of the parity-violating elastic electron scattering asymmetry on ^{27}Al. The ^{27}Al elastic asymmetry is A_{PV}=2.16±0.11(stat)±0.16(syst) ppm, and was measured at ⟨Q^{2}⟩=0.02357±0.00010 GeV^{2}, ⟨θ_{lab}⟩=7.61°±0.02°, and ⟨E_{lab}⟩=1.157 GeV with the Q_{weak} apparatus at Jefferson Lab. Predictions using a simple Born approximation as well as more sophisticated distorted-wave calculations are in good agreement with this result. From this asymmetry the ^{27}Al neutron radius R_{n}=2.89±0.12 fm was determined using a many-models correlation technique. The corresponding neutron skin thickness R_{n}-R_{p}=-0.04±0.12 fm is small, as expected for a light nucleus with a neutron excess of only 1. This result thus serves as a successful benchmark for electroweak determinations of neutron radii on heavier nuclei. A tree-level approach was used to extract the ^{27}Al weak radius R_{w}=3.00±0.15 fm, and the weak skin thickness R_{wk}-R_{ch}=-0.04±0.15 fm. The weak form factor at this Q^{2} is F_{wk}=0.39±0.04.

Precision Measurement of the Beam-Normal Single-Spin Asymmetry in Forward-Angle Elastic Electron-Proton Scattering.

A beam-normal single-spin asymmetry generated in the scattering of transversely polarized electrons from unpolarized nucleons is an observable related to the imaginary part of the two-photon exchange process. We report a 2% precision measurement of the beam-normal single-spin asymmetry in elastic electron-proton scattering with a mean scattering angle of θ_{lab}=7.9° and a mean energy of 1.149 GeV. The asymmetry result is B_{n}=-5.194±0.067(stat)±0.082 (syst) ppm. This is the most precise measurement of this quantity available to date and therefore provides a stringent test of two-photon exchange models at far-forward scattering angles (θ_{lab}→0) where they should be most reliable.

Long-term results of an intensive cognitive behavioral pain management program for patients with chronic low back pain: a concise report of an extended cohort with a minimum of 5-year follow-up.

PURPOSE: Treatment options for chronic low back pain (CLBP) include cognitive behavioral interventions. Most of these interventions only have small and short-lived effects. Using strict inclusion criteria for participation in an intensive combined physical and psychological program, encouraging effects were reported at 1-year follow-up. This study evaluates the long-term follow-up results of the same program. The hypothesis is that previously reported results are maintained. METHODS: Structured interviews were conducted in a prospective extended cohort with a minimum of 5-year follow-up in a similar fashion as in the 1-year follow-up report. The median follow-up in this cohort was 6.5 years. The extended cohort consisted of 277 patients (85% response). RESULTS: Outcomes include daily functioning, quality of life, current pain intensity, pain disturbance in daily activities and indicators of the use of pain medication and healthcare services. The previously reported positive 1-year follow-up results were maintained at a minimum of 5-year follow-up. Disability as measured with the Oswestry disability index (ODIv2.1a) decreased from 40 to 27 in the first year. This positive result was maintained at the 6.5-year follow-up with an ODI of 28. Pain intensity (NRS 0-100) improved from 60 to 39 in the first year, and at 6.5 years, this had further improved to 33. Improvement in quality of life (SF 36) at 1-year follow-up was maintained at 6.5-year follow-up, and healthcare consumption had decreased substantially as measured with doctor visits and analgesics used for CLBP. CONCLUSION: Selected and motivated patients with longstanding CLBP improve fast after an intensive combined physical and psychological program in daily functioning, pain and quality of life. Positive 1-year results are maintained, and healthcare utilization was still reduced at a minimum of 5-year follow-up. These slides can be retrieved under Electronic Supplementary Material.

The impact of pathogen burden on leukocyte telomere length in the Multi-Ethnic Study of Atherosclerosis.

Several infections have been linked to telomere shortening and in some cases these associations have varied by sex. We assessed the association between seropositivity to four persistent pathogens (cytomegalovirus (CMV), herpes simplex virus-1, Helicobacter pylori, Chlamydia pneumoniae), and total pathogen burden on leukocyte telomere length in a diverse US sample. Data came from the Multi-Ethnic Study of Atherosclerosis, a population-based cohort study. We utilized cross-sectional survey data, and biological samples from participants tested for pathogens and telomere length (N = 163). Linear regression was used to examine the association between seropositivity for individual pathogens as well as total pathogen burden and telomere length, adjusting for various confounders. CMV seropositivity and increased total pathogen burden level were significantly associated with shorter telomere length among females (ß = -0·1204 (standard error (s.e.) 0·06), P = 0·044) and (ß = -0·1057 (s.e. = 0·05), P = 0·033), respectively. There was no statistically significant association among males. Our findings suggest that prevention or treatment of persistent pathogens, in particular CMV, may play an important role in reducing telomere shortening over the life course among women. Future research is needed to confirm these novel findings in larger longitudinal samples.

Long-term obesity and physical functioning in older Americans.

BACKGROUND: Americans are becoming obese earlier in their lives, increasing the average exposure to obesity. Nonetheless, the impact of long-term obesity on later life functioning is not well known. METHODS: We analyzed data from 7258 adults aged 60-79 years from the US 1999-2010 National Health and Nutrition Examination Survey. Respondents were defined as limited if they reported 'some difficulty' 'much difficulty' or 'unable to do' any of the eight functional tasks. Respondents were defined as severely limited if they reported 'much difficulty' or 'unable to do' any task. Generalized regression models (logistic and Poisson) predicted the relative odds of any limitation, severe limitation, the total number of limitations and each individual limitation as a function of body mass index (BMI) at age 25 years and current BMI. Models were adjusted for age, sex, race/ethnicity and level of education. RESULTS: Overall, being overweight or obese at age 25 years was associated with higher odds of being functionally limited, but these associations were greatly diminished or eliminated after adjustment for current BMI. For example, those obese at age 25 years had 2.38 times the odds (95% confidence interval (CI): 1.77, 3.20) of reporting any functional limitations compared with those normal weight at 25 years, but only 1.28 times the odds (95% CI: 0.93, 1.76) after adjustment for current BMI. For severe limitations, the corresponding results were 2.72 (95% CI: 2.13-3.46) and 1.32 (95% CI:1.00-1.75) before and after adjustment for current BMI. Some associations between obesity at age 25 years and individual tasks remained significant after adjustment for current BMI. CONCLUSIONS: We conclude that long-term overweight/obesity are significantly associated with later life functional limitations, though this is largely explained by their strong association with higher levels of later-life BMI. Prevention of additional weight gain for those who are overweight or obese early in life could help mitigate their risk of future loss of functioning.

Unpacking the 'black box' of total pathogen burden: is number or type of pathogens most predictive of all-cause mortality in the United States?

A 'black box' paradigm has prevailed in which researchers have focused on the association between the total number of pathogens for which individuals are seropositive (i.e. total pathogen burden) and various chronic diseases, while largely ignoring the role that seropositivity for specific combinations of pathogens may play in the aetiology of such outcomes and consequently mortality. We examined the association between total pathogen burden as well as specific pathogen combinations and all-cause mortality in the United States. Data were from individuals aged ⩾25 years tested for cytomegalovirus (CMV), herpes simplex virus (HSV)-1, HSV-2 and Helicobacter pylori, with mortality follow-up to 31 December 2006 in the National Health and Nutrition Examination Survey (NHANES) III (N = 6522). We did not observe a statistically significant graded relationship between total pathogen burden level and all-cause mortality. Furthermore, compared to those seronegative for all four pathogens, the greatest statistically significant rate of all-cause mortality was for those CMV+/HSV-2+ (hazard ratio 1·95, 95% confidence interval 1·13-3·35) adjusting for age, gender, race/ethnicity, education level, body mass index (kg/m2) and smoking status. Interventions targeting prevention or treatment of particular pathogens may be more effective for reducing mortality than those focused solely on reducing overall pathogen burden.

First determination of the weak charge of the proton.

The Q(weak) experiment has measured the parity-violating asymmetry in ep elastic scattering at Q(2)=0.025(GeV/c)(2), employing 145 µA of 89% longitudinally polarized electrons on a 34.4 cm long liquid hydrogen target at Jefferson Lab. The results of the experiment's commissioning run, constituting approximately 4% of the data collected in the experiment, are reported here. From these initial results, the measured asymmetry is A(ep)=-279±35 (stat) ± 31 (syst) ppb, which is the smallest and most precise asymmetry ever measured in ep scattering. The small Q(2) of this experiment has made possible the first determination of the weak charge of the proton Q(W)(p) by incorporating earlier parity-violating electron scattering (PVES) data at higher Q(2) to constrain hadronic corrections. The value of Q(W)(p) obtained in this way is Q(W)(p)(PVES)=0.064±0.012, which is in good agreement with the standard model prediction of Q(W)(p)(SM)=0.0710±0.0007. When this result is further combined with the Cs atomic parity violation (APV) measurement, significant constraints on the weak charges of the up and down quarks can also be extracted. That PVES+APV analysis reveals the neutron's weak charge to be Q(W)(n)(PVES+APV)=-0.975±0.010.

Circulating levels of the cytokines IL10, IFNγ and resistin in an obese mouse model of developmental programming.

An infant's early developmental environment plays a pivotal role in the programming of its physiological phenotype. The identification of the factors in the maternal environment that mediate the effects of maternal obesity and diet is essential to the development of clinical intervention strategies. Maternal hyperglycaemia, hyperinsulinaemia, hypertriglyceridaemia, hyperleptinaemia and altered inflammatory cytokines concentrations are potentially important predictive factors of her future offspring's susceptibility to metabolic disease. Using a diet-induced obese mouse model, we have investigated which of these maternal factors could induce adverse metabolic programming in the offspring. Female C57Bl/6 mice were fed either laboratory chow (10% fat) or high fat diet (42% fat) for 10 weeks before mating and throughout gestation. At day 18 of pregnancy, maternal body weight, body composition and glucose tolerance were measured, as well as plasma insulin, adiponectin, RBP4, leptin, resistin and the inflammatory cytokines (IL6, IL10, IL12, IL1ß, IFNγ, KC, TNF-α). At day 18 of pregnancy, high fat-fed dams were significantly heavier than the chow dams and had increased fat mass. High fat-fed dams had higher 5 h fasting blood glucose than chow dams and elevated plasma insulin. Although the obese dams had both reduced plasma adiponectin and resistin levels compared with lean dams, their plasma IL6, IL10 and IFNγ levels were all increased. High fat feeding in pregnancy leads to altered plasma concentrations of both adipokines and adipocytokines in the dam that may directly pass to the fetus and affect their development.

Horizontal gaze palsy and scoliosis: a case report and review of the literature.

BACKGROUND: The syndrome of horizontal gaze palsy with progressive scoliosis (HGPPS) is a rare human disease and while its association with scoliosis was first reported in 1974, thirty years later the responsible genetic mutations are being elucidated. This progress was due to the reporting of single interesting cases. CASE DESCRIPTION: We present the case of a 27 year-old male patient who was admitted for elective scoliosis correction surgery and who represented after an uncomplicated discharge with headache and vomiting; because of a gaze palsy he underwent brain imaging that confirmed a brainstem abnormality, consistent with the syndrome of horizontal gaze palsy with progressive scoliosis (HGPPS), a rare autosomal recessive human disease. CONCLUSION: This rare syndrome is a good example of how single case reports can lead to advances in laboratory research and genetic characterisation of diseases, together with implications for neurodevelopment. Vigilance in the neurological examination in an otherwise 'non-neurological' scoliosis will help identify potential such cases, whilst further genetic/molecular analysis may shed further light into neuro-embryological development and patterning.

Leanness in postnatally nutritionally programmed rats is associated with increased sensitivity to leptin and a melanocortin receptor agonist and decreased sensitivity to neuropeptide Y.

BACKGROUND: Pups of normally nourished dams that are cross-fostered after birth to dams fed a low-protein (8% by weight) diet (postnatal low protein (PLP)) grow slower during the suckling period and remain small and lean throughout adulthood. At weaning, they have increased expression in the arcuate nucleus (ARC) of the hypothalamus of the orexigenic neuropeptide Y (NPY) and decreased expression of pro-opiomelanocortin, the precursor of anorexigenic melanocortins. OBJECTIVES AND METHODS: We investigated, using third ventricle administration, whether 3-month-old male PLP rats display altered sensitivity to leptin with respect to food intake, NPY and the melanocortin 3/4-receptor agonist MTII, and using in situ hybridization or laser capture microdissection of the ARC followed by RT-PCR, whether the differences observed were associated with changes in the hypothalamic expression of NPY or the leptin receptor, NPY receptors and melanocortin receptors. RESULTS: PLP rats were smaller and had reduced percentage body fat content and plasma leptin concentration compared with control rats. Leptin (5 µg) reduced food intake over 0-48 h more in PLP than control rats (P<0.05). Submaximal doses of NPY increased the food intake less in PLP rats than in controls, whereas submaximal doses of MTII reduced the food intake more in PLP rats. Maximal responses did not differ between PLP and control rats. Leptin and melanocortin-3 receptor (MC3R) expression were increased in both ARC and ventromedial hypothalamic nuclei in PLP animals compared with the controls. MC4R, NPY Y1R, Y5R and NPY expression were unchanged. CONCLUSION: Postnatal undernourishment results in food intake in adult rats being more sensitive to reduction by leptin and melanocortins, and less sensitive to stimulation by NPY. We propose that this contributes to increased leptin sensitivity and resistance to obesity. Increased expression of ObRb and MC3R may partly explain these findings but other downstream mechanisms must also be involved.

Basic principles of management for cervical spine trauma.

This article reviews the basic principles of management of cervical trauma. The technique and critical importance of careful assessment is described. Instability is defined, and the incidence of a second injury is highlighted. The concept of spinal clearance is discussed. Early reduction and stabilisation techniques are described, and the indications, and approach for surgery reviewed. The importance of the role of post-injury rehabilitation is identified.

Socioeconomic disparities in the seroprevalence of cytomegalovirus infection in the US population: NHANES III.

There is a strong relationship between socioeconomic status (SES) and health outcomes in the United States, although the mechanisms are poorly understood. Increasing evidence points to links between lifelong exposure to infectious disease and subsequent chronic disease. Exposure and susceptibility to infections may be one way SES affects long-term health, although little population-based research to date has examined social patterning of infections in the United States. This paper tests the relationship between income, education, race/ethnicity and seroprevalence of cytomegalovirus (CMV) infection at different ages in a representative sample of the US population, and tests potential mediators for these relationships. The study finds significant racial and socioeconomic disparities in CMV seroprevalence beginning at early ages and persisting into middle age. Potential exposures do not explain the relationship between SES and CMV positivity. Because reactivation of latent CMV infections may contribute to chronic disease and immune decline later in life, future research should determine the exposure or susceptibility pathways responsible for these disparities in the prevalence of CMV infection.

Polarization dependence of a GaAs-based two-photon absorption microcavity photodetector.

In this paper, the polarization response of a GaAs based two-photon absorption microcavity photodetector has been studied. The deviation in the dependence of the detector response from that of bulk GaAs is shown to be due to the birefringence of the cavity. A theoretical model based on the convolution of the cavity birefringence and the polarization dependence of two-photon absorption in GaAs is described and shown to match the measured polarization dependence of the microcavity detector very well.

Metabolic responses to BRL37344 and clenbuterol in soleus muscle and C2C12 cells via different atypical pharmacologies and beta2-adrenoceptor mechanisms.

BACKGROUND AND PURPOSE: Picomolar concentrations of the beta3-adrenoceptor agonist BRL37344 stimulate 2-deoxyglucose uptake in soleus muscle via undefined receptors. Higher concentrations alter uptake, apparently via beta2-adrenoceptors. Effects of BRL37344 and beta2-adrenoceptor agonists are compared. EXPERIMENTAL APPROACH: Mouse soleus muscles were incubated with 2-deoxy[1-(14)C]-glucose, [1-(14)C]-palmitate or [2-(14)C]-pyruvate, and BRL37344, beta2-adrenoceptor agonists and selective beta-adrenoceptor antagonists. Formation of 2-deoxy[1-(14)C]-glucose-6-phosphate or (14)CO2 was measured. 2-Deoxy[1-(14)C]-glucose uptake and beta-adrenoceptor mRNA were measured in C2C12 cells. KEY RESULTS: 10 pM BRL37344, 10 pM clenbuterol and 100 pM salbutamol stimulated 2-deoxyglucose uptake in soleus muscle by 33-54%. The effect of BRL37344 was prevented by 1 microM atenolol but not by 300 nM CGP20712A or IC3118551, or 1 microM SR59230A; that of clenbuterol was prevented by ICI118551 but not atenolol. 10 nM BRL37344 stimulated 2-deoxyglucose uptake, whereas 100 nM clenbuterol and salbutamol inhibited uptake. These effects were blocked by ICI118551. Similar results were obtained in C2C12 cells, in which only beta2-adrenoceptor mRNA could be detected by RT-PCR. 10 nM BRL37344 and 10 pM clenbuterol stimulated muscle palmitate oxidation. In the presence of palmitate, BRL37344 no longer stimulated 2-deoxyglucose uptake and the effect of clenbuterol was not significant. CONCLUSIONS AND IMPLICATIONS: Stimulation of glucose uptake by 10 pM BRL37344 and clenbuterol involves different atypical pharmacologies. Nanomolar concentrations of BRL37344 and clenbuterol, probably acting via beta2-adrenoceptors, have opposite effects on glucose uptake. The agonists preferentially stimulate fat rather than carbohydrate oxidation, but stimulation of endogenous fat oxidation cannot explain why 100 nM clenbuterol inhibited 2-deoxyglucose uptake.

Assignment of two loci for autosomal dominant adolescent idiopathic scoliosis to chromosomes 9q31.2-q34.2 and 17q25.3-qtel.

BACKGROUND: Adolescent idiopathic scoliosis (AIS) is the most common form of spinal deformity, affecting up to 4% of children worldwide. Familial inheritance of AIS is now recognised and several potential candidate loci have been found. METHODS: We studied 25 multi-generation AIS families of British descent with at least 3 affected members in each family. A genomewide screen was performed using microsatellite markers spanning approximately 10-cM intervals throughout the genome. This analysis revealed linkage to several candidate chromosomal regions throughout the genome. Two-point linkage analysis was performed in all families to evaluate candidate loci. After identification of candidate loci, two-point linkage analysis was performed in the 10 families that segregated, to further refine disease intervals. RESULTS: Significant linkage was obtained in a total of 10 families: 8 families to the telomeric region of chromosome 9q, and 2 families to the telomeric region of 17q. A significant LOD score was detected at marker D9S2157 Z(max) = 3.64 ( theta= 0.0) in a four-generation family (SC32). Saturation mapping of the 9q region in family SC32 defined the critical disease interval to be flanked by markers D9S930 and D9S1818, spanning approximately 21 Mb at 9q31.2-q34.2. In addition, seven other families segregated with this locus on 9q. In two multi-generation families (SC36 and SC23) not segregating with the 9q locus, a maximum combined LOD score of Z(max) = 4.08 ( = 0.0) was obtained for marker AAT095 on 17q. Fine mapping of the 17q candidate region defined the AIS critical region to be distal to marker D17S1806, spanning approximately 3.2 Mb on chromosome 17q25.3-qtel. CONCLUSION: This study reports a common locus for AIS in the British population, mapping to a refined interval on chromosome 9q31.2-q34.2 and defines a novel AIS locus on chromosome 17q25.3-qtel.