Understanding and addressing vaccine hesitancy in the context of COVID-19: development of a digital intervention.

OBJECTIVES: Severe Acute Respiratory Coronavirus 2 (SARS-CoV-2) was identified in late 2019, spreading to over 200 countries and resulting in almost two million deaths worldwide. The emergence of safe and effective vaccines provides a route out of the pandemic, with vaccination uptake of 75-90% needed to achieve population protection. Vaccine hesitancy is problematic for vaccine rollout; global reports suggest only 73% of the population may agree to being vaccinated. As a result, there is an urgent need to develop equitable and accessible interventions to address vaccine hesitancy at the population level. STUDY DESIGN: & Method: We report the development of a scalable digital intervention seeking to address COVID-19 vaccine hesitancy and enhance uptake of COVID-19 vaccines in the United Kingdom. Guided by motivational interviewing (MI) principles, the intervention includes a series of therapeutic dialogues addressing 10 key concerns of vaccine-hesitant individuals. Development of the intervention occurred linearly across four stages. During stage 1, we identified common reasons for COVID-19 vaccine hesitancy through analysis of existing survey data, a rapid systematic literature review, and public engagement workshops. Stage 2 comprised qualitative interviews with medical, immunological, and public health experts. Rapid content and thematic analysis of the data provided evidence-based responses to common vaccine concerns. Stage 3 involved the development of therapeutic dialogues through workshops with psychological and digital behaviour change experts. Dialogues were developed to address concerns using MI principles, including embracing resistance and supporting self-efficacy. Finally, stage 4 involved digitisation of the dialogues and pilot testing with members of the public. DISCUSSION: The digital intervention provides an evidence-based approach to addressing vaccine hesitancy through MI principles. The dialogues are user-selected, allowing exploration of relevant issues associated with hesitancy in a non-judgmental context. The text-based content and digital format allow for rapid modification to changing information and scalability for wider dissemination.

Organic food consumption and the incidence of cancer in a large prospective study of women in the United Kingdom.

BACKGROUND: Organically produced foods are less likely than conventionally produced foods to contain pesticide residues. METHODS: We examined the hypothesis that eating organic food may reduce the risk of soft tissue sarcoma, breast cancer, non-Hodgkin lymphoma and other common cancers in a large prospective study of 623 080 middle-aged UK women. Women reported their consumption of organic food and were followed for cancer incidence over the next 9.3 years. Cox regression models were used to estimate adjusted relative risks for cancer incidence by the reported frequency of consumption of organic foods. RESULTS: At baseline, 30%, 63% and 7% of women reported never, sometimes, or usually/always eating organic food, respectively. Consumption of organic food was not associated with a reduction in the incidence of all cancer (n=53 769 cases in total) (RR for usually/always vs never=1.03, 95% confidence interval (CI): 0.99-1.07), soft tissue sarcoma (RR=1.37, 95% CI: 0.82-2.27), or breast cancer (RR=1.09, 95% CI: 1.02-1.15), but was associated for non-Hodgkin lymphoma (RR=0.79, 95% CI: 0.65-0.96). CONCLUSIONS: In this large prospective study there was little or no decrease in the incidence of cancer associated with consumption of organic food, except possibly for non-Hodgkin lymphoma.

Lifestyle and health behaviour change support in traditional acupuncture: a mixed method survey study of reported practice (UK).

AIMS: Complementary medicine therapists such as traditional acupuncturists are a large resource for supporting public health targets to improve health behaviours. Our objectives were to determine the prevalence and patterns of UK acupuncturists' provision of lifestyle change support, test theory-based hypotheses about facilitators and barriers to supporting lifestyle changes and to explore associated characteristics and attitudes. METHODS: A mixed methods design in which British Acupuncture Council members (Sept 2019-April 2020) completed an online questionnaire assessing prevalence of lifestyle change support, typical patterns across patients and behaviours, Theory of Planned Behaviour constructs, practitioner characteristics and open-text responses regarding additional behaviours and clinical decisions to introduce lifestyle change. RESULTS: Three hundred fifty-two traditional acupuncturists participated (Mean age = 51.5 years, SD 9.9; 81.8% (n = 288) female). 57.7% (n = 203) reported offering support for lifestyle change during their most recent consultation. 91.7% (n = 323) reported supporting lifestyle change 'always or most of the time' for patients with chronic conditions and 67.9% (n = 239) reported this for patients with acute conditions. The pattern of typical support for different health behaviours ranged from 44.6% (n = 157) for smoking reduction (acute conditions) to 95.2% (n = 335) for diet support (chronic conditions). A linear regression model found that frequency of support for lifestyle change in acute patients was predicted by acupuncturists' attitudes to both clinical role and importance of health behaviours, confidence in their ability to provide lifestyle change support and use of fewer behaviour change techniques. The decision to first offer lifestyle change support was guided by perceived patient receptiveness, whether presenting condition/diagnosis were likely to improve with lifestyle change and whether a strong therapeutic relationship was established. CONCLUSIONS: Traditional acupuncturists' reports suggest their work supports key public health targets for promoting healthy behaviours. Less frequent support for alcohol/smoking may reflect user characteristics but may suggest training needs for acupuncturists. Increase could be made for support in acute presentations, however the importance of patient receptiveness, linking advice to condition, and therapeutic alliance should be explored further. There may be important differences between acupuncture practice and mainstream healthcare (e.g. high level of contact, longer visits, holistic approach) which impact mechanisms of action of behaviour change.

Physical activity, dietary protein and insulin-like growth factor 1: Cross-sectional analysis utilising UK Biobank.

BACKGROUND: Insulin-like growth factor-I (IGF-1) is an anabolic hormone that stimulates cell growth and division. The effects of IGF-1 may be beneficial (muscle growth/repair) or detrimental (increased risk of several types of cancer and mortality) for health. Dietary protein and physical activity are thought to be factors that modulate IGF-1. OBJECTIVE: This study analysed the relationships dietary protein vs IGF-1 and physical activity vs IGF-1 independently with a large sample size, and determined if/how physical activity affected the association between dietary protein and IGF-1 in healthy adults. METHODS: Regression models were used to assess the association between dietary protein and/or physical activity on serum IGF-1 in a cross-sectional sample of 60,677 healthy adults that were enrolled in the UK Biobank project. RESULTS: Dietary protein was positively associated with IGF-1 (0.030 nmol/L;95%CI 0.027-0.033;p < 0.001). Individuals undertaking 10-50 excess MET h/week of physical activity had 0.129 nmol/L greater IGF-1 than participants completing less than 10 excess MET h/week (95%CI 0.028-0.230). The "high" category of physical activity (>50 excess MET h/week) was not correlated with IGF-1 (-0.055 nmol/L;95%CI -0.185-0.076). When dietary protein and physical activity were included in the same model, physical activity did not change the relationship between dietary protein and IGF-1, nor visa-versa. CONCLUSIONS: The positive association between dietary protein and IGF-1 was not influenced by physical activity. The former association was stronger than the latter. Thus, when seeking to adjust IGF-1 for possible health concerns, regulating dietary protein may be more pertinent than physical activity as a primary intervention.

California Gonorrhea Surveillance System: Methodologic Aspects and Key Results of a Sample-Based System.

OBJECTIVES: This article describes findings from the California Gonorrhea Surveillance System (CGSS), developed in response to the need for detailed risk behavior data and clinical data required to control increasing gonorrhea (GC) infections in California. METHODS: CGSS is a sample-based surveillance system implemented throughout California in 2007. In 34 of 61 local health jurisdictions (LHJs), 10% of GC cases are sampled for interview; in the other 27 LHJs, all cases are followed. A standardized case investigation record collects case-reported risk data and provider-reported clinical data, and is electronically prepopulated with available contact data. Exclusion criteria include age younger than 14 years, a GC diagnosis within the previous 30 days, and provider request that patient not be contacted. Analyses are weighted to account for sample design. RESULTS: In 2007, 31,192 cases of GC were reported in California. Of these, 5,388 were sampled for follow-up and 2,715 were interviewed, for a response rate of 54.2%. Of those interviewed, 49.6% were female, 28.8% were heterosexual males, and 21.6% were men who have sex with men (MSM). CGSS collects a wide range of behavioral and clinical data for targeted programmatic action. Findings from the 2007 CGSS included data on the following areas: incarceration (highest among heterosexual males [22.4%]); methamphetamine use (high overall [12.2%] and lower among African Americans [4.6%]); co-infection with human immunodeficiency virus (high among MSM [31.9%] and very low among heterosexual males and females [<0.5%]); and improper antibiotic use (8.3% overall; 25.6% among patients attending urgent care clinics). CONCLUSION: CGSS, an innovative sample-based surveillance system, is effective and flexible. The system provides actionable data on an ongoing basis.

Broad neuroprotective profile of nicotinamide in different mouse models of MPTP-induced parkinsonism.

The factors contributing to substantia nigra pars compacta (SNc) dopamine (DA) neuron death and striatal DA depletion in Parkinson's disease (PD) are still poorly understood. However, mitochondrial dysfunction, cellular energy depletion and oxidative stress appear to play important roles in the pathogenesis of PD. In view of this, the current study examined the potential of nicotinamide, a form of the B-complex vitamin niacin, to protect against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced SNc cell loss and striatal DA depletion in two mouse MPTP models that respond differently to putative neuroprotective agents. Adult male C57Bl/6 mice received nicotinamide (125, 250 or 500 mg/kg i.p.) prior to either acute (four injections in 1 day at 2-h intervals) or sub-acute (two injections per day at 4-h intervals for 5 days) MPTP administration. Striatal DA levels, changes in numbers of tyrosine hydroxylase (TH)- and cresyl violet-stained cells in the SNc at 2 and 6 weeks following the last MPTP exposure were analyzed. Nicotinamide administration resulted in a dose-dependent sparing of striatal DA levels and SNc neurons in acute MPTP-treated animals. Only the highest dose of nicotinamide had similar effects in sub-acute MPTP-treated animals. At 6 weeks after MPTP exposure, there was some spontaneous recovery of striatal DA levels in both models: neuroprotective effects were still apparent in acute but not sub-acute MPTP-treated animals. These results show neuroprotective effects of nicotinamide in different mouse Parkinson models associated with different forms of cell death and suggest that nicotinamide may have broad neuroprotective potential in PD.

Influence of recent altitude exposure on sea level sympathetic neural & hemodynamic responses to orthostasis.

Although it has been shown that muscle sympathetic nerve activity increases during high altitude exposure, mechanisms of sympathoexcitation and blood pressure control after return from altitude are not well described. We hypothesized that: (1) living for 12days at 4300m (Pikes Peak, Colorado) would result in increased muscle sympathetic nerve activity 24h after return to sea level; (2) post-Pikes Peak sympathetic neural and hemodynamic responses to orthostasis would be decreased due to a potential 'ceiling effect' on sympathetic activity; and (3) the magnitude of individual increases in sympathetic nerve activity post-Pikes Peak would be inversely related to baseline sympathetic nerve activity before traveling to altitude. Muscle sympathetic nerve activity, heart rate and blood pressure were measured in 9 healthy individuals (24±8years) in supine, 30° and 45° head-up tilt positions. Measurements were conducted twice at sea level, once before (pre-Pikes Peak) a 12day residence at 4300m, and once within 24h of return (post-Pikes Peak). Supine muscle sympathetic nerve activity was higher (post: 27±5 vs pre: 17±6bursts/min) upon return from altitude (p<0.05). Individual values for pre-Pikes Peak sympathetic activity were inversely related to post-altitude sympathoexcitation (r=-0.69, p<0.05). There were no differences in neural or cardiovascular responses to tilt between pre and post- Pikes Peak (p>0.05). We conclude that 12days' residence at 4300m causes a sustained sympathoexcitation which does not impair the ability of muscle sympathetic nerves to respond appropriately to orthostasis.

The synthetic ceramide analog L-PDMP partially protects striatal dopamine levels but does not promote dopamine neuron survival in murine models of parkinsonism.

A number of previous studies have demonstrated a positive effect of exogenously administered monosialoganglioside GM1 on striatal dopamine (DA) levels and DA neuron survival in animal models of parkinsonism. However, due to low bioavailability of peripherally administered GM1, the present study investigated the neuroprotective/neurorestorative potential of enhancing endogenous GM1 biosynthesis by administration of the synthetic ceramide analog L-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol (L-PDMP) in two mouse models of Parkinsonism produced by acute or subacute 1-methy-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) administration. L-PDMP treatment caused an increase in brain GM1 levels in both Parkinson models and resulted in a partial sparing of striatal DA levels in the subacute MPTP model but not in the acute MPTP model. L-PDMP treatment had no effect on DA neuron survival in either model. These data suggest that the administration of L-PDMP as a means to enhance endogenous brain GM1 levels may hold limited promise as a potential neuroprotective or neurorestorative therapeutic strategy for Parkinson's disease.

Use of antimicrobial agents in a university teaching hospital. Evolution of a comprehensive control program.

A comprehensive control program for utilization of anti-microbial agents in a large tertiary university teaching hospital regulates both dosage and duration of therapy and requires the prior approval of an infectious disease specialist for utilization of restricted antimicrobial agents. Benefits of the program include more cost-effective antimicrobial therapy and increased physician education in the use of these drugs. Gross savings in pharmacy costs for antibiotics during the first year of the program (1985) amounted to +483,032 for an average monthly savings of +40,252. Gross savings for 1986 were +211,786 with monthly savings of +17,648. The control of the use of one agent may lead to overuse of another agent. Antimicrobial prescribing patterns of physicians are quickly influenced by changing regulations of the program. An ongoing surveillance and review program of in-hospital utilization of antimicrobial agents is necessary to maintain effective and flexible controls.

Dietary folate intake and breast cancer risk: European prospective investigation into cancer and nutrition.

BACKGROUND: There is limited evidence on the association between dietary folate intake and the risk of breast cancer (BC) by hormone receptor expression in the tumors. We investigated the relationship between dietary folate and BC risk using data from the European Prospective Investigation into Cancer and Nutrition (EPIC). METHODS: A total of 367993 women age 35 to 70 years were recruited in 10 European countries. During a median follow-up of 11.5 years, 11575 women with BC were identified. Dietary folate intake was estimated from country-specific dietary questionnaires. Cox proportional hazards regression models were used to quantify the association between dietary variables and BC risk. BC tumors were classified by receptor status. Subgroup analyses were performed by menopausal status and alcohol intake. Intake of other B vitamins was considered. All statistical tests were two-sided. RESULTS: A borderline inverse association was observed between dietary folate and BC risk (hazard ratio comparing top vs bottom quintile [HRQ5-Q1] = 0.92, 95% CI = 0.83 to 1.01, P trend = .037). In premenopausal women, we observed a statistically significant trend towards lower risk in estrogen receptor-negative BC (HRQ5-Q1 = 0.66, 95% CI = 0.45 to 0.96, P trend = .042) and progesterone receptor-negative BC (HRQ5-Q1 = 0.70, 95% CI = 0.51 to 0.97, P trend = .021). No associations were found in postmenopausal women. A 14% reduction in BC risk was observed when comparing the highest with the lowest dietary folate tertiles in women having a high (>12 alcoholic drinks/week) alcohol intake (HRT3-T1 = 0.86, 95% CI = 0.75 to 0.98, P interaction = .035). CONCLUSIONS: Higher dietary folate intake may be associated with a lower risk of sex hormone receptor-negative BC in premenopausal women.

Multiple sclerosis: effects of activated T-lymphocyte-derived products on organ cultures of nervous tissue.

Supernatants from multiple sclerosis (MS) T-lymphocytes cause damage to both myelin and glial cells in cerebellar cultures assessed visually and by radiolabel release. Control T-lymphocytes, even after phytohaemagglutinin (PHA) stimulation, yielded supernatants which induced only slight damage, and at later times patients with other neurological diseases (OND) gave variable results. These differences suggest that MS T-lymphocytes are pre-activated in vivo to produce demyelinating factors while control T-lymphocytes are not pre-activated to the same extent. The visual evidence of activation of cerebellar macrophage-like cells was a common finding after MS T-lymphocyte supernatant treatment but there was no correlation with the severity of demyelination. There was a positive correlation between the percentage IL-2 receptor-bearing lymphocytes and the degree of supernatant-induced in vitro demyelination.

Generation of a human hybridoma producing a pure anti-HLA-A2 monoclonal antibody.

We report the production and characterization of a human monoclonal IgM hybridoma antibody recognizing antigen HLA-A2. B lymphocytes obtained from the peripheral blood of a multiparous volunteer 1 week postpartum were transformed in vitro by Epstein-Barr virus, screened by a microlymphocytotoxicity assay, and electrofused with the heterohybridoma fusion partner, K6H6/B5. A specifically anti-A2 secreting hybridoma cell line. MBW1, was then identified and cloned. The cytotoxic IgM antibody produced showed complete correlation (r = 1.00) with the A2 antigen on a large panel of unrelated donors' lymphocytes, and no cross-reactivity with A28, Aw68, or Aw69 antigens was observed.

Late Niemann-Pick disease with neurovisceral storage: a classification problem.

A 51 year old man presented in 1969 with slowly progressive cerebellar ataxia of unknown origin. He was admitted to hospital aged 68 after a fall, and a ruptured spleen was removed at laparotomy. Histological analysis of the spleen suggested Niemann-Pick disease, which was subsequently confirmed. He deteriorated and died of bronchopneumonia shortly afterwards: subdural haemorrhage with storage material in neurones was found at necropsy. This late onset case of Niemann-Pick disease with neurovisceral storage is unusual and may represent a variant.

Pharmacokinetic properties of mezlocillin in ambulatory elderly subjects.

Twelve healthy ambulatory elderly subjects (mean age, 73-78 years) randomly received either a 4-g or 5-g dose of mezlocillin intravenously. One week later the regimen was repeated and patients crossed over to the other dose. Peak serum concentrations were 165 mg/L and 281 mg/L for the 4-g and 5-g doses, respectively. For both doses, differences in t1/2 beta (1.32 hr vs 1.13 hr), AUC (275 mg.hr/L vs 403 mg.hr/L), CL (207 mL/min vs 174 mL/min), CLR (59 mL/min vs 45 mL/min), CLNR (152 mL/min vs 130 mL/min) were not statistically significant. The differences in Varea (22.4L vs 168.8L, P less than or equal to .01) and Cmax (216.6 mg/L vs 317 mg/L, P less than or equal to .05) were statistically significant. Comparison with pharmacokinetic parameters obtained in younger subjects following the 5-g dose reveals that in the elderly the AUC, Varea, and CLNR are higher whereas the CL and CLR are lower. The elderly demonstrated an increase in nonrenal clearance compared with young subjects that is not fully compensatory. The increased AUC in the elderly group suggests that clinical studies examining mezlocillin doses and dose intervals in the treatment of serious infections are warranted in infected elderly patients.

Role of complement in demyelination in vitro by multiple sclerosis serum and other neurological disease sera.

Multiple sclerosis (MS) sera can demyelinate and cause selective cellular changes to organ cultures of rodent CNS which suggests possible immunoglobulin involvement. The complement dependence of this serum action was investigated using complement-inactivating agents and radiolabelled rat cerebellar cultures. After heat inactivation at 56 degrees C, the in vitro effects of MS, chronic relapsing experimental allergic encephalomyelitis (cr-EAE) and Guillain-Barré syndrome (GBS) sera were severely reduced or eliminated as measured by radiolabel release. On introducing a source of fresh complement, the cr-EAE and GBS serum effects were largely restored whereas MS serum effects remained suppressed. Inactivation of serum complement with mercaptoethanol and Zymosan was associated with marked reduction in serum myelinotoxicity; some restoration of in vitro effects was possible on adding fresh complement although this occurred to a greater extent with cr-EAE and GBS than with MS sera. Inactivation of the alternative complement pathway brought a limited reduction in MS serum activity in vitro which was not restored with fresh complement. It is concluded that complement is involved only to a limited extent in MS serum myelinotoxic effects and that MS serum effects in vitro are due to several components of which thermolabile substances make a significant contribution and are as yet uncharacterised.

New approach to study of in vitro toxicity of multiple sclerosis and other sera.

The in vitro effects of MS and control sera were quantified by the measurement of radiolabel released from myelinated cultures of rat cerebellum and compared with a visual assessment of myelin damage. Radiolabel release gave a sensitive index of serum effects in vitro which was free of the score assignment decisions that are associated with the visual assessment of myelin damage. Examination of the patterns of radiolabel release elicited by MS and control sera on cultures labelled with either L-[5-3H]tryptophan or galacto-D-[6-3H]cerebroside indicates that MS serum effects are not simply a stronger expression of the weak control serum effects.

Comparison of in vitro demyelination and cytotoxicity of humoral factors in multiple sclerosis and other neurological diseases.

The distribution and nature of serum factors causing in vitro demyelination and glial lysis were investigated in multiple sclerosis (MS), other neurological diseases (OND), ill control and control groups. MS sera were unique in affecting only CNS myelin and glia whereas stroke and Guillain-Barré syndrome (GBS) sera brought changes to both CNS and PNS tissue. Through both visual scoring of myelin damage and the quantitative measurement of radiolabel release from cerebellar cultures, it was evident that the MS and OND groups have similar myelino- and cytotoxic effects. This may reflect MS and OND sera sharing similar humoral factors. 74% MS, 68% OND and 22% of control scores were above a score threshold designed to exclude culture handling trauma effects. When classified by their current disease state MS patients with severe and mild disease yielded higher in vitro scores than did those with moderate disease who comprised an older age group. No other clinical features of MS patients gave any association with in vitro serum effects. The rare demonstration of bound Fab IgG in cultures after MS serum tests indicates that immune mechanisms are unlikely to make a large contribution to serum-induced demyelination and cellular change in vitro.

Prevention of medication errors. Developing a continuous-quality-improvement approach.

Medication errors can be a serious problem that exposes patients to preventable risks. Although medication errors are often considered primarily a nursing issue, every health care provider plays an important role in medication error prevention. A continuous quality improvement philosophy with involvement of a multidisciplinary team is the optimal method for identifying and correcting the causes of medication errors. Careful analysis of the medication distribution system and identification of system flaws is an integral part of the continuous quality improvement process.

Abnormal myelin maturation in vitro: the role of cerebrosides.

Myelinating neonatal rat cerebellar explants were maintained for up to 130 days in vitro. Myelin fractions were extracted from explants of different ages and purified by density gradient centrifugation. Three fractions obtained were termed "light myelin", "heavy myelin" and "membrane fraction" and were deficient in glycolipids compared to myelin fractions prepared from 15-day-old rat cerebellum. The culture myelin has an apparently normal ultrastructure but may not be as stable as myelin with a normal glycolipid composition.

Brain graft surgery: a new treatment for Parkinson's disease.

Brain graft surgery remains controversial, and the beneficial effects, though promising, are mixed. For those patients who are eligible, it offers new hope for an alternative to early disability and family hardship. Outlined here are the etiology, pathophysiology, and manifestations of Parkinson's disease, plus the surgical procedure and postoperative nursing care.