The effect of a digital health coaching and health education protocol on cognition in adults at-risk for Alzheimer's.

Several modifiable lifestyle factors have been linked to cognitive ability and the risk of developing Alzheimer's disease and related dementias (ADRD). Health coaching (HC) is an intervention that addresses lifestyle factors associated with cognition. The effectiveness of an HC protocol was evaluated and compared with a health education (HE) intervention, representing the current standard of care, in a sample of 216 adults between the ages of 45 and 75 years who were at-risk for developing ADRD. Outcomes examined were global cognition, neuropsychological cognition, and Alzheimer's risk. HC participants received personalized coaching from a health coach focusing on nutrition, physical activity, sleep, stress, social engagement, and cognitive activity. HE participants received biweekly education materials focusing on the same modifiable lifestyle factors addressed by HC. Participants were assessed at baseline and again 4 months later. Self-reported global cognition scores improved only in the HC group (16.18 to 15.52, p = .03) and neuropsychological cognitive ability improved in the HE group (104.48 to 108.76, p < .001). When non-adherence in the HC group was accounted for, however, the mean change in neuropsychological score was similar between groups (p > .05), self-reported global cognition demonstrated an even larger mean improvement in the HC group (16.20 to 15.41, p = .01), and the HC group saw an improvement in ADRD protective risk score (- 10.39 to - 11.45, p = .007). These results indicate that HC and HE can both improve cognition, but HC may be more effective and may yield increased protection against ADRD risk.

Pasifika women's knowledge and perceptions of cervical-cancer screening and the implementation of self-testing in Aotearoa New Zealand: A qualitative study.

Background: In Aotearoa New Zealand, Pasifika women have a higher rate of cervical cancer incidence and mortality than European/Other women and a lower screening rate. Despite actions to reduce the barriers, there has been little change in screening coverage for Pasifika women since 2007. Novel strategies are therefore required. Persistent cervical infection with oncogenic human papillomavirus (HPV) causes virtually all cervical cancers and HPV testing will be implemented in Aotearoa in 2023, with women being able to choose to self-test. We undertook a qualitative focus group (FG) study with Pasifika women to explore their perspectives on the barriers to, and facilitators of, HPV self-testing and how best to implement this in Aotearoa. Methods: A trained female Pasifika Research Assistant facilitated participant recruitment and the FGs. Eligible participants self-identified as Pasifika, were aged 30-69 years, in the Wellington area, who had never been screened or who were overdue (≥5 years) for cervical-cancer screening. Recruitment was predominantly through Pasifika key-informant networks and in collaboration with Pasifika primary care providers. Participants were offered face-to-face FGs but, due to occasional Covid-19 restrictions and personal preferences, FGs via Zoom were also used. The FGs were audio-recorded and transcribed verbatim. The FG transcripts were thematically analysed. Findings: Seven FGs were conducted with 24 participants. We identified five main themes around barriers and potential facilitators of HPV self-testing in Pasifika women: 1) perceptions and knowledge of cervical-cancer screening; 2) challenges to engaging in organised cervical screening; 3) perceptions of self-testing for HPV and challenges women face when deciding to self-test; 4) enthusiasm for an HPV self-test; and 5) information and communication. Knowledge about cervical cancer and screening varied considerably among participants, with some never having heard about cervical-cancer screening. The main challenges that were raised were personal privacy and confidentiality and time management. There was consensus around the need for adequate, consistent, and accurate accessible information to boost the confidence of women undertaking self-testing. In general, the participants were eager for self-testing to be made available soon. This was accompanied by the need for the promotion and implementation of self-testing to include a collective/community approach consistent with Pasifika worldviews. Interpretation: Although participants were enthusiastic about HPV self-testing, multi-level and interacting barriers exist to participation by Pasifika women in HPV self-testing. Implementation of self-testing in Aotearoa New Zealand should be accompanied by clear information about the entire process, using culturally appropriate tailored educational campaigns in different Pasifika languages. Funding: The study was supported by the Collaboration for Cancer Research Aotearoa New Zealand (CCR).

Heterophilic and homophilic cadherin interactions in intestinal intermicrovillar links are species dependent.

Enterocytes are specialized epithelial cells lining the luminal surface of the small intestine that build densely packed arrays of microvilli known as brush borders. These microvilli drive nutrient absorption and are arranged in a hexagonal pattern maintained by intermicrovillar links formed by 2 nonclassical members of the cadherin superfamily of calcium-dependent cell adhesion proteins: protocadherin-24 (PCDH24, also known as CDHR2) and the mucin-like protocadherin (CDHR5). The extracellular domains of these proteins are involved in heterophilic and homophilic interactions important for intermicrovillar function, yet the structural determinants of these interactions remain unresolved. Here, we present X-ray crystal structures of the PCDH24 and CDHR5 extracellular tips and analyze their species-specific features relevant for adhesive interactions. In parallel, we use binding assays to identify the PCDH24 and CDHR5 domains involved in both heterophilic and homophilic adhesion for human and mouse proteins. Our results suggest that homophilic and heterophilic interactions involving PCDH24 and CDHR5 are species dependent with unique and distinct minimal adhesive units.

Germline CDH1 mutations are a significant contributor to the high frequency of early-onset diffuse gastric cancer cases in New Zealand Maori.

New Zealand Maori have a considerably higher incidence of gastric cancer compared to non-Maori, and are one of the few populations worldwide with a higher prevalence of diffuse-type disease. Pathogenic germline CDH1 mutations are causative of hereditary diffuse gastric cancer, a cancer predisposition syndrome primarily characterised by an extreme lifetime risk of developing diffuse gastric cancer. Pathogenic CDH1 mutations are well described in Maori families in New Zealand. However, the contribution of these mutations to the high incidence of gastric cancer is unknown. We have used next-generation sequencing, Sanger sequencing, and Multiplex Ligation-dependent Probe Amplification to examine germline CDH1 in an unselected series of 94 Maori gastric cancer patients and 200 healthy matched controls. Overall, 18% of all cases, 34% of cases diagnosed with diffuse-type gastric cancer, and 67% of cases diagnosed aged less than 45 years carried pathogenic CDH1 mutations. After adjusting for the effect of screening known HDGC families, we estimate that 6% of all advanced gastric cancers and 13% of all advanced diffuse-type gastric cancers would carry germline CDH1 mutations. Our results demonstrate that germline CDH1 mutations are a significant contributor to the high frequency of diffuse gastric cancer in New Zealand Maori.

Risk of stomach cancer in Aotearoa/New Zealand: A Maori population based case-control study.

Maori, the indigenous people of New Zealand, experience disproportionate rates of stomach cancer, compared to non-Maori. The overall aim of the study was to better understand the reasons for the considerable excess of stomach cancer in Maori and to identify priorities for prevention. Maori stomach cancer cases from the New Zealand Cancer Registry between 1 February 2009 and 31 October 2013 and Maori controls, randomly selected from the New Zealand electoral roll were matched by 5-year age bands to cases. Logistic regression was used to estimate odd ratios (OR) and 95% confidence intervals (CI) between exposures and stomach cancer risk. Post-stratification weighting of controls was used to account for differential non-response by deprivation category. The study comprised 165 cases and 480 controls. Nearly half (47.9%) of cases were of the diffuse subtype. There were differences in the distribution of risk factors between cases and controls. Of interest were the strong relationships seen with increased stomach risk and having >2 people sharing a bedroom in childhood (OR 3.30, 95%CI 1.95-5.59), testing for H pylori (OR 12.17, 95%CI 6.15-24.08), being an ex-smoker (OR 2.26, 95%CI 1.44-3.54) and exposure to environmental tobacco smoke in adulthood (OR 3.29, 95%CI 1.94-5.59). Some results were attenuated following post-stratification weighting. This is the first national study of stomach cancer in any indigenous population and the first Maori-only population-based study of stomach cancer undertaken in New Zealand. We emphasize caution in interpreting the findings given the possibility of selection bias. Population-level strategies to reduce the incidence of stomach cancer in Maori include expanding measures to screen and treat those infected with H pylori and a continued policy focus on reducing tobacco consumption and uptake.

Barriers to and delays in accessing breast cancer care among New Zealand women: disparities by ethnicity.

BACKGROUND: Unequal access to health care contributes to disparities in cancer outcomes. We examined the ethnic disparity in barriers to accessing primary and specialist health care experienced by New Zealand women with breast cancer. METHODS: Women diagnosed with a primary invasive breast cancer between 2005 and 2007 were eligible. There were 1,799 respondents, n = 302 Maori (the indigenous population of NZ), n = 70 Pacific and n = 1,427 non-Maori/non-Pacific women. Participants completed a questionnaire listing 12 barriers grouped into three domains for analysis: personal; practical; and health care process factors, and reported the number of days between seeing a primary and a specialist care provider. Chi-squared, Fisher exact tests and logistic regression were used to assess uni- and multivariable differences in prevalence between ethnic groupings. RESULTS: The prevalence of reporting three or more barriers was 18% among Pacific, 10% among Maori and 3% among non-Maori/non-Pacific women (P <0.001). The most commonly reported barriers were fear (Maori women) and cost (Pacific and non-Maori/non-Pacific women). Ethnic differences in reported barriers were not explained by deprivation or diabetes prevalence. Women with diabetes reported a two-fold higher risk of experiencing barriers to care compared to those without diabetes (odds ratio [OR]: 2.06, 95%CI 1.20 to 3.57). Maori and Pacific women were more likely to face delays (median 14 days) in seeing a specialist than non-Maori/non-Pacific women (median 7 days); these differences were not explained by the reported barriers. CONCLUSIONS: Patterns of reported barriers to care differed according to ethnicity and were not explained by deprivation, or presence of co-morbidity. Maori and Pacific women are more likely to experience barriers to breast cancer care compared to non- Maori/non-Pacific women. We identified two key barriers affecting care for Maori and Pacific women; (a) delays in follow-up, and (b) the impact of co-morbid conditions. Future New Zealand work needs to focus attention on health care process factors and improving the interface between primary and secondary care to ensure quality health care is realised for all women with breast cancer.

Outcomes of cataract surgery in graft-versus-host disease.

PURPOSE: To study the outcomes of cataract surgery in patients with graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation (HSCT). METHODS: Retrospective review of 72 eyes of 41 patients (age, 17-69 years at the time of surgery) with chronic GVHD after HSCT, who underwent cataract surgery between 2008 and 2012 at the Department of Ophthalmology and Visual Sciences, W. K. Kellogg Eye Center, University of Michigan. Ophthalmic data collected included best-corrected visual acuity (BCVA), responses to Ocular Surface Disease Index (OSDI) questionnaire, dry eye severity, and postoperative complications. RESULTS: BCVA improved from 20/49 to 20/25 (P < 0.0001) after surgery. Eight patients (20%) had pretransplantation total body irradiation and 39 patients (95%) received systemic corticosteroids for the treatment of GVHD. Postoperative complications included cystoid macular edema (4 eyes), corneal ulceration with perforation (2 eyes: 1 infected and 1 sterile), and band keratopathy (1 eye). After surgery, subjective OSDI responses and dry eye disease (DED) did not change significantly from before cataract surgery, although OSDI showed a trend toward worsening. CONCLUSIONS: With careful monitoring and management of DED and concurrent ocular surface disease, cataract surgery generally has good visual outcomes in patients with GVHD. However, aggravation of the preexisting ocular surface disease is frequent, and despite meticulous postoperative maintenance therapy, vision-threatening complications may occur.

Postoperative Hemorrhagic Occlusive Retinal Vasculitis: Expanding the Clinical Spectrum and Possible Association with Vancomycin.

PURPOSE: To describe a syndrome of hemorrhagic occlusive retinal vasculitis (HORV) that developed after seemingly uncomplicated cataract surgery. DESIGN: Retrospective case series. SUBJECTS: Eleven eyes of 6 patients from 6 different institutions. METHODS: Cases were identified after discussion among retina specialists. The findings on presentation, clinical course, and outcome of a series of 7 eyes of 4 patients were compared with a previous report of 4 eyes of 2 patients, and data from both series were combined for a comprehensive analysis. MAIN OUTCOME MEASURES: Historical data, examination findings, imaging results, systemic evaluation findings, treatment regimens, and visual outcomes. RESULTS: Eleven eyes of 6 patients underwent otherwise uncomplicated cataract surgery, receiving viscoelastic and prophylactic intracameral vancomycin during the procedure. Despite good initial vision on postoperative day 1, between 1 to 14 days after surgery, all eyes demonstrated painless vision loss resulting from HORV. Extensive ocular and systemic evaluations were unrevealing in all patients. All patients were treated with aggressive systemic and topical corticosteroids. Additional treatments included systemic antiviral medication in 4 patients, intravitreal antibiotics in 4 eyes, and pars plana vitrectomy in 4 eyes. Skin testing for vancomycin sensitivity showed negative results in 3 patients and was not performed in the others. Neovascular glaucoma developed in 7 eyes, and all eyes received intravitreal anti-vascular endothelial growth factor (VEGF) injection, panretinal photocoagulation, or both for retinal ischemia. Final visual acuity was less than 20/100 in 8 of 11 eyes. CONCLUSIONS: Postoperative HORV is an exceedingly rare and potentially devastating condition that can occur after otherwise uncomplicated cataract surgery. Although the precise cause remains unknown, this disease may represent a delayed immune reaction similar to vancomycin-induced leukocytoclastic vasculitis. Despite treatment with high-dose corticosteroids, antiviral medication, and early vitrectomy in many patients, visual outcomes typically were poor in this series. Early intervention with intravitreal anti-VEGF medication and panretinal photocoagulation may help to prevent additional vision loss resulting from neovascular glaucoma.

Outcomes of cataract surgery in eyes with previous herpes zoster ophthalmicus.

PURPOSE: To report the outcomes of cataract surgery in eyes with previous herpes zoster ophthalmicus (HZO). SETTING: Kellogg Eye Center, University of Michigan, Ann Arbor, Michigan, USA. DESIGN: Retrospective case series. METHODS: Eyes with a history of HZO that had phacoemulsification and intraocular lens implantation were reviewed. The information analyzed included the ophthalmologic history, visual acuity, preoperative and postoperative adjunct treatments, and complications. Analysis of the mean corrected distance visual acuity (CDVA) at 1 month, 1 year, and the last follow-up was performed. RESULTS: Twenty-four eyes were evaluated. The mean CDVA improved from 20/112 (0.75 logMAR ± 0.63 [SD]) preoperatively to 20/53 (0.42 ± 0.56 logMAR) 1 month postoperatively (P = .007) and 20/44 (0.34 ± 0.55 logMAR) at 1 year (P = .052) but decreased to 20/71 (0.55 ± 0.72 logMAR) by last follow-up (P = .605 versus preoperative CDVA). Eleven patients (45.8%) had recurrent keratouveitis after the first episode, 5 before cataract surgery and 6 after cataract surgery. Three had penetrating keratoplasty for worsening corneal opacification. Two patients had tractional retinal detachment from chronic uveitis and required vitrectomy and retinal repair. CONCLUSIONS: Visual recovery after cataract surgery in HZO might be compromised by chronic factors such as ocular surface disease and keratouveitis. Despite long quiescent waiting periods before surgery and aggressive preoperative and postoperative maintenance therapy, visual improvement might be hindered by the inherent pathology associated with HZO. Nevertheless, with careful patient selection, reasonable visual improvement can be achieved. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned.

α-Synuclein overexpression represses 14-3-3θ transcription.

Previous gene microarray studies have shown that expression of 14-3-3θ is significantly decreased in an α-synuclein transgenic mouse model. In this study, we tested whether α-synuclein can regulate 14-3-3θ transcription. We demonstrate that the 14-3-3θ mRNA level is decreased in SH-SY5Y cells overexpressing α-synuclein. Luciferase activity under the control of the 14-3-3θ promoter is reduced both in stable SH-SY5Y cells constitutively overexpressing α-synuclein and in doxycycline-inducible SH-SY5Y cells upon α-synuclein induction, suggesting that the regulation of 14-3-3θ by α-synuclein occurs at the transcriptional level. Knockdown of α-synuclein by RNA interference does not increase the 14-3-3θ mRNA level. These findings suggest that α-synuclein represses 14-3-3θ transcription under pathologic conditions, but that regulation of 14-3-3θ expression is not a function of endogenous α-synuclein at baseline.

A multi-ethnic breast cancer case-control study in New Zealand: evidence of differential risk patterns.

PURPOSE: To investigate whether the relationships between established risk factors and breast cancer risk differ between three ethnic groups in New Zealand, namely Maori, Pacific, and non-Maori/non-Pacific women. METHODS: The study is a multi-ethnic, age-, and ethnicity-matched population-based case-control study of breast cancer in women. Women with a primary, invasive breast cancer registered on the New Zealand Cancer Registry between 1 April 2005 and 30 April 2006, and Maori or Pacific women diagnosed to 30 April 2007 were eligible. Control women were identified from the New Zealand Electoral Roll, stratified by ethnicity, then frequency matched on age to the cases. Logistic regression was used to estimate odds ratios (OR) and 95 % confidence intervals (CI) between exposures and breast cancer risk in three ethnic groups separately. Likelihood ratio tests were used to test for modification of the effects by ethnicity. Post-stratification weighting of the controls was used to account for differential non-response by deprivation category. RESULTS: The study comprised 1,799 cases (302 Maori, 70 Pacific, 1,427 non-Maori/non-Pacific) and 2,543 controls (746 Maori, 194 Pacific, 1,603 non-Maori/non-Pacific), based on self-identified ethnicity. Maori women were more likely to have ER and PR positive breast cancer compared to other ethnicities. There were marked differences in exposure prevalence between ethnicities and some differing patterns of risk factors for breast cancer between the three main ethnic groups. Of interest was the strong relationship between number of children and lower breast cancer risk in Pacific women (OR for 4 or more vs. 1 child OR 0.13, 95 % CI 0.05-0.35) and a higher risk of breast cancer associated with smoking (OR 1.76, 95 % CI 1.25-2.48) and binge drinking (5 or more vs. 1-2 drinks per occasion, OR 1.55, 95 % CI 1.07-2.26) in Maori women. Some of the documented results were attenuated following post-stratification weighting. CONCLUSIONS: The findings of this study need to be interpreted with caution, given the possibility of selection bias due to low response rates among some groups of women. Reducing the burden of breast cancer in New Zealand is likely to require different approaches for different ethnic groups.

Identifying polyglutamine protein species in situ that best predict neurodegeneration.

Polyglutamine (polyQ) stretches exceeding a threshold length confer a toxic function to proteins that contain them and cause at least nine neurological disorders. The basis for this toxicity threshold is unclear. Although polyQ expansions render proteins prone to aggregate into inclusion bodies, this may be a neuronal coping response to more toxic forms of polyQ. The exact structure of these more toxic forms is unknown. Here we show that the monoclonal antibody 3B5H10 recognizes a species of polyQ protein in situ that strongly predicts neuronal death. The epitope selectively appears among some of the many low-molecular-weight conformational states assumed by expanded polyQ and disappears in higher-molecular-weight aggregated forms, such as inclusion bodies. These results suggest that protein monomers and possibly small oligomers containing expanded polyQ stretches can adopt a conformation that is recognized by 3B5H10 and is toxic or closely related to a toxic species.

Puromycin-sensitive aminopeptidase (PSA/NPEPPS) impedes development of neuropathology in hPSA/TAU(P301L) double-transgenic mice.

Accumulation of neurotoxic hyperphosphorylated TAU protein is a major pathological hallmark of Alzheimer disease and other neurodegenerative dementias collectively called tauopathies. Puromycin-sensitive aminopeptidase (PSA/NPEPPS) is a novel modifier of TAU-induced neurodegeneration with neuroprotective effects via direct proteolysis of TAU protein. Here, to examine the effects of PSA/NPEPPS overexpression in vivo in the mammalian system, we generated and crossed BAC-PSA/NPEPPS transgenic mice with the TAU(P301L) mouse model of neurodegeneration. PSA/NPEPPS activity in the brain and peripheral tissues of human PSA/NPEPPS (hPSA) mice was elevated by ∼2-3-fold with no noticeable deleterious physiological effects. Double-transgenic animals for hPSA and TAU(P301L) transgenes demonstrated a distinct trend for delayed paralysis and showed significantly improved motor neuron counts, no gliosis and markedly reduced levels of total and hyperphosphorylated TAU in the spinal cord, brain stem, cortex, hippocampus and cerebellum of adult and aged animals when compared with TAU(P301L) mice. Furthermore, endogenous TAU protein abundance in human neuroblastoma SH-SY5Y cells was significantly reduced or augmented by overexpression or knockdown of PSA/NPEPPS, respectively. This study demonstrated that without showing neurotoxic effects, elevation of PSA/NPEPPS activity in vivo effectively blocks accumulation of soluble hyperphosphorylated TAU protein and slows down the disease progression in the mammalian system. Our data suggest that increasing PSA/NPEPPS activity may be a feasible therapeutic approach to eliminate accumulation of unwanted toxic substrates such as TAU.

Serum dioxin levels in former New Zealand sawmill workers twenty years after exposure to pentachlorophenol (PCP) ceased.

From the 1950s to the late 1980s pentachlorophenol (PCP) based anti-sapstain fungicides were widely used in the New Zealand timber industry. Workers involved in treatment, or those handling freshly treated timber, experienced significant PCP exposure. Commercial grade PCP contained contaminants including 2,3,7,8-substituted polychlorinated dibenzo-p-dioxin (PCDD) and dibenzofuran (PCDF) congeners. To determine whether PCP exposure had resulted in elevated serum dioxin levels twenty years after its use had ceased we tested 94 former sawmill workers randomly selected from surviving members of a cohort enumerated for a mortality and cancer incidence study. After interviewing these individuals to collect demographic data and a comprehensive work history, they were divided into 71 PCP-exposed and 23 non-exposed individuals on the basis of job title and work tasks performed. We compared age-adjusted dioxin levels in the exposed and non-exposed groups, examined the effect of PCP exposure duration and intensity, and compared congener profiles with those found in the commercial grade PCP used at the time. Mean levels in exposed workers were elevated when compared with the non-exposed, with levels of 1,2,3,6,7,8-HxCDD, 1,2,3,4,6,7,8-HpCDD and OCDD being two to three times higher. The congener profiles in serum were consistent with those in PCP solutions, and dioxin levels increased with both employment duration and estimated exposure intensity. Serum dioxin levels in former New Zealand sawmill workers remain elevated twenty years after exposure to PCP ceased, and reflect the pattern of past PCP exposure.

Full-length human mutant huntingtin with a stable polyglutamine repeat can elicit progressive and selective neuropathogenesis in BACHD mice.

To elucidate the pathogenic mechanisms in Huntington's disease (HD) elicited by expression of full-length human mutant huntingtin (fl-mhtt), a bacterial artificial chromosome (BAC)-mediated transgenic mouse model (BACHD) was developed expressing fl-mhtt with 97 glutamine repeats under the control of endogenous htt regulatory machinery on the BAC. BACHD mice exhibit progressive motor deficits, neuronal synaptic dysfunction, and late-onset selective neuropathology, which includes significant cortical and striatal atrophy and striatal dark neuron degeneration. Power analyses reveal the robustness of the behavioral and neuropathological phenotypes, suggesting BACHD as a suitable fl-mhtt mouse model for preclinical studies. Additional analyses of BACHD mice provide novel insights into how mhtt may elicit neuropathogenesis. First, unlike previous fl-mhtt mouse models, BACHD mice reveal that the slowly progressive and selective pathogenic process in HD mouse brains can occur without early and diffuse nuclear accumulation of aggregated mhtt (i.e., as detected by immunostaining with the EM48 antibody). Instead, a relatively steady-state level of predominantly full-length mhtt and a small amount of mhtt N-terminal fragments are sufficient to elicit the disease process. Second, the polyglutamine repeat within fl-mhtt in BACHD mice is encoded by a mixed CAA-CAG repeat, which is stable in both the germline and somatic tissues including the cortex and striatum at the onset of neuropathology. Therefore, our results suggest that somatic repeat instability does not play a necessary role in selective neuropathogenesis in BACHD mice. In summary, the BACHD model constitutes a novel and robust in vivo paradigm for the investigation of HD pathogenesis and treatment.