Life Course Predictors of Young Men Surviving to Age 90 in a Cohort Study: The Manitoba Follow-up Study.

The purpose of this study was to identify factors at various time points in life that are associated with surviving to age 90. Data from men enrolled in a cohort study since 1948 were considered in 12-year intervals. Logistic regression models were constructed with the outcome of surviving to age 90. Factors were: childhood illness, blood pressure (BP), body mass index (BMI), chronic diseases, and electrocardiogram (ECG) findings. After 1996, the Short Form-36 was added. A total of 3,976 men were born in 1928 or earlier, and hence by the end of our study window in 2018, each had the opportunity of surviving to age 90. Of these, 721 did live to beyond his 90th birthday.The factors in 1948 which predicted surviving were: lower diastolic BP, lower BMI, and not smoking. In 1960, these factors were: lower BP, lower BMI, not smoking, and no major ECG changes. In 1972, these factors were lower BP, not smoking, and fewer disease states. In 1984, these factors were lower systolic BP, not smoking, ECG changes, and fewer disease states. In 1996, the factors were fewer disease states and higher physical and mental health functioning. In 2008, only higher physical functioning predicted survival to the age of 90. In young adulthood, risk factors are important predictors of surviving to age 90; in mid-life, chronic illnesses emerge, and in later life, functional status becomes predominant.

Body talk and resilience: Aging men's experiences with mastectomy and prostatectomy.

Men's experiences with gendered cancers hinge on at least two axes - their masculinities and their age. This article offers a thematic synthesis of the qualitative research on men living with breast cancer or prostate cancer. This is a qualitative meta-analysis assessing how masculinities and aging may jointly affect men's narratives post-mastectomy or post-prostatectomy. Of particular interest was whether and how aging mediates the experience of these gendered cancers. Reviewed were all qualitative studies published between 2000 and 2020 addressing men's breast cancer and post-mastectomy experiences (N = 15) and men's lives after their prostatectomy (N = 28). The analysis followed the guidelines for thematic synthesis and grounded theory. Free codes of findings were organized into "descriptive" themes, which are then further interpreted to yield "analytical" themes. Seven descriptive themes were identified and these underlie two analytical themes - body talk and resilience. Collectively, men's illness narratives spoke about how cancer challenges their gendered identities and practices, and how they repair identities. The common experience was one of men coming to live with their post-surgical bodies by practicing 'wider,' hybrid forms of masculinities. The principal finding is that men with either type of cancer saw themselves as men and remained seen by others in terms of their gender, not their anatomically changed bodies. Unresolved was the full way aging complemented and mediated the cancer journey.

ABCB4 Mutations in Adults Cause a Spectrum Cholestatic Disorder Histologically Distinct from Other Biliary Disease.

BACKGROUND: Mutations in the ABCB4 gene are associated with failure of bile acid emulsification leading to cholestatic liver disease. Presentations range from progressive familial intrahepatic cholestasis type 3 (PFIC3) in childhood, to milder forms seen in adulthood. AIMS: We sought to characterize adult disease with particular reference to histology which has been hitherto poorly defined. METHODS: Four unrelated adults (three female, mean age 39 years) and three sisters presenting with cholestatic liver disease in adulthood, associated with variants in the ABCB4 gene, were identified. Clinical review and detailed blinded histopathological analysis were performed. RESULTS: Two novel pathogenic ABCB4 variants were identified: c.620 T > G, p.(Ile207Arg) and c.2301dupT, p.(Thr768TyrfsTer26). Sub-phenotypes observed included low-phospholipid-associated cholelithiasis syndrome (LPAC), intrahepatic cholestasis of pregnancy (ICP), drug-induced cholestasis, idiopathic adulthood ductopenia, and adult PFIC3. Of note, 5/7 had presented with gallstone complications (4 meeting LPAC definition) and 4/6 females had a history of ICP. Considerable overlap was observed phenotypically and liver transplantation was required in 3/7 of patients. Histologically, cases generally demonstrated ductopenia of the smaller tracts, mild non-ductocentric portal inflammation, bilirubinostasis, significant copper-associated protein deposition, and varying degrees of fibrosis. CONCLUSIONS: Adults with ABCB4 mutations may harbor a spectrum of cholestatic disease phenotypes and can progress to liver transplantation. We observed a distinct histological pattern which differs from classical biliary disease and describe two novel pathogenic ABCB4 variants. ABCB4 sequencing should be considered in patients with relevant cholestatic phenotypes and/or suggestive histology; accurate diagnosis can guide potential interventions to delay progression and inform family screening.

Cerebrospinal fluid metallomics in cerebral amyloid angiopathy: an exploratory analysis.

INTRODUCTION: Cerebral amyloid angiopathy (CAA) is associated with symptomatic intracerebral haemorrhage. Biomarkers of clinically silent bleeding events, such as cerebrospinal fluid (CSF) ferritin and iron, might provide novel measures of disease presence and severity. METHODS: We performed an exploratory study comparing CSF iron, ferritin, and other metal levels in patients with CAA, control subjects (CS) and patients with Alzheimer's disease (AD). Ferritin was measured using a latex fixation test; metal analyses were performed using inductively coupled plasma mass spectrometry. RESULTS: CAA patients (n = 10) had higher levels of CSF iron than the AD (n = 20) and CS (n = 10) groups (medians 23.42, 15.48 and 17.71 µg/L, respectively, p = 0.0015); the difference between CAA and AD groups was significant in unadjusted and age-adjusted analyses. We observed a difference in CSF ferritin (medians 10.10, 7.77 and 8.01 ng/ml, for CAA, AD and CS groups, respectively, p = 0.01); the difference between the CAA and AD groups was significant in unadjusted, but not age-adjusted, analyses. We also observed differences between the CAA and AD groups in CSF nickel and cobalt (unadjusted analyses). CONCLUSIONS: In this exploratory study, we provide preliminary evidence for a distinct CSF metallomic profile in patients with CAA. Replication and validation of these results in larger cohorts is needed.

Genetic testing for hereditary hyperparathyroidism and familial hypocalciuric hypercalcaemia in a large UK cohort.

BACKGROUND: Primary hyperparathyroidism (PHPTH) is a common endocrine disorder and an estimated 10% of cases are hereditary, related to syndromes including; multiple endocrine neoplasia (MEN) type 1, MEN type 4, MEN2A and hereditary hyperparathyroidism-jaw tumour syndrome. Establishing the underlying genetic cause for PHPTH allows for personalized and cost-effective management. Familial hypocalicuric hypercalcaemia (FHH) is a benign disorder of hypercalcaemia associated with an inappropriately low urinary calcium excretion, which is quantified by the calcium creatinine clearance ratio (CCCR). Recent NHS England National Genomic Test Directory testing criteria for familial hyperparathyroidism state testing patients presenting with PHPTH and CCCR > 0.02 presenting (i) <35 years of age, or (ii) <45y with one of (a) multiglandular disease, or (b) hyperplasia on histology, or (c) ossifying fibroma(s) of the maxilla and/ or mandible, or (d) a family history of unexplained PHPTH. The testing criterion for FHH is a CCCR < 0.02. AIMS AND METHODS: A retrospective review of patients referred for genetic testing over a 4 year period for suspected hereditary HPTH was performed. Genetic analysis was performed by next-generation sequencing of the following genes; MEN1, CDC73, CASR, CDKN1A, CDKN1B, CDKN2B, CDKN2C, RET, GCM2, GNA11, and AP2S1 in NHS-accredited Regional Genetic laboratories. Aims of this study were to better define testing criteria for suspected hereditary PHPTH in a UK cohort. RESULTS: A total of 121 patients were included in this study (92 female) with a mean age of 41 years (SD 17). A pathogenic germline variant was identified in 16% (n = 19). A pathogenic variant was identified in the PHPTH genes CDC73 in a single patient and MEN1 in six patients (6% of total), in the FHH genes, CASR in 11 patients and AP2S1 in a single paediatric case (10% of total). A variant of uncertain significance (VUS) was identified in eight patients (6%) but over the course of this study familial segregation studies and computational analysis enabled re-classification of four of the variants, with two VUS's in the CASR gene being upgraded to likely pathogenic variants. Age at diagnosis and multiglandular disease as sole risk factors were not predictive of a pathogenic germline variant in this cohort but a positive family history was strongly predictive (P = .0002). A significant difference in the mean calcium creatinine clearance ratio (CCCR) in those patients with an identified CASR pathogenic variant versus those without (P = .0001) was demonstrated in this study. Thirty-three patients were aged over 50 years and the diagnostic rate of a pathogenic variant was 15.1% in those patients >50 years of age compared to 15.9% in those <50 years. Five patients >50 years and with a CCCR of <0.01, were diagnosed with a pathogenic variant in CASR. CONCLUSION: Family history was the strongest predictor of hereditary PHPTH in this cohort. This study has highlighted the importance of re-evaluating VUS's in order to inform patient management and enable appropriate genetic counselling. Finally, this study has demonstrated the need to consider genetic testing for PHPTH in patients of any age, particularly those with additional risk factors.

Renal anomalies and lymphedema distichiasis syndrome. A rare association?

Lymphedema distichiasis syndrome (LDS) is a rare, autosomal dominant genetic condition, characterized by lower limb lymphedema and distichiasis. Other associated features that have been reported include varicose veins, cleft palate, congenital heart defects, and ptosis. We update a previously reported family with a pathogenic variant in FOXC2 (c.412-413insT) where five affected individuals from the youngest generation had congenital renal anomalies detected on prenatal ultrasound scan. These included four fetuses with hydronephrosis and one with bilateral renal agenesis. A further child with LDS had prominence of the left renal pelvis on postnatal renal ultrasound. We also describe a second family in whom the proband and his affected son had congenital renal anomalies; left ectopic kidney, right duplex kidney, and bilateral duplex collecting systems with partial duplex kidney with mild degree of malrotation, respectively. Foxc2 is expressed in the developing kidney and therefore congenital renal anomalies may well be associated, potentially as a low penetrance feature. We propose that all individuals diagnosed with LDS should have a baseline renal ultrasound scan at diagnosis. It would also be important to consider the possibility of renal anomalies during prenatal ultrasound of at risk pregnancies, and that the presence of hydronephrosis may be an indication that the baby is affected with LDS.

Implementation of a Simplified Regional Citrate Anticoagulation Protocol for Post-Dilution Continuous Hemofiltration Using a Bicarbonate Buffered, Calcium Containing Replacement Solution.

BACKGROUND/AIMS: Recent updates to the Nikkiso Aquarius continuous renal replacement therapy (CRRT) platform allowed us to develop a post-dilution protocol for regional citrate anticoagulation (RCA) using standard bicarbonate buffered, calcium containing replacement solution with acid citrate dextrose formula-A as a citrate source. Our objective was to demonstrate that the protocol was safe and effective. METHODS: Prospective audit of consecutive patients receiving RCA for CRRT within intensive care unit, who were either contraindicated to heparin or had poor filter lifespan (<12 h for 2 consecutive filters) on heparin. RESULTS: We present the first 29 patients who used 98 filters. After excluding 'non-clot' filter loss, 50% had a duration of >27 h. Calcium supplementation was required for 30 (30%) filter circuits, in 17 of 29 (58%) patients. One patient discontinued the treatment due to metabolic alkalosis, but there were no adverse bleeding events. CONCLUSION: Post-dilution RCA system is effective and simple to use on the Aquarius platform and results in comparable filter life for patients relatively contraindicated to heparin.

New paradigms for BRCA1/BRCA2 testing in women with ovarian cancer: results of the Genetic Testing in Epithelial Ovarian Cancer (GTEOC) study.

BACKGROUND: Over recent years genetic testing for germline mutations in BRCA1/BRCA2 has become more readily available because of technological advances and reducing costs. OBJECTIVE: To explore the feasibility and acceptability of offering genetic testing to all women recently diagnosed with epithelial ovarian cancer (EOC). METHODS: Between 1 July 2013 and 30 June 2015 women newly diagnosed with EOC were recruited through six sites in East Anglia, UK into the Genetic Testing in Epithelial Ovarian Cancer (GTEOC) study. Eligibility was irrespective of patient age and family history of cancer. The psychosocial arm of the study used self-report, psychometrically validated questionnaires (Depression Anxiety and Stress Scale (DASS-21); Impact of Event Scale (IES)) and cost analysis was performed. RESULTS: 232 women were recruited and 18 mutations were detected (12 in BRCA1, 6 in BRCA2), giving a mutation yield of 8%, which increased to 12% in unselected women aged <70 years (17/146) but was only 1% in unselected women aged ≥70 years (1/86). IES and DASS-21 scores in response to genetic testing were significantly lower than equivalent scores in response to cancer diagnosis (p<0.001). Correlation tests indicated that although older age is a protective factor against any traumatic impacts of genetic testing, no significant correlation exists between age and distress outcomes. CONCLUSIONS: The mutation yield in unselected women diagnosed with EOC from a heterogeneous population with no founder mutations was 8% in all ages and 12% in women under 70. Unselected genetic testing in women with EOC was acceptable to patients and is potentially less resource-intensive than current standard practice.

Making Connections: The Legacy of an Intergenerational Program.

PURPOSE OF THE STUDY: On the face of the shrinking opportunities for children and older adults to routinely interact with one another-sometimes the result of adolescent geographies, age-segregated and gated communities, families' geographical mobility-many communities have introduced intergenerational programs within the school curriculum. For more than a decade one Massachusetts community has maintained an intergenerational program that brings fourth grade students together with older adults. The question is, does students' involvement in an intergenerational program lessened ageist beliefs 5-9 years later. DESIGN AND METHODS: A quasi-experimental research design examined the "images of aging" held by 944 students who grew up in neighboring towns and attend a regional high school. Participants completed brief questionnaire. RESULTS: Separate regression analyses of positive and negative images of aging-controlling for students' frequency and self-reported quality of interaction with older adults, ethnicity, age, and gender-reveal a town difference in students' positive, but not negative, images of aging. IMPLICATIONS: What is certain is that the high school students from one community with ongoing intergenerational programming hold a more positive image of older adults. Further research is needed to parse out exactly how short- and long-term legacy effects arise when young students have an opportunity to interact closely with older adults who are not their grandparents or neighbors.

Effects of behavioral stress reduction Transcendental Meditation intervention in persons with HIV.

Stress is implicated in the pathogenesis and progression of HIV. The Transcendental Meditation (TM) is a behavioral stress reduction program that incorporates mind-body approach, and has demonstrated effectiveness in improving outcomes via stress reduction. We evaluated the feasibility of implementing TM and its effects on outcomes in persons with HIV. In this community-based single blinded Phase-I, randomized controlled trial, outcomes (psychological and physiological stress, immune activation, generic and HIV-specific health-related quality of life, depression and quality of well-being) were assessed at baseline and at six months, and were compared using parametric and nonparametric tests. Twenty-two persons with HIV were equally randomized to TM intervention or healthy eating (HE) education control group. Retention was 100% in TM group and 91% in HE control group. The TM group exhibited significant improvement in vitality. Significant between group differences were observed for generic and HIV-specific health-related quality of life. Small sample size may possibly limit the ability to observe significant differences in some outcomes. TM stress reduction intervention in community dwelling adults with HIV is viable and can enhance health-related quality of life. Further research with large sample and longer follow-up is needed to validate our results.

"Widowerhood": masculinities and spousal loss in the late-1960s.

This study examined the distinctly gendered experiences of young widowers. Using qualitative longitudinal data from the 1960's Harvard Bereavement Study, we evaluated the interview transcripts of 19 widowers (median age = 38) who had been interviewed 3 weeks, 8 weeks, 13 months, and 2-4 years after the wife's death. Our findings indicate that the off-time spousal loss ruptured the ontological security that marriage provided and created two types of difficult situations for the widowers. Coping with deep sadness and grief, the men divulged their unspoken dependency on their marriage and on their late wife. They also struggled as single fathers, especially if they tried to singlehandedly care for their children. Becoming an off-time widower in the 1960s compelled the men to reclaim their masculine identity. Men's identity-rebuilding strategies involved promptly returning to work, and many men began dating and repartnering to recoup the normalcy of being married.

Adoptive transfer of autologous T cells improves T-cell repertoire diversity and long-term B-cell function in pediatric patients with neuroblastoma.

PURPOSE: Children with high-risk neuroblastoma have a poor prognosis with chemotherapy alone, and hematopoietic stem cell transplantation offers improved survival. As a dose-escalation strategy, tandem transplants have been used, but are associated with persistent immunocompromise. This study evaluated the provision of an autologous costimulated, activated T-cell product to support immunologic function. EXPERIMENTAL DESIGN: Nineteen subjects with high-risk neuroblastoma were enrolled in a pilot phase and 23 subjects were entered in to the randomized study. Immunologic reconstitution was defined by flow cytometric and functional assays. Next-generation sequencing was conducted to identify changes to the T-cell repertoire. Twenty-two patients were vaccinated to define effects on antibody responses. RESULTS: Subjects who received their autologous costimulated T-cell product on day 2 had significantly superior T-cell counts and T-cell proliferation compared with those who received T cells on day 90. Early administration of autologous T cells suppressed oligoclonality and enhanced repertoire diversity. The subjects who received the day 2 T-cell product also had better responses to the pneumococcal vaccine. CONCLUSIONS: The infusion of activated T cells can improve immunologic function especially when given early after transplant. This study showed the benefit of providing cell therapies during periods of maximum lymphopenia.

White matter abnormalities and dystonic motor disorder associated with mutations in the SLC16A2 gene.

AIM: Mutations in the SLC16A2 gene have been implicated in Allan-Herndon-Dudley syndrome (AHDS), an X-linked learning disability* syndrome associated with thyroid function test (TFT) abnormalities. Delayed myelination is a non-specific finding in individuals with learning disability whose genetic basis is often uncertain. The aim of this study was to describe neuroimaging findings and neurological features in males with SLC16A2 gene mutations. METHOD: We reviewed brain magnetic resonance imaging (MRI) findings and neurological features in a cohort of five males aged between 1 year 6 months and 6 years (median 4y) from four families harbouring SLC16A2 gene mutations. RESULTS: The participants presented aged between 4 and 9 months with initial hypotonia and subsequent spastic paraparesis with dystonic posturing and superimposed paroxysmal dyskinesias. Dystonic cerebral palsy was the most common initial clinical diagnosis, and AHDS was suspected only retrospectively, considering the characteristically abnormal thyroid function tests, with high serum tri-iodothyronine (T(3)), as the most consistent finding. Brain MRI showed absent or markedly delayed myelination in all five participants, prompting the suspicion of Pelizaeus-Merzbacher disease in one patient. INTERPRETATION: Our findings indicate a consistent association between defective neuronal T(3) uptake and delayed myelination. SLC16A2 involvement should be considered in males with learning disability, an associated motor or movement disorder, and evidence of delayed myelination on brain MRI. Although dysmorphic features suggestive of AHDS are not always present, T(3) measurement is a reliable screening test.

"Heart trouble" and religious involvement among older white men and women.

Objective Few studies examine how older adults' health status affects spiritual and religious involvement. This study examined the effects of gender and poor cardiac health on older adults' ends, means, and quest religious motivations and frequency of private devotion. Method Longitudinal data (12 months between the T1 and T2 interviews) with 182 older adults sampled from a Northeast city were used to examine in a multivariate analysis of covariance whether gender and the existence of cardiac health problems at T1 affected older adults' spiritual and religious involvement at T2. Findings A gender and cardiac health condition interaction showed older men with heart trouble had more changes in religious involvement-they engaged in more religious doubt, prayed less, and were not as intrinsically oriented at T2. Discussion The findings strongly suggest that older men with heart trouble may maintain a masculine style and shun seeking divine help.

Longitudinal one-year study of levels and stoichiometry of neurofilament heavy and light chain concentrations in CSF in patients with multiple system atrophy.

BACKGROUND: Two cerebrospinal fluid (CSF) biomarkers specific for neurodegeneration have recently emerged - the neurofilament light (NfL, 68 kDa) and heavy (NfH, 190-210 kDa) chains. This study investigated whether the CSF NfH and NfL levels or their stoichiometric relationship changed over time in a neuroprotective treatment trial. METHODS: Serial CSF samples (n=95) from 42 patients with multiple system atrophy (MSA), half randomized to treatment with recombinant human growth hormone (r-hGH) and the other half to placebo, were collected at baseline, 6 and 12 months. The concentration of CSF NfL and NfH was determined using standard ELISAs. RESULTS: There was no consistent change in the levels of either protein over the 12 month period, or between treatment with active r-hGH versus placebo. The molar stoichiometry of CSF NfL:NfH was 4:1 (R=0.37, p=0.0002) and increased following treatment with r-hGH (p=0.03). CONCLUSION: These results indicate that CSF levels of both NfL and NfH on their own are not useful markers of disease progression in MSA, at least over a 12-month period. Future work is needed to elucidate whether the CSF stoichiometry and dynamics of Nf subunits in individual patients are a feature of the underlying pathology and of diagnostic or prognostic value.

Phosphorylation and compactness of neurofilaments in multiple sclerosis: indicators of axonal pathology.

AIMS: Axonal pathology extends to the axonal cytoarchitecture leaving its signature on axoskeletal proteins. This study investigated whether neurofilament (NfH) phosphorylation would relate to the dynamics of axonal pathology in multiple sclerosis (MS). METHODS: NfH phosphoforms (SMI32, SMI34, SMI35) were quantified by ELISA from microdissected samples of control and MS brain and spinal cord. Individual axons were analysed by electron microscopy, densitometrically and morphologically in adjacent tissue sections. Experiments were carried out pre- and post enzymatic dephosphorylation. RESULTS: In control tissue a rostro-caudal gradient of NfH indicated an increase in axonal density from the brain gray matter towards the spinal cord. The highest levels of phosphorylated and hyperphosphorylated NfH were found in acute lesions of brain and spinal cord, in contrast to chronic lesions where levels were lower than in white matter, consistent with axonal loss. Dephosphorylated NfH was higher, but less densly packed in MS white matter axons compared to control tissue. CONCLUSIONS: The findings suggest that a less organised/compact axoskeleton or impaired axonal transport may represent an early sign of axonal pathology within the normal appearing white matter in MS. Subsequently a proportional increase of dephosphorylated NfH, aberrant phosphorylation and/or aggregation may occur whilst the protein is transported through the white matter towards the MS plaque, where hyperphosphorylated NfH dominates.

Discrepancies between qualitative and quantitative analysis of cerebrospinal fluid IgG: densitometric comparison of nephelometry-silver versus immuno-enzymes.

BACKGROUND: Detection of local synthesis of IgG within the central nervous system is important for the diagnosis of brain inflammatory diseases such as multiple sclerosis. This is typically done by comparing the amounts of IgG in serum and parallel cerebrospinal fluid (CSF). Although there have been well-described problems with qualitative versus quantitative measurements of abnormal IgG, such as in myeloma paraproteins, similar difficulties are also found with CSF IgG. METHODS: Traditional quantitative analysis of IgG by rate nephelometry was followed by separation of the IgG using isoelectric focusing and then either silver stain or immunofixation. Finally, quantitative analysis was performed by scanning densitometry using public domain software downloaded from the National Institutes of Health. RESULTS: We report here the major discrepancies that can occur with CSF IgG between the silver stain versus the IgG stain. CONCLUSIONS: We concur with the earlier recommendation that qualitative separation followed by densitometric estimation of enzyme-linked immunofixation is also more useful than simple quantitative nephelometric analysis followed by silver staining in the detection of local synthesis of IgG, analogous to the earlier work on paraproteins.