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This chapter examines how imperialism has formed the region of Southern Africa and how the peoples of the region have over the last century constituted a major anti-imperialist force. This complex narrative traces the historical periods of imperialist rule and accumulation, from the formation of a regional mineral-labour network in the late nineteenth century to contemporary ‘neo-liberal’ forms of imperialism; the multitudinous, region-specific, forms of value extraction from natural resources, industrial enterprises, to financial and commercial flows; South Africa’s changing role as the centre of the region; transitions in northern rule and rivalry, from British to American to new intrusions from Asia; the new wave of accumulation by extraction in the region; and the failure of opposition by postcolonial states and the emergence of new movements from below (e.g., urban, land, worker).

Cancers, including cutaneous melanoma, can cluster in families. In addition to environmental etiological factors such as ultraviolet radiation, cutaneous melanoma has a strong genetic component. Genetic risks for cutaneous melanoma range from rare, high-penetrance mutations to common, low-penetrance variants. Known high-penetrance mutations account for only about half of all densely affected cutaneous melanoma families, and the causes of familial clustering in the remainder are unknown. We hypothesize that some clustering is due to the cumulative effect of a large number of variants of individually small effect. Common, low-penetrance genetic risk variants can be combined into polygenic risk scores. We used a polygenic risk score for cutaneous melanoma to compare families without known high-penetrance mutations with unrelated melanoma cases and melanoma-free controls. Family members had significantly higher mean polygenic load for cutaneous melanoma than unrelated cases or melanoma-free healthy controls (Bonferroni-corrected t-test P = 1.5 × 10−5 and 6.3 × 10−45, respectively). Whole genome sequencing of germline DNA from 51 members of 21 families with low polygenic risk for melanoma identified a CDKN2A p.G101W mutation in a single family but no other candidate high-penetrance melanoma susceptibility genes. This work provides further evidence that melanoma, like many other common complex disorders, can arise from the joint action of multiple predisposing factors, including rare high-penetrance mutations, as well as via a combination of large numbers of alleles of small effect.

Glucose-galactose malabsorption (GGM) is due to mutations in the gene coding for the intestinal sodium glucose cotransporter SGLT1 (SLC5A1). Here we identify the rare variant Gln457Arg (Q457R) in a large pedigree of patients in the Västerbotten County in Northern Sweden with the clinical phenotype of GGM. The functional effect of the Q457R mutation was determined in protein expressed in Xenopus laevis oocytes using biophysical and biochemical methods. The mutant failed to transport the specific SGLT1 sugar analog α-methyl-D-glucopyranoside (αMDG). Q457R SGLT1 was synthesized in amounts comparable to the wild-type (WT) transporter. SGLT1 charge measurements and freeze-fracture electron microscopy demonstrated that the mutant protein was inserted into the plasma membrane. Electrophysiological experiments, both steady-state and presteady-state, demonstrated that the mutant bound sugar with an affinity lower than the WT transporter. Together with our previous studies on Q457C and Q457E mutants, we established that the positive charge on Q457R prevented the translocation of sugar from the outward-facing to inward-facing conformation. This is contrary to other GGM cases where missense mutations caused defects in trafficking SGLT1 to the plasma membrane. Thirteen GGM patients are now added to the pedigree traced back to the late 17th century. The frequency of the Q457R variant in Västerbotten County genomes, 0.0067, is higher than in the general Swedish population, 0.0015, and higher than the general European population, 0.000067. This explains the high number of GGM cases in this region of Sweden.

Background New Jersey experienced a 64% decrease in HIV screening during the COVID-19 pandemic, hampering the Federal “End the Epidemic Initiative”. From March 2020- May 2021, North Jersey Community Research Initiative, a community-based organization in Newark, NJ, noted a HIV seropositivity of 3.1% despite a decrease of 25% in testing. Qualitative interviews conducted virtually with community individuals and focus groups during that time period indicated that COVID-19 suggested clients were taking more risks due to feelings of isolation, depression and anxiety. NJCRI in collaboration with Robert Wood Johnson Medical School in Somerset, NJ and five other community-based partners in NJ wanted to assess if offering community combination COVID-19 screening and HIV screenings during the pandemic would increase community screening for HIV. Methods CLIA Waived Screening for COVID-19 from two antigen assays, LumiraDx and BD Veritor was combined with a referenced laboratory based molecular screening from saliva Infinity Biologix under FDA emergency use authorization within CDC guidance with HIV Alere/Determine and INSTI in those individuals that identified as asymptomatic for COVID-19 but with high risk for HIV Results NJCRI began the COVID-19 and HIV rapid screening to clients on January 4, 2021.Clients tested for COVID-19 (N=274), 3% tested positive for HIV and < 3% are self-reported HIV+ (94% of the sample tested negative for HIV). Overall, 92% of clients tested negative for COVID-19. Clients testing positive for COVID-19 (N=19), there was a 6% positivity rate utilizing COVID-19 Antigen by nasal swab. Those positive via COVID-19 Molecular (N=19) method, results indicate clients also tested positive 6% of the time using a saliva indicator. Approximately, 5% of the study sample are confirmed COVID-19 positives via both testing methods (separately 1% Antigen and < 2% Molecular). 19% of the sample (N=3) tested positive for both HIV and COVID-19. Figure 2. Demographics Figure 3. Social and Economic Risk Factors Conclusion Newly diagnosed patients were treated the same day with antiretroviral therapy; linked to medical care, behavioral health and risk reduction services. Combining COVID-19 and HIV screening in a trusted community-based setting improved delivery of HIV care and linkage to care for newly diagnosed individuals in Newark, NJ. Figure 4. Behavioral Risk Factors Figure 3. Social and Behavioral Risk Factors Disclosures All Authors: No reported disclosures

A circumbinary disc around a pair of merging stellar-mass black holes may be shocked and heated during the recoil of the merged hole, causing a near-simultaneous electromagnetic counterpart to the gravitational wave event. The shocks occur around the recoil radius, where the disc orbital velocity is equal to the recoil velocity. The amount of mass present near this radius at the time of the merger is critical in determining how much radiation is released. We explore the evolution of a circumbinary disc in two limits. First, we consider an accretion disc that feels no torque from the binary. The disc does not survive until the merger unless there is a dead zone, a region of low turbulence. Even with the dead zone, the surface density in this case may be small. Second, we consider a disc that feels a strong binary torque that prevents accretion on to the binary. In this case there is significantly more mass in regions of interest at the time of the merger. A dead zone in this disc increases the mass close to the recoil radius. For typical binary-disc parameters we expect accretion to be significantly slowed by the resonant torque from the binary, and for a dead zone to be present. We conclude that provided significant mass orbits the binary after the formation of the black hole binary and that the radiation produced in recoil shocks can escape the flow efficiently, there is likely to be an observable electromagnetic signal from black hole binary mergers., Comment: Accepted for publication in MNRAS

Hispanic minorities have a higher incidence of chronic disease which may result in increased hospitalizations and life-threatening illness. Our growing geriatric population led our community hospital to create a dedicated Palliative Care department, an interprofessional team of physicians, nursing, pharmacy, social work, counselors, and chaplains whose collaborative practice has improved outcomes thus strengthening healthcare delivery. When our new medical school established graduate programs, including Internal Medicine residency and Hospice/Palliative Medicine fellowship, our team embraced the opportunity to optimize our palliative service through enhanced interprofessional care. We created a geriatric rotation on July 1, 2018 in which 60% of residents worked with palliative care professionals as a consult team bringing together the inpatient resident service and palliative interdisciplinary team. This collaborative model allowed the palliative team to interface with our trainees and teach them to identify the range of needs of older adults early on in their care. Residents reported 100% satisfaction on evaluations, specifically on clinical training, goal fulfillment, and team support. Our learners valued the opportunity to learn with and from other healthcare professionals. Supervising providers also felt that working with residents was beneficial to their practice habits (i.e., providing evidence-based practices, application of guidelines), which offered them a more holistic approach in caring for patients and families. The interprofessional collaboration between a community hospital and medical school to educate and train clinicians who care for individuals with advanced illness has fostered confidence, trust, mutual respect, open communication and effective sharing of critical information for both clinicians and patients.

BACKGROUND: Individual differences in human perception of sweetness are partly due to genetics; however, which genes are associated with the perception and the consumption of sweet substances remains unclear. OBJECTIVE: The aim of this study was to verify previous reported associations within genes involved in the peripheral receptor systems (i.e., TAS1R2, TAS1R3, and GNAT3) and reveal novel loci. METHODS: We performed genome-wide association scans (GWASs) of the perceived intensity of 2 sugars (glucose and fructose) and 2 high-potency sweeteners (neohesperidin dihydrochalcone and aspartame) in an Australian adolescent twin sample (n = 1757), and the perceived intensity and sweetness and the liking of sucrose in a US adult twin sample (n = 686). We further performed GWASs of the intake of total sugars (i.e., total grams of all dietary mono- and disaccharides per day) and sweets (i.e., handfuls of candies per day) in the UK Biobank sample (n = ≤174,424 white-British individuals). All participants from the 3 independent samples were of European ancestry. RESULTS: We found a strong association between the intake of total sugars and the single nucleotide polymorphism rs11642841 within the FTO gene on chromosome 16 (P = 3.8 × 10(−8)) and many suggestive associations (P

We present early results from the JCMT (James Clerk Maxwell Telescope) Plane Survey (JPS), which has surveyed the northern inner Galactic plane between longitudes ℓ = 7° and ℓ = 63° in the 850-μm continuum with SCUBA-2 (Submm Common-User Bolometer Array 2), as part of the JCMT Legacy Survey programme. Data from the ℓ = 30° survey region, which contains the massive-star-forming regions W43 and G29.96, are analysed after approximately 40 per cent of the observations had been completed. The pixel-to-pixel noise is found to be 19 mJy beam−1 after a smooth over the beam area, and the projected equivalent noise levels in the final survey are expected to be around 10 mJy beam−1. An initial extraction of compact sources was performed using the FELLWALKER method, resulting in the detection of 1029 sources above a 5σ surface-brightness threshold. The completeness limits in these data are estimated to be around 0.2 Jy beam−1 (peak flux density) and 0.8 Jy (integrated flux density) and are therefore probably already dominated by source confusion in this relatively crowded section of the survey. The flux densities of extracted compact sources are consistent with those of matching detections in the shallower APEX (Atacama Pathfinder Experiment) Telescope Large Area Survey of the Galaxy (ATLASGAL) survey. We analyse the virial and evolutionary state of the detected clumps in the W43 star-forming complex and find that they appear younger than the Galactic-plane average.

The UTRGV DHR Internal Medicine Program conducted a study addressing end of life (EOL) care focused on our Hispanic community in regards to communication and trust between patients, caregivers, and healthcare providers. Our residents train at a community hospital which cares for an 89% Hispanic population of 1.2 million, spanning over 4 counties of the Rio Grande Valley. Trainees are often involved in family meetings while treating hospitalized, terminally ill patients. Although family meetings are a standard approach in palliative care, Hispanic family meetings tend to occur more often and with a larger, extended family unit. Our intent was to educate our residents to initiate conversations about EOL care choices promoting delivery of patient-centered, family oriented care utilizing culturally appropriate information regarding EOL issues. Baseline surveys were provided to all 39 trainees which assessed anxiety, incompetence, and communication skills in delivering bad news during family meetings. An advanced care planning process was implemented over 3 months with a goal to engage patients in EOL conversations, initiation, and completion of advanced directives. Residents received weekly training on interactive methods and ethical concepts including group discussions, role-playing, and demonstrations which were culturally and linguistically appropriate. We found that physician competence in conducting Hispanic family meetings is vital. Residents completed a post-training survey resulting in 100% improved attitudes and behaviors such as confidence, satisfaction, caring and empathy. They felt more comfortable and prepared to speak to a larger family unit who was likely to ask a lot of questions and request multiple meetings.

Serum gamma-glutamyl transferase (GGT) activity is a marker of liver disease which is also prospectively associated with the risk of all-cause mortality, cardiovascular disease, type 2 diabetes and cancers. We have discovered novel loci affecting GGT in a genome-wide association study (rs1497406 in an intergenic region of chromosome 1, P = 3.9 × 10 -8 ; rs944002 in C14orf73 on chromosome 14, P = 4.7 × 10 -13 ; rs340005 in RORA on chromosome 15, P = 2.4 × 10 -8 ), and a highly significant heterogeneity between adult and adolescent results at the GGT1 locus on chromosome 22 (maximum P HET = 5.6 × 10 -12 at rs6519520). Pathway analysis of significant and suggestive single-nucleotide polymorphism associations showed significant overlap between genes affecting GGT and those affecting common metabolic and inflammatory diseases, and identified the hepatic nuclear factor (HNF) family as controllers of a network of genes affecting GGT. Our results reinforce the disease associations of GGT and demonstrate that control by the GGT1 locus varies with age. Refereed/Peer-reviewed

Genome-wide association studies (GWAS) of breast cancer defined by hormone receptor status have revealed loci contributing to susceptibility of estrogen receptor (ER)-negative subtypes. To identify additional genetic variants for ER-negative breast cancer, we conducted the largest meta-analysis of ER-negative disease to date, comprising 4754 ER-negative cases and 31 663 controls from three GWAS: NCI Breast and Prostate Cancer Cohort Consortium (BPC3) (2188 ER-negative cases; 25 519 controls of European ancestry), Triple Negative Breast Cancer Consortium (TNBCC) (1562 triple negative cases; 3399 controls of European ancestry) and African American Breast Cancer Consortium (AABC) (1004 ER-negative cases; 2745 controls). We performed in silico replication of 86 SNPs at P ≤ 1 × 10(-5) in an additional 11 209 breast cancer cases (946 with ER-negative disease) and 16 057 controls of Japanese, Latino and European ancestry. We identified two novel loci for breast cancer at 20q11 and 6q14. SNP rs2284378 at 20q11 was associated with ER-negative breast cancer (combined two-stage OR = 1.16; P = 1.1 × 10(-8)) but showed a weaker association with overall breast cancer (OR = 1.08, P = 1.3 × 10(-6)) based on 17 869 cases and 43 745 controls and no association with ER-positive disease (OR = 1.01, P = 0.67) based on 9965 cases and 22 902 controls. Similarly, rs17530068 at 6q14 was associated with breast cancer (OR = 1.12; P = 1.1 × 10(-9)), and with both ER-positive (OR = 1.09; P = 1.5 × 10(-5)) and ER-negative (OR = 1.16, P = 2.5 × 10(-7)) disease. We also confirmed three known loci associated with ER-negative (19p13) and both ER-negative and ER-positive breast cancer (6q25 and 12p11). Our results highlight the value of large-scale collaborative studies to identify novel breast cancer risk loci.

Background Individuals with schizophrenia are at increased risk for cardiovascular diseases, and this risk cannot be fully explained by antipsychotic medications or lifestyle factors. Retinal imaging offers a non-invasive means of visualizing the microvasculature in living individuals with schizophrenia. Here we test whether individuals with schizophrenia exhibit retinal microvascular abnormality (Meier et al., AJP, 2013), and test for overlap in the genetic variants associated with schizophrenia and retinal microvascular abnormality. Methods To test whether individuals diagnosed with schizophrenia showed microvascular abnormality, we used data from the Dunedin Study, a representative cohort of 1,000 New Zealanders followed from birth to age 38. The cohort underwent retinal imaging at age 38, and retinal venular (small veins) and arteriolar (small arteries) diameters were obtained. Analyses compared individuals with schizophrenia (n=27), healthy individuals (n=412), and individuals with medical or psychiatric conditions (ns ranged from 110–210) on retinal vessel diameter. To test for overlap in the genetic variants associated with schizophrenia and retinal vessel diameter, we used linkage disequilibrium-score regression (LD regression) to obtain the genetic correlation between schizophrenia and retinal vessel diameter. This method requires only GWAS (genome wide associate studies) summary statistics rather than actual genotypes. Summary statistics for schizophrenia and retinal vessel diameter came from published meta-analyses. Results Adults diagnosed with schizophrenia had wider retinal venules (standardized mean=0.59) compared with same-age healthy adults (standardized mean=-0.20) and compared with individuals diagnosed with hypertension, diabetes, and tobacco dependence. Findings could not be explained by antipsychotic medication, as venular diameter was similar in the subset of individuals diagnosed with schizophrenia who had not taken antipsychotic medication in the year prior to retinal imaging (n=22; standardized mean=0.69). There were no differences in arteriolar diameter between individuals diagnosed with schizophrenia and all other groups. Results from LD regression showed a small genetic correlation between schizophrenia and venular diameter (r=0.05, p=.31) and a slightly larger genetic correlation between schizophrenia and arteriolar diameter (r=0.17, p=.02). Discussion Wider venular diameter is a distinguishing feature of schizophrenia, but genetic variants associated with schizophrenia overlap more strongly with variants associated with arteriolar diameter. It is possible that environmental influences associated with schizophrenia tend to narrow arterioles, obscuring a phenotypic link between schizophrenia and wider arterioles. Pathophysiological mechanisms underlying vessel diameter, including inflammation and endothelial dysfunction, might be related to the development of schizophrenia, and particular genes might contribute to both schizophrenia and arteriolar diameter. Findings will be discussed in relation to links between retinal vessel diameter and IQ (Shalev, Meier et al., Psychol Sci, 2013) and depression (Meier et al., Psychosom Med, 2014).

STUDY QUESTION: Are single-nucleotide polymorphisms (SNPs) at the interleukin 1A (IL1A) gene locus associated with endometriosis risk? SUMMARY ANSWER: We found evidence for strong association between IL1A SNPs and endometriosis risk. WHAT IS KNOWN ALREADY: Genetic factors contribute substantially to the complex aetiology of endometriosis and the disease has an estimated heritability of ∼51%. We, and others, have conducted genome-wide association (GWA) studies for endometriosis, which identified a total of nine independent risk loci. Recently, two small Japanese studies reported eight SNPs (rs6542095, rs11677416, rs3783550, rs3783525, rs3783553, rs2856836, rs1304037 and rs17561) at the IL1A gene locus as suggestively associated with endometriosis risk. There is also evidence of a link between inflammation and endometriosis. STUDY DESIGN, SIZE, DURATION: We sought to further investigate the eight IL1A SNPs for association with endometriosis using an independent sample of 3908 endometriosis cases and 8568 controls of European and Japanese ancestry. The study was conducted between October 2013 and July 2014. PARTICIPANTS/MATERIALS, SETTING, METHODS: By leveraging GWA data from our previous multi-ethnic GWA meta-analysis for endometriosis, we imputed variants in the IL1A region, using a recent 1000 Genomes reference panel. After combining summary statistics for the eight SNPs from our European and Japanese imputed data with the published results, a fixed-effect meta-analysis was performed. An additional meta-analysis restricted to endometriosis cases with moderate-to-severe (revised American Fertility Society stage 3 or 4) disease versus controls was also performed. MAIN RESULTS AND THE ROLE OF CHANCE: All eight IL1A SNPs successfully replicated at P < 0.014 in the European imputed data with concordant direction and similar size to the effects reported in the original Japanese studies. Of these, three SNPs (rs6542095, rs3783550 and rs3783525) also showed association with endometriosis at a nominal P < 0.05 in our independent Japanese sample. Fixed-effect meta-analysis of the eight SNPs for moderate-to-severe endometriosis produced a genome-wide significant association for rs6542095 (odds ratio = 1.21; 95% confidence interval = 1.13-1.29; P = 3.43 × 10(-8)). LIMITATIONS, REASONS FOR CAUTION: The meta-analysis for moderate-to-severe endometriosis included results of moderate-to-severe endometriosis cases from our European data sets and all endometriosis cases from the Japanese data sets, as disease stage information was not available for endometriosis cases in the Japanese data sets. WIDER IMPLICATIONS OF THE FINDINGS: SNP rs6542095 is located ∼2.3 kb downstream of the IL1A gene and ∼6.9 kb upstream of cytoskeleton-associated protein 2-like (CKAP2L) gene. The IL1A gene encodes the IL1a protein, a member of the interleukin 1 cytokine family which is involved in various immune responses and inflammatory processes. These results provide important replication in an independent Japanese sample and, for the first time, association of the IL1A locus in endometriosis patients of European ancestry. SNPs within the IL1A locus may regulate other genes, but if IL1A is the target, our results provide supporting evidence for a link between inflammatory responses and the pathogenesis of endometriosis. STUDY FUNDING/COMPETING INTERESTS: The research was funded by grants from the Australian National Health and Medical Research Council and Wellcome Trust. None of the authors has competing interests for the study.

Triple-negative (TN) breast cancer is an aggressive subtype of breast cancer associated with a unique set of epidemiologic and genetic risk factors. We conducted a two-stage genome-wide association study of TN breast cancer (stage 1: 1529 TN cases, 3399 controls; stage 2: 2148 cases, 1309 controls) to identify loci that influence TN breast cancer risk. Variants in the 19p13.1 and PTHLH loci showed genome-wide significant associations (P < 5 × 10(-) (8)) in stage 1 and 2 combined. Results also suggested a substantial enrichment of significantly associated variants among the single nucleotide polymorphisms (SNPs) analyzed in stage 2. Variants from 25 of 74 known breast cancer susceptibility loci were also associated with risk of TN breast cancer (P < 0.05). Associations with TN breast cancer were confirmed for 10 loci (LGR6, MDM4, CASP8, 2q35, 2p24.1, TERT-rs10069690, ESR1, TOX3, 19p13.1, RALY), and we identified associations with TN breast cancer for 15 additional breast cancer loci (P < 0.05: PEX14, 2q24.1, 2q31.1, ADAM29, EBF1, TCF7L2, 11q13.1, 11q24.3, 12p13.1, PTHLH, NTN4, 12q24, BRCA2, RAD51L1-rs2588809, MKL1). Further, two SNPs independent of previously reported signals in ESR1 [rs12525163 odds ratio (OR) = 1.15, P = 4.9 × 10(-) (4)] and 19p13.1 (rs1864112 OR = 0.84, P = 1.8 × 10(-) (9)) were associated with TN breast cancer. A polygenic risk score (PRS) for TN breast cancer based on known breast cancer risk variants showed a 4-fold difference in risk between the highest and lowest PRS quintiles (OR = 4.03, 95% confidence interval 3.46-4.70, P = 4.8 × 10(-) (69)). This translates to an absolute risk for TN breast cancer ranging from 0.8% to 3.4%, suggesting that genetic variation may be used for TN breast cancer risk prediction.

Background: Basal-like and triple-negative breast tumours encompass an important clinical subgroup and\ud biomarkers that can prognostically stratify these patients are required.\ud Materials and methods: We investigated two breast cancer tissue microarrays for the expression of calpain-1,\ud calpain-2 and calpastatin using immunohistochemistry. The first microarray was comprised of invasive tumours from\ud 1371 unselected patients, and the verification microarray was comprised of invasive tumours from 387 oestrogen\ud receptor (ER)-negative patients.\ud Results: The calpain system contains a number of proteases and an endogenous inhibitor, calpastatin. Calpain activity\ud is implicated in important cellular processes including cytoskeletal remodelling, apoptosis and survival. Our results show\ud that the expression of calpastatin and calpain-1 are significantly associated with various clinicopathological criteria\ud including tumour grade and ER expression. High expression of calpain-2 in basal-like or triple-negative disease was\ud associated with adverse breast cancer-specific survival (P = 0.003 and

To the Editor: We read with interest the article by Fuller-Thomson and colleagues (1) and their conclusion that estimates from the American Community Survey (ACS) showed an increase in difficulty with activities of daily living (ADLs) and a plateau in physical activity limitation between 2000 and 2005 for the U.S. population aged 65 years and older. Although the authors provided caveats in their interpretation of their findings, we believe that additional caution is warranted. We recently considered using the 2000–2007 ACS to assess late-life disability trends. However, we decided that because of changes in survey administration over time, we could not reliably estimate trends from the ACS. Our greatest concern was the change in interview mode. The proportion of ACS interviews that were completed via mail declined from 58% in 2000 to 52% in 2005 (and to 48% in 2007), and the proportion completed through computer-assisted interviews concomitantly increased (2–4). For people aged 16–64 years, estimates of limitation are higher using computer-assisted interviews versus mail. For example, in 2003, the differences for ADL limitation (difficulty dressing, bathing, or getting around inside) were 1.9% versus 1.8%, respectively, and for physical functional limitation (substantial limitation in walking, climbing stairs, reaching, lifting, or carrying) were 7.4% versus 6.5%, respectively (5). We were not able to find mode-specific estimates for the older population. However, if the older group experienced similar patterns, the increase in the proportion of computer-assisted interviews would likely account for some of the estimated increase in limitations. Unfortunately, the public ACS micro data sets do not provide an indicator of interview mode to use in modeling trends. Accordingly, we chose not to use the ACS. Another factor that appears to have contributed to an upward bias in the trends found by Fuller-Thompson and colleagues is aging of the population. They mentioned in their discussion the changes in the age distribution within the population aged 65 years and older from 2000 to 2005, especially the rapid increase of those aged 80 years and older. But they were not able to adjust for age in their analyses because they simply fitted regression lines across the published aggregate prevalences of limitations for each of the six survey years. We were not able to access from the internet the prevalence figures that Fuller-Thompson and colleagues used, but based on the micro data sets for each year, we calculated our own estimates of the aggregate prevalences for those aged 65 years and older, which track closely the data points graphed in figure 1 of their article. Indeed, when we fitted trend regression models using our prevalences, we found that ADL limitation increased at a rate of 1.56% per year in comparison to the 1.81% per year found by Fuller-Thomson and colleagues (calculated by dividing their regression coefficient on [year−2000] of .16 by the intercept of 8.84). However, when we calculated age-specific prevalences by 5-year age groups from the micro data, standardized the overall 65+ annual prevalence rates to the 5-year age distribution from various populations (2000, 2005, and an average of 2000–2005), and then estimated models based on these standardized prevalences, we found for ADL limitation that the p value on the trend coefficient was reduced from .005 to a range from .07 to .09, and the estimated annual change was reduced to 0.7%–0.8%. For functional limitations, the results of Fuller-Thomson and colleagues implied an annual increase of 0.37%, and we found annual change of 0.24% in our model of unadjusted prevalences and −0.14% to −0.16% for our models of age-standardized prevalences [none of the trend coefficients for functional limitations significantly different from 0, as in (1)]. As an alternative test of the importance of adjusting for age, we ran logit regressions of individual-level ADL and functional limitations on trend using the micro data set. For ADLs, our results implied an annual change of 1.67% in the unadjusted model and 0.85% in the model with 5-year age group controls. For functional limitations, the estimates were 0.34% and −0.23%, respectively. (All logit trend coefficients were statistically different from 0.) Accordingly, it appears that controlling for age results in a halving of the rate of increase for ADLs and in a trend downward, as opposed to upward, for functional limitations. We applaud Fuller-Thomson and colleagues for their attempt to shed light on the most recent disability trends and especially for their care in accounting for the institutionalized population. We also agree that tracking trends going forward is critical. However, estimated trends may be contaminated by changes over time in a variety of factors, some of which they note, such as survey design and administration, use of proxies, population coverage, question wording, and age distribution (6). Moreover, differences across surveys may also affect comparisons of trends (7). In sum, we do not think that the analysis of the ACS by Fuller-Thomson and colleagues provides sufficient evidence to reach even tentative conclusions about recent late-life disability trends.

The clinical overlap between monogenic Familial Hemiplegic Migraine (FHM) and common migraine subtypes, and the fact that all three FHM genes are involved in the transport of ions, suggest that ion transport genes may underlie susceptibility to common forms of migraine. To test this leading hypothesis, we examined common variation in 155 ion transport genes using 5257 single nucleotide polymorphisms (SNPs) in a Finnish sample of 841 unrelated migraine with aura cases and 884 unrelated non-migraine controls. The top signals were then tested for replication in four independent migraine case-control samples from the Netherlands, Germany and Australia, totalling 2835 unrelated migraine cases and 2740 unrelated controls. SNPs within 12 genes (KCNB2, KCNQ3, CLIC5, ATP2C2, CACNA1E, CACNB2, KCNE2, KCNK12, KCNK2, KCNS3, SCN5A and SCN9A) with promising nominal association (0.00041 < P < 0.005) in the Finnish sample were selected for replication. Although no variant remained significant after adjusting for multiple testing nor produced consistent evidence for association across all cohorts, a significant epistatic interaction between KCNB2 SNP rs1431656 (chromosome 8q13.3) and CACNB2 SNP rs7076100 (chromosome 10p12.33) (pointwise P = 0.00002; global P = 0.02) was observed in the Finnish case-control sample. We conclude that common variants of moderate effect size in ion transport genes do not play a major role in susceptibility to common migraine within these European populations, although there is some evidence for epistatic interaction between potassium and calcium channel genes, KCNB2 and CACNB2. Multiple rare variants or trans-regulatory elements of these genes are not ruled out.