Health checks in general practice: another example of inverse care?

OBJECTIVE--To assess attendance at and the characteristics of patients attending health checks for cardiovascular disease offered in a general practice over a period of five years (1984-9). DESIGN--Medical record audit and postal questionnaire survey. SETTING--One general practice in Oxfordshire with a socially diverse population. PARTICIPANTS--1101 Men and 1110 women aged 35-64 registered with the practice. MAIN OUTCOME MEASURES--Age, sex, marital state, social class, smoking habits, alcohol consumption, and diet. RESULTS--Of the 2211 men and women in the target age group (35-64) in 1989, 1458 (65.9%) had been offered screening and 963 (43.6%) had attended for a health check. Attenders were more likely to be women, aged greater than or equal to 45, married, non-smokers, and of higher social class than patients who did not respond to the invitation. The relative likelihood of non-attendance was 1.24 for smokers, 1.20 for the overweight, 1.16 for heavy drinkers, and 1.28 for those with a less healthy diet, even after adjustment for age, sex, marital state, and social class. CONCLUSIONS--After five years of offering health checks, opportunistically (to men) and in the context of cervical smear tests (to women), less than half of the eligible patients had attended. The likelihood of acceptance of an invitation to attend was inversely related to the patient''s cardiovascular risk for all factors measured except age. A coherent strategy to reduce cardiovascular disease depends on more careful targeting of scarce health service resources and more emphasis on public health measures (such as dietary regulation and tobacco taxation). Doctors should be careful not to absolve the government of its public health obligations by substituting unproved preventive interventions aimed at the individual patient.     

The rabbit alpha-like globin gene cluster is polymorphic both in the sizes of BamHI fragments and in the numbers of duplicated sets of genes

The alpha-like globin gene cluster in rabbits contains embryonic zeta- globin genes, an adult alpha-globin gene, and theta-globin genes of undetermined function. The basic arrangement of genes, deduced from analysis of cloned DNA fragments, is 5'-zeta 0-zeta 1-alpha 1-theta 1- zeta 2-zeta 3-theta 2-3'. However, the pattern of restriction fragments containing zeta- and theta-globin genes varies among individual rabbits. Analysis of BamHI fragments of genomic DNA from 24 New Zealand white rabbits revealed eight different patterns of fragments containing zeta-globin genes. The large BamHI fragments containing genes zeta 0 and zeta 1 are polymorphic in length, whereas a 1.9-kb fragment containing the zeta 2 gene and the 3.5-kb fragment containing the zeta 3 gene do not vary in size. In contrast to this constancy in the size of the restriction fragments, the copy number of the zeta 2 and zeta 3 genes does vary among different rabbits. No length polymorphism was detected in the BamHI fragments containing the theta-globin genes, but again the copy number varies for restriction fragments containing the theta 2 gene. The alpha 1- and theta 1-globin genes are located in a nonpolymorphic 7.2-kb BamHI fragment. The combined data from hybridization with both zeta and theta probes shows that the BamHI cleavage pattern does not vary within the region 5'-alpha 1-theta 1- zeta 2-zeta 3-theta 2-3', but the pattern genomic blot-hybridization patterns for the progeny of parental rabbits with different zeta-globin gene patterns shows that the polymorphic patterns are inherited in a Mendelian fashion. Two different haplotypes have been mapped based on the genomic blot-hybridization data. The variation in the alpha-like globin gene cluster in the rabbit population results both from differences in the copy number of the duplication block containing the zeta-zeta-theta gene set and from the presence or absence of polymorphic BamHI sites.      

Assignment of orthologous relationships among mammalian alpha-globin genes by examining flanking regions reveals a rapid rate of evolution

In order to study the relationships among mammalian alpha-globin genes, we have determined the sequence of the 3' flanking region of the human alpha 1 globin gene and have made pairwise comparisons between sequenced alpha-globin genes. The flanking regions were examined in detail because sequence matches in these regions could be interpreted with the least complication from the gene duplications and conversions that have occurred frequently in mammalian alpha-like globin gene clusters. We found good matches between the flanking regions of human alpha 1 and rabbit alpha 1, human psi alpha 1 and goat I alpha, human alpha 2 and goat II alpha, and horse alpha 1 and goat II alpha. These matches were used to align the alpha-globin genes in gene clusters from different mammals. This alignment shows that genes at equivalent positions in the gene clusters of different mammals can be functional or nonfunctional, depending on whether they corrected against a functional alpha-globin gene in recent evolutionary history. The number of alpha-globin genes (including pseudogenes) appears to differ among species, although highly divergent pseudogenes may not have been detected in all species examined. Although matching sequences could be found in interspecies comparisons of the flanking regions of alpha- globin genes, these matches are not as extensive as those found in the flanking regions of mammalian beta-like globin genes. This observation suggests that the noncoding sequences in the mammalian alpha-globin gene clusters are evolving at a faster rate than those in the beta-like globin gene clusters. The proposed faster rate of evolution fits with the poor conservation of the genetic linkage map around alpha-globin gene clusters when compared to that of the beta-like globin gene clusters. Analysis of the 3' flanking regions of alpha-globin genes has revealed a conserved sequence approximately 100-150 bp 3' to the polyadenylation site; this sequence may be involved in the expression or regulation of alpha-globin genes.      

Combined ipilimumab and nivolumab first‐line and after BRAF‐targeted therapy in advanced melanoma

The combination of ipilimumab and nivolumab is a highly active systemic therapy for metastatic melanoma but can cause significant toxicity. We explore the safety and efficacy of this treatment in routine clinical practice, particularly in the setting of serine/threonine‐protein kinase B‐Raf (BRAF)‐targeted therapy. Consecutive patients with unresectable stage IIIC/IV melanoma commenced on ipilimumab and nivolumab across 10 tertiary melanoma institutions in Australia were identified retrospectively. Data collected included demographics, response and survival outcomes. A total of 152 patients were included for analysis, 39% were treatment‐naïve and 22% failed first‐line BRAF/MEK inhibitors. Treatment‐related adverse events occurred in 67% of patients, grade 3–5 in 38%. The overall objective response rate was 41%, 57% in treatment‐naïve and 21% in BRAF/MEK failure patients. Median progression‐free survival was 4.0 months (95% CI, 3.0–6.0) in the whole cohort, 11.0 months (95% CI, 6.0‐NR) in treatment‐naïve and 2.0 months (95% CI, 1.4–4.6) in BRAF/MEK failure patients. The combination of ipilimumab and nivolumab can be used safely and effectively in a real‐world population. While first‐line efficacy appears comparable to trial populations, BRAF‐mutant patients failing prior BRAF/MEK inhibitors show less response.     

Intersectionality and trauma analysis in bioarchaeology

Intersectionality, the theory named by Kimberlé Crenshaw, outlines how multiple elements of an individual's social identity overlap to create and preserve societal inequalities and discrimination. Recently bioarchaeology's engagement with intersectionality has become increasingly explicit, as the field recognizes the lived experience of multiple axes of an individual's identity. Evidence of trauma can remain observable in an individual's skeleton for years, making it an ideal subject of study for intersectional analyses in bioarchaeology. Using contrasting case studies of two individuals who died in hospitals and were unclaimed after death, we explore the theoretical and methodological application of intersectionality to investigations of accidental and interpersonal trauma. Differences in identities and structural inequalities affect bone quality and health outcomes. As we demonstrate, a broken bone is the intersecting result of biological, histomorphological, sociocultural, and behavioral factors. This approach allows for a better acknowledgement of the inherent complexity of past lives, elevating and amplifying previously silenced voices. In this way, intersectionality in bioarchaeology demands social justice.     

Characterisation of an Arabidopsis thaliana cDNA encoding a novel thylakoid lumen protein imported by the ΔpH-dependent pathway

An Arabidopsis thaliana (L.) Heynh. cDNA encoding a novel 16-kDa protein (P16) of the chloroplast thylakoid lumen has been characterised. The function of the protein is unknown but it shares some sequence similarity with alpha allophycocyanins. P16 is synthesised with a bipartite, lumen-targeting presequence, and import experiments demonstrated that this protein follows the ΔpH-dependent pathway. Analysis of the thylakoid transfer peptide revealed two unusual features. Firstly, the key targeting determinant is predicted to be a twin-arginine followed by a highly hydrophobic residue two residues later, rather than at the third position as in most transfer peptides. Secondly, the C-terminal domain of the transfer peptide contains multiple charged residues which may help to prevent mistargeting by the Sec-type protein translocase. Received: 16 October 1998 / Accepted: 29 October 1998