Evaluation of glucose tolerance in cystic fibrosis: Comparison of 50-g and 75-g tests

AbstractBackgroundThe recommended tests for evaluation of glucose tolerance in cystic fibrosis are the fasting blood glucose (FBG) and the 75-g, fasting, 2-h oral glucose tolerance test (OGTT). We compared a 50 g, non-fasting, 1-h glucose challenge test (GCT) to the standard OGTT.MethodsDuring their regularly scheduled visit to the cystic fibrosis clinic, patients underwent a 50-g, non-fasting 1-h GCT and were asked to complete a standard 75-g, fasting, 2-h OGTT within one week of their clinic visit.ResultsFifty-seven patients underwent glucose tolerance testing. Of these, 31/57 (54%) completed both tests. Hyperglycemia was detected on both tests in 9/31 (29%) patients, 11/31 (35%) tested positive only on the GCT, while all those with positive OGTTs had positive GCTs (p<0.01).ConclusionsIn this study, the GCT identified all patients who meet the criteria for abnormal glucose tolerance on an OGTT. There was a large subgroup that was positive for glucose intolerance only on the GCT. These individuals represent a distinct biochemical subgroup of uncertain significance that warrants closer evaluation. Although the GCT can be completed in a non-fasting state and in conjunction with regular blood work or clinic visits, the anticipated greater compliance was not seen

Coming Back to Life: The Permeability of Past and Present, Mortality and Immortality, Death and Life in the Ancient Mediterranean

The lines between death and life were neither fixed nor finite to the peoples of the ancient Mediterranean. For most, death was a passageway into a new and uncertain existence. The dead were not so much extinguished as understood to be elsewhere, and many perceived the deceased to continue to exercise agency among the living. Even for those more skeptical of an afterlife, notions of coming back to life provided frameworks in which to conceptualize the on-going social, political, and cultural influence of the past. This collection of essays examines how notions of coming back to life shape practices and ideals throughout the ancient Mediterranean. All contributors focus on the common theme of coming back to life as a discursive and descriptive space in which antique peoples construct, maintain, and negotiate the porous boundaries between past and present, mortality and immortality, death and life

Resolving the paradox of increased mental health expenditure and stable prevalence.

A doubling of Australian expenditure on mental health services over two decades, inflation-adjusted, has reduced prevalence of neither psychological distress nor mental disorders. Low rates of help-seeking, and inadequate and inequitable delivery of effective care may explain this partially, but not fully. Focusing on depressive disorders, drawing initially on ideas from the work of philosopher and socio-cultural critic Ivan Illich, we use evidence-based medicine statistics and simulation modelling approaches to develop testable hypotheses as to how iatrogenic influences on the course of depression may help explain this seeming paradox. Combined psychological treatment and antidepressant medication may be available, and beneficial, for depressed people in socioeconomically advantaged areas. But more Australians with depression live in disadvantaged areas where antidepressant medication provision without formal psychotherapy is more typical; there also are urban/non-urban disparities. Depressed people often engage in self-help strategies consistent with psychological treatments, probably often with some benefit to these people. We propose then, if people are encouraged to rely heavily on antidepressant medication only, and if they consequently reduce spontaneous self-help activity, that the benefits of the antidepressant medication may be more than offset by reductions in beneficial effects as a consequence of reduced self-help activity. While in advantaged areas, more comprehensive service delivery may result in observed prevalence lower than it would be without services, in less well-serviced areas, observed prevalence may be higher than it would otherwise be. Overall, then, we see no change. If the hypotheses receive support from the proposed research, then implications for service prioritisation and delivery could include a case for wider application of recovery-oriented practice. Critically, it would strengthen the case for action to correct inequities in the delivery of psychological treatments for depression in Australia so that combined psychological therapy and antidepressant medication, accessible and administered within an empowering framework, should be a nationally implemented standard

Preventing HIV Among Young People: Research Priorities for the Future

To review the current state of knowledge on the prevention of sexual transmission of HIV in adolescents and to highlight existing gaps and priority areas for future research

Universal cures for idiosyncratic illnesses: a genealogy of therapeutic reasoning in the mental health field

Over the past decades, there has been a significant increase in prescriptions of psychotropic drugs for mental disorders. So far, most of the explanations of the phenomenon have focused on the process of medicalization, but little attention has been cast towards physicians' day-to-day clinical reasoning, and the way it affects therapeutic decision-making. This article addresses the complex relationship between aetiology, diagnosis and drug treatment by examining the style of reasoning underlying prescribing practices through an historical lens. A genealogy of contemporary prescribing practices is proposed, that draws significant comparisons between 19th-century medicine and modern psychiatry. Tensions between specific, standardized cures and specific, idiosyncratic patients have been historically at play in clinical reasoning - and still are today. This inquiry into the epistemological foundations of contemporary drug prescription reveals an underlying search for scientific legitimacy

Susceptibility of Anopheles campestris-like and Anopheles barbirostris species complexes to Plasmodium falciparum and Plasmodium vivax in Thailand

Nine colonies of five sibling species members of Anopheles barbirostris complexes were experimentally infected with Plasmodium falciparum and Plasmodium vivax. They were then dissected eight and 14 days after feeding for oocyst and sporozoite rates, respectively, and compared with Anopheles cracens. The results revealed that Anopheles campestris-like Forms E (Chiang Mai) and F (Udon Thani) as well as An. barbirostris species A3 and A4 were non-potential vectors for P. falciparum because 0% oocyst rates were obtained, in comparison to the 86.67-100% oocyst rates recovered from An. cracens. Likewise, An. campestris-like Forms E (Sa Kaeo) and F (Ayuttaya), as well as An. barbirostris species A4, were non-potential vectors for P. vivax because 0% sporozoite rates were obtained, in comparison to the 85.71-92.31% sporozoite rates recovered from An. cracens. An. barbirostris species A1, A2 and A3 were low potential vectors for P. vivax because 9.09%, 6.67% and 11.76% sporozoite rates were obtained, respectively, in comparison to the 85.71-92.31% sporozoite rates recovered from An. cracens. An. campestris-like Forms B and E (Chiang Mai) were high-potential vectors for P. vivax because 66.67% and 64.29% sporozoite rates were obtained, respectively, in comparison to 90% sporozoite rates recovered from An. cracens

Transient Nature of Long-Term Nonprogression and Broad Virus-Specific Proliferative T-Cell Responses with Sustained Thymic Output in HIV-1 Controllers

HIV-1(+) individuals who, without therapy, conserve cellular anti-HIV-1 responses, present with high, stable CD4(+) T-cell numbers, and control viral replication, facilitate analysis of atypical viro-immunopathology. In the absence of universal definition, immune function in such HIV controllers remains an indication of non-progression.CD4 T-cell responses to a number of HIV-1 proteins and peptide pools were assessed by IFN-gamma ELISpot and lymphoproliferative assays in HIV controllers and chronic progressors. Thymic output was assessed by sjTRECs levels. Follow-up of 41 HIV-1(+) individuals originally identified as "Long-term non-progressors" in 1996 according to clinical criteria, and longitudinal analysis of two HIV controllers over 22 years, was also performed. HIV controllers exhibited substantial IFN-gamma producing and proliferative HIV-1-specific CD4 T-cell responses to both recombinant proteins and peptide pools of Tat, Rev, Nef, Gag and Env, demonstrating functional processing and presentation. Conversely, HIV-specific T-cell responses were limited to IFN-gamma production in chronic progressors. Additionally, thymic output was approximately 19 fold higher in HIV controllers than in age-matched chronic progressors. Follow-up of 41 HIV-1(+) patients identified as LTNP in 1996 revealed the transitory characteristics of this status. IFN-gamma production and proliferative T-cell function also declines in 2 HIV controllers over 22 years.Although increased thymic output and anti-HIV-1 T-cell responses are observed in HIV controllers compared to chronic progressors, the nature of nonprogressor/controller status appears to be transitory

Immune checkpoint inhibitor PD-1 pathway is down-regulated in synovium at various stages of rheumatoid arthritis disease progression.

Immune checkpoint blockade with therapeutic anti-cytotoxic T lymphocyte-associated antigen (CTLA)-4 (Ipilimumab) and anti-programmed death (PD)-1 (Nivolumab and Pembrolizumab) antibodies alone or in combination has shown remarkable efficacy in multiple cancer types, concomitant with immune-related adverse events, including arthralgia and inflammatory arthritis (IA) in some patients. Herein, using Nivolumab (anti-PD-1 antagonist)-responsive genes along with transcriptomics of synovial tissue from multiple stages of rheumatoid arthritis (RA) disease progression, we have interrogated the activity status of PD-1 pathway during RA development. We demonstrate that the expression of PD-1 was increased in early and established RA synovial tissue compared to normal and OA synovium, whereas that of its ligands, programmed death ligand-1 (PD-L1) and PD-L2, was increased at all the stages of RA disease progression, namely arthralgia, IA/undifferentiated arthritis, early RA and established RA. Further, we show that RA patients expressed PD-1 on a majority of synovial tissue infiltrating CD4+ and CD8+ T cells. Moreover, enrichment of Nivolumab gene signature was observed in IA and RA, indicating that the PD-1 pathway was downregulated during RA disease progression. Furthermore, serum soluble (s) PD-1 levels were increased in autoantibody positive early RA patients. Interestingly, most of the early RA synovium tissue sections showed negative PD-L1 staining by immunohistochemistry. Therefore, downregulation in PD-1 inhibitory signaling in RA could be attributed to increased serum sPD-1 and decreased synovial tissue PD-L1 levels. Taken together, these data suggest that agonistic PD1 antibody-based therapeutics may show efficacy in RA treatment and interception

Beyond humanization and de-immunization: tolerization as a method for reducing the immunogenicity of biologics

Immune responses to some monoclonal antibodies (mAbs) and biologic proteins interfere with their efficacy due to the development of anti-drug antibodies (ADA). In the case of mAbs, most ADA target ‘foreign’ sequences present in the complementarity determining regions (CDRs). Humanization of the mAb sequence is one approach that has been used to render biologics less foreign to the human immune system. However, fully human mAbs can also drive immunogenicity. De-immunization (removing epitopes) has been used to reduce biologic protein immunogenicity. Here, we discuss a third approach to reducing the immunogenicity of biologics: introduction of Treg epitopes that stimulate Treg function and induce tolerance to the biologic protein. Supplementing humanization (replacing xenosequences with human) and de-immunization (reducing T effector epitopes) with tolerization (introducing Treg epitopes) where feasible, as a means of improving biologics ‘quality by design’, may lead to the development of ever more clinically effective, but less immunogenic, biologics