The Effect of Standard Versus Longer Intestinal Bypass on GLP-1 Regulation and Glucose Metabolism in Patients With Type 2 Diabetes Undergoing Roux-en-Y Gastric Bypass: The Long-Limb Study

OBJECTIVERoux-en-Y gastric bypass (RYGB) characteristically enhances postprandial levels of glucagon-like peptide 1 (GLP-1), a mechanism that contributes to its profound glucose-lowering effects. This enhancement is thought to be triggered by bypass of food to the distal small intestine with higher densities of neuroendocrine L-cells. We hypothesized that if this is the predominant mechanism behind the enhanced secretion of GLP-1, a longer intestinal bypass would potentiate the postprandial peak in GLP-1, translating into higher insulin secretion and, thus, additional improvements in glucose tolerance. To investigate this, we conducted a mechanistic study comparing two variants of RYGB that differ in the length of intestinal bypass.RESEARCH DESIGN AND METHODSA total of 53 patients with type 2 diabetes (T2D) and obesity were randomized to either standard limb RYGB (50-cm biliopancreatic limb) or long limb RYGB (150-cm biliopancreatic limb). They underwent measurements of GLP-1 and insulin secretion following a mixed meal and insulin sensitivity using euglycemic hyperinsulinemic clamps at baseline and 2 weeks and at 20% weight loss after surgery.RESULTSBoth groups exhibited enhancement in postprandial GLP-1 secretion and improvements in glycemia compared with baseline. There were no significant differences in postprandial peak concentrations of GLP-1, time to peak, insulin secretion, and insulin sensitivity.CONCLUSIONSThe findings of this study demonstrate that lengthening of the intestinal bypass in RYGB does not affect GLP-1 secretion. Thus, the characteristic enhancement of GLP-1 response after RYGB might not depend on delivery of nutrients to more distal intestinal segments.     

Association of Implementation of a Comprehensive Preconception-to-Pregnancy Management Plan With Pregnancy Outcomes Among Chinese Pregnant Women With Type 1 Diabetes: The CARNATION Study

OBJECTIVETo investigate the effect on pregnancy outcome of integrating a comprehensive management plan for patients with type 1 diabetes (T1D) into the World Health Organization universal maternal care infrastructure.RESEARCH DESIGN AND METHODSA comprehensive preconception-to-pregnancy management plan for women with T1D was implemented in 11 centers from 8 Chinese cities from 2015 to 2017. Sequential eligible pregnant women (n = 133 out of 137 initially enrolled) with T1D and singleton pregnancies attending these management centers formed the prospective cohort. The main outcome was severe adverse pregnancy outcome comprising maternal mortality, neonatal death, congenital malformations, miscarriage in the second trimester, and stillbirth. We compared pregnancy outcomes in this prospective cohort with two control groups with the same inclusion and exclusion criteria: a retrospective cohort (n = 153) of all eligible pregnant women with T1D attending the same management centers from 2012 to 2014 and a comparison cohort (n = 116) of all eligible pregnant women with T1D receiving routine care from 2015 to 2017 in 11 different centers from 7 cities.RESULTSThe rate of severe adverse pregnancy outcome was lower in the prospective cohort (6.02%) than in either the retrospective cohort (18.30%; adjusted odds ratio [aOR] 0.31 [95% CI 0.13–0.74]) or the contemporaneous comparison cohort (25.00%; aOR 0.22 [95% CI 0.09–0.52]).CONCLUSIONSThe substantial improvements in the prospective cohort are evidence of a potentially clinically important effect of the comprehensive management plan on pregnancy outcomes among Chinese pregnant women with pregestational T1D. This supports the development of similar approaches in other countries.     

Elevated antigen-specific Th2 type response is associated with the poor prognosis of hand,foot and mouth disease

The immunopathogenesis of severe hand, foot and mouth disease (HFMD) remains elusive. This study revealed that enterovirus 71 (EV71) epitope-specific CD4+ T cell responses of HFMD patients were skewed toward a Th2 cytokine profile. Patients that demonstrated higher levels of IL-4 expression in their CD4 T cells following antigen stimulation in vitro tended to have a more prolonged period of high fevers and a longer duration of illness. Thus, an increase of EV71 epitope-specific Th2 type response may portend the poor prognosis for some HFMD patients.     

Supportive evidence for 11 loci from genome-wide association studies in Parkinson's disease

Genome-wide association studies have identified a number of susceptibility loci in sporadic Parkinson's disease (PD). Recent larger studies and meta-analyses have greatly expanded the list of proposed association signals. We performed a case-control replication study in a Scandinavian population, analyzing samples from 1345 unrelated PD patients and 1225 control subjects collected by collaborating centers in Norway and Sweden. Single-nucleotide polymorphisms representing 18 loci previously reported at genome-wide significance levels were genotyped, as well as 4 near-significant, suggestive, loci. We replicated 11 association signals at p < 0.05 (SNCA, STK39, MAPT, GPNMB, CCDC62/HIP1R, SYT11, GAK, STX1B, MCCC1/LAMP3, ACMSD, and FGF20). The more recently nominated susceptibility loci were well represented among our positive findings, including 3 which have not previously been validated in independent studies. Conversely, some of the more well-established loci failed to replicate. While future meta-analyses should corroborate disease associations further on the level of common markers, efforts to pinpoint functional variants and understand the biological implications of each risk locus in PD are also warranted.     

Cure or Protection? The meaning of smallpox inoculation,ca 1750–1775

The idea that smallpox could be eradicated was not necessarily the ultimate aim when inoculation was introduced in Europe in the 1720s. This potentiality was not clearly articulated as an aim until the end of the eighteenth century. This article argues that during most of the eighteenth century, the main aim of inoculation was to lead people as safely as possible through what was regarded as an unavoidable disease. Inoculation became safer, simpler and less expensive from the 1760s, but the changing ideas about its potentiality had more complex roots. A new understanding was produced through an interaction between inoculation practice, more general medical theory and developments within probabilistic thinking and political arithmetic. The first part of the article explores how smallpox inoculation was incorporated into existing medical thinking based on traditional humoral pathology. Inoculation was a new technology, but as it was perceived in the early eighteenth century, the innovation did not first and foremost concern the medical principles of the treatment. The second part of the article investigates arguments about why and when to inoculate: what kind of remedy was inoculation for eighteenth-century agents? The article concludes with a discussion on changes emerging towards the end of the century, and relates them to developments during the preceding decades rather than seeing them as inspired precursors of events and ideas to come. Keywords : Smallpox inoculation, Eighteenth century, Humoral pathology, Reluctance to changeWhat was the meaning of eighteenth-century smallpox inoculation? Traditional medical history used to present a continuity from inoculation to Jenner’s vaccine in 1798 and subsequently to the national vaccination programmes of the nineteenth and twentieth centuries, ending in total triumph with the global eradication of smallpox in the 1980s. ¹ The new medical history from the 1970s onwards has done much to change the general perspectives claiming a linear progressive development in medicine. ² As early as in 1985, Roy Porter argued the importance of studying beliefs about illness and health, situated in their historical contexts. ³ While Porter drew attention chiefly towards beliefs among the laity, recent studies in the history of technology and science have also pointed to the influence of cultural factors among scientists themselves. Not least can this be claimed to be relevant in the case of medicine, situated as it is between science and social practice. Ludmila Jordanova contrasts this modern interest in investigating meanings, beliefs and interest with traditional history of science and medicine, saying that ‘in a progressivist narrative, the search for truth was told in terms of blind alleys and right answers; the model was a journey, and the main emphasis was on content’. ⁴ She goes on to point out that few questions were asked about mediating processes, or about ‘how problems requiring explanations were defined’. ⁵ The new medical history, on the other hand, was, as Jordanova argues, shaped by a number of theoretical influences which may all be grouped as ‘social constructionist’. This implied a shifting of focus from the content of the ‘right’ answers to the processes by which knowledge – including scientific knowledge – is produced and negotiated. Jordanova describes this by saying that ‘between the material world and our representations of it there now appeared to be a space, which it was the job of historians (and sociologists and philosophers) to examine’. ⁶ This article will enter such a space, and ask how smallpox and smallpox inoculation were understood in the second part of the eighteenth century.The idea that smallpox could be conquered, even eradicated, was not a necessary companion to the new method when it was introduced in Europe. This potentiality only gradually emerged and was not clearly articulated until the end of the eighteenth century. The main focus of the present article will be the years approximately between 1750 and 1775. Often called the second phase of smallpox inoculation in Europe (after its introduction in the 1720s), this period saw important changes in the way inoculation was carried out. The method became both safer, simpler and less expensive than before. The changes made new ideas possible, but it is important that they were not initiated by the ideas and projects which they later inspired. It also would be overly simplistic to view changing understandings as mere reflections of improved method. The new ideas had more complex roots than technical improvements alone. This article will argue that the slowly changing understanding of the potentialities of inoculation was produced by an interaction between inoculation practice, more general medical theory and developments within probabilistic thinking and political arithmetic.Because the idea of the article is not to discuss the actual practice of inoculation, some issues that have figured prominently in historical research on inoculation will not be touched upon. This concerns the questions of mortality rates and population growth, as well as popular resistance against inoculation. Moreover, the article will discuss a period before the more extensive state initiatives to combat smallpox epidemics had been launched, and thus not go into the idea of public health as it emerged through such programmes. What rather is at stake in the following is the meaning of smallpox inoculation to its eighteenth-century advocates and practitioners. What was inoculation to them? As will appear from the following investigation, this question concerns the medical workings of the new remedy, but also its religious and ethical implications. The meaning of inoculation moreover relates to understandings of chance, luck, hazard and risk, and to the changing conceptualisation of the relation between the individual subject and the population at large.The method chosen to explore this is a close reading of influential texts on inoculation, produced in three different European countries. They represent voices in a public debate on why, when and, to some degree, how to inoculate.As a method of analysis, close reading insists on taking seriously what goes on in the text. The aim is not primarily to detect the intentions of the authors or the influence of their historical contexts, but to study texts as historical realities carrying meaning in themselves. The texts to be investigated here reflect how inoculation was spoken of, what kind of metaphors it was surrounded by, how disease and epidemics were conceptualised. Moreover, they provide the possibility of understanding something about the self-evident premises of the arguments. What is not said, what is not made an issue in these text – because it was unthinkable, or because it was self-evident? To understand the motives and ideas of eighteenth-century medical agents, studies of technology and medical practices alone are not sufficient. The ways the disease and its remedies were spoken of and turned into arguments of a public debate are equally important.The first part of the article explores how smallpox inoculation in Europe was incorporated into existing medical thinking based on traditional humoral pathology. Inoculation was a new technology, and radically so, but as it was perceived in the eighteenth century the radicality did not first and foremost concern the medical principles of the treatment. The middle part of the article investigates arguments as to why and when to employ the new technology. What kind of remedy was inoculation to mid-eighteenth century agents? What kind of situations made its use relevant, and what was the expected outcome? The article concludes with a discussion on changes that emerged towards the end of the century, relating them to developments during the preceding decades rather than seeing them as inspired precursors of events and ideas to come.The material for this study is taken from England, France and Denmark–Norway. England was the first country in Europe where inoculation was introduced from the Middle East, and also the country where it was most generally used. Comparing England to France, where inoculation never became common practice and powerful institutions like the Sorbonne even pronounced themselves against it, it appears obvious that even the arguments in favour of the method differed. One reason for this difference, as Andrea A. Rusnock has pointed out, was that in England the physicians themselves advocated the method, which made it possible to unite practical experience with theoretical argument. In France, local corporations controlled medical practice to a far greater extent, and most of them opposed inoculation for a longer period of time. Here the method was advocated by philosophes who were not physicians, or by physicians who were not French. ⁷ Both countries hold central positions in the history of European smallpox inoculation.Denmark, and not least its northern province Norway, represents a European periphery. The first inoculations in this twin monarchy appear to have taken place in Trondheim (Norway) in 1754. In the capital Copenhagen, a royal inoculation house was established in 1755, but met with little success and closed down after just five years. Apart from this, inoculation in Denmark–Norway seems to have occurred only sporadically and due to private and in some cases lay initiatives. ⁸   Pro-inoculation debate was strongly influenced by texts in English and French, some of which were read in the original, others translated. The earliest text on inoculation to have been published in Denmark–Norway was by J.-A. Butini, originally published in 1752 and translated from French in 1753. La Condamine’s internationally influential pamphlet appeared in Danish in 1755, one year after the French original. ⁹ The texts examined in this article are two medical treatises, written by the English physician J. Kirkpatrick and the Danish professor of medicine Chr. Friis Rottböll, respectively. ¹⁰ Together with a short article by the Swedish physician L. Montin, these texts discuss medical theory concerning smallpox and the effect of inoculation. ¹¹ The texts by the Swiss physicians J.-A. Butini and S.A.D. Tissot, the Italian Angelo Gatti and the English Thomas Dimsdale are manuals, giving instructions on how to carry out inoculation. ¹² They cite arguments in defence of the new technology, but do not enter into discussions on how it works. The texts by Cramer and Bredal, la Condamine, Tronchin and Smith, finally, all promote inoculation by explaining its advantages and also by answering the objections that were most commonly raised against it. ¹³ The aim of the investigation is not to elaborate on national differences, but rather to show how the inoculation debate was fairly international. Influential texts circulated widely and crossed national borders. Pro-inoculation arguments were quoted extensively, and long passages of texts by one author could be incorporated into that of another. Works advocating inoculation constituted an intertextual network, explicitly and implicitly referring to each other. In this network, the three countries of this investigation held different roles. All produced texts and arguments that circulated. The English and French texts had international influence, the Danish and Norwegian probably merely national. Including material from this part of Europe nonetheless adds to our general knowledge about the history of inoculation. It demonstrates the range and significance of ideas and literature from the larger countries, but it also shows that the time lag was small. Despite their role mainly as receivers of ideas, the physicians and intellectuals in the northern periphery were well oriented, quick to import novelties and to relate themselves to international debates.All the texts have been influential. They set the debates and shaped opinion, though in different contexts. Some of their authors, like Dimsdale, la Condamine and Tissot, were men of international renown. As a general trait, it may also be worth noting that medical men were not the only ones to contribute to the inoculations debate. Other men of letters and enlightened philosophy took part, which is an indication that inoculation was not only considered to be a matter of medicine but also concerned the welfare of society at large. On the other hand, it is equally interesting to note that no statesmen or men of political influence are to be found among the authors. In all three countries there were only few and mostly weak attempts at organising larger public programs of inoculation in this period, and they do not seem to have resulted in texts that can be taken to indicate pro-inoculation engagements or ideas on the official level of the state.     

LIFE AFTER SUPPORTED HOUSING: A CASE SERIES OF FORMERLY HOMELESS CLIENTS IN THE DEPARTMENT OF VETERANS AFFAIRS‐SUPPORTIVE HOUSING (HUD‐VASH) PROGRAM 20 YEARS LATER

This article presents a case series of three formerly homeless clients who were in the Housing and Urban Development‐Veterans Affairs Supportive Housing (HUD‐VASH) program 20 years ago and describes their progress since. Clients were identified from a 1992 client roster at one of the original HUD‐VASH sites. Clients were interviewed and their medical records were reviewed. The case studies were characterized as “sustained involvement in subsidized housing,” “successful discharge followed by re‐engagement,” and “case management more important than the voucher.” These cases illustrate that, first, long‐term success in supported housing has not been defined, but perhaps social integration and self‐sufficiency should be a focus. Second, mental health and substance abuse treatment appear to be important in long‐term client success, but when and how they should be promoted remains unclear. Last, case management services may represent a crucial and necessary form of support for clients in supported housing programs.     

Infection Due to Mycobacterium thermoresistibile: a Case Associated with an Orthopedic Device

Mycobacterium thermoresistibile is a rapidly growing environmental nontuberculous mycobacterium, seldom reported in human infections. Here, we describe a rare case of tibial-nail-related osteomyelitis due to Mycobacterium thermoresistibile. We also review the literature about the infections caused by this pathogen.     

Switching to darunavir/ritonavir 800/100 mg once‐daily containing regimen maintains virological control in fully suppressed pre‐treated patients infected with HIV‐1

The objective of this study was to evaluate the switch to once‐daily darunavir/ritonavir 800/100 mg in treatment‐experienced patients with suppressed HIV‐1 replication on a twice‐daily ritonavir‐boosted protease‐inhibitor (bid PI/r) containing regimen, that is in a setting where genotypic resistance test cannot be performed. In this open label, non‐comparative, multicenter study, patients on a bid PI/r‐containing triple combination, with suppressed viral replication, were switched to once‐daily darunavir/r 800/100 mg containing triple combination. The primary endpoint was the proportion of patients with plasma HIV‐RNA < 50 copies/ml 24 weeks after the switch. Intensive darunavir pharmacokinetic evaluation was performed at Week 4 (W4) in 11 patients. Eighty‐five patients were enrolled. All had HIV‐RNA < 50 copies/ml at screening with a pre‐exposure to a median of 2 PI/r (1–5). By intent‐to‐treat analysis (missing = failure), 78/85 patients (92%, 95% CI [83;96]) maintained an HIV‐RNA < 50 copies/ml at W24. Seven patients experienced protocol‐defined treatment failure between baseline and W24: Two had confirmed low‐level viral rebound, one discontinued study treatment for adverse event, three withdrew their consent, and one was lost to follow‐up. By on‐treatment analysis, 78/80 patients (97%, 95% CI [91;99]) maintained an HIV‐RNA < 50 copies/ml at W24. Results were similar at Week 48. The median area under the darunavir plasma concentration–time curve measured in 11 patients was 61,380 ng hr/ml; darunavir median trough concentration 1,340 ng/ml and darunavir half‐life was 12.2 hr. Tolerability of once‐daily darunavir/r 800/100 mg was excellent. Optimally suppressed, treatment‐experienced patients can switch safely from a twice‐daily PI/r regimen to a once‐daily darunavir/r 800/100 mg containing regimen. J. Med. Virol. 85:8–15, 2012. © 2012 Wiley Periodicals, Inc.