The costs of surgical site infection after abdominal surgery in middle-income countries: Key resource use In Wound Infection (KIWI) study.

BACKGROUND: Surgical site infection (SSI) is the most common complication of abdominal surgery, with substantial costs to patients and health systems. Heterogeneity in costing methods in existing SSI studies makes multi-country comparison challenging. The objective of the study was to assess the costs of SSI across middle-income countries. METHODS: Centres from a randomized controlled trial assessing interventions to reduce SSI (FALCON, ClinicalTrials.gov, NCT03700749NCT) were sampled from two upper-middle- (India, Mexico) and two lower-middle- (Ghana, Nigeria) income countries. The Key resource use In Wound Infection (KIWI) study collected data on postoperative resource use and costs from consecutive patients undergoing abdominal surgery with an incision >5 cm (including caesarean section) that were recruited to FALCON between April and October 2020. The overall costs faced by patients with and without SSI were compared by operative field contamination (clean-contaminated vs contaminated-dirty), country and timing (inpatient vs outpatient). FINDINGS: A total of 335 patients were included in KIWI; SSI occurred in 7% of clean-contaminated cases and 27% of contaminated-dirty cases. Overall, SSI was associated with an increase in postoperative healthcare costs by 75.3% (€412 international Euros) after clean-contaminated surgery and 66.6% (€331) after contaminated-dirty surgery. The highest and lowest cost increases were in India for clean-contaminated cases (€517) and contaminated-dirty cases (€223), respectively. Overall, inpatient costs accounted for 96.4% of the total healthcare costs after clean-contaminated surgery and 92.5% after contaminated-dirty surgery. CONCLUSION: SSI was associated with substantial additional postoperative costs across a range of settings. Investment in health technologies to reduce SSI may mitigate the financial burden to patients and low-resource health systems.

Evaluation of a co-facilitated information and learning programme for service users: the EOLAS programme.

BACKGROUND: The co-production and co-facilitation of recovery-focused education programmes is one way in which service users may be meaningfully involved as partners. OBJECTIVES: To evaluate the impact of a clinician and peer co-facilitated information programme on service users' knowledge, confidence, recovery attitudes, advocacy and hope, and to explore their experience of the programme. METHODS: A sequential design was used involving a pre-post survey to assess changes in knowledge, confidence, advocacy, recovery attitudes and hope following programme participation. In addition, semi-structured interviews with programme participants were completed. Fifty-three participants completed both pre- and post-surveys and twelve individuals consented to interviews. RESULTS: The results demonstrated statistically significant changes in service users' knowledge about mental health issues, confidence and advocacy. These improvements were reflected in the themes which emerged from the interviews with participants (n = 12), who reported enhanced knowledge and awareness of distress and wellness, and a greater sense of hope. In addition, the peer influence helped to normalise experiences for participants, while the dual facilitation engendered equality of participation and increased the opportunity for meaningful collaboration between service users and practitioners. CONCLUSIONS: The evaluation highlights the potential strengths of a service user and clinician co-facilitated education programme that acknowledges and respects the difference between the knowledge gained through self-experience and the knowledge gained through formal learning.

Economic evaluation of strategies for restarting anticoagulation therapy after a first event of unprovoked venous thromboembolism.

Essentials Correct duration of treatment after a first unprovoked venous thromboembolism (VTE) is unknown. We assessed when restarting anticoagulation was worthwhile based on patient risk of recurrent VTE. When the risk over a one-year period is 17.5%, restarting is cost-effective. However, sensitivity analyses indicate large uncertainty in the estimates. SUMMARY: Background Following at least 3 months of anticoagulation therapy after a first unprovoked venous thromboembolism (VTE), there is uncertainty about the duration of therapy. Further anticoagulation therapy reduces the risk of having a potentially fatal recurrent VTE but at the expense of a higher risk of bleeding, which can also be fatal. Objective An economic evaluation sought to estimate the long-term cost-effectiveness of using a decision rule for restarting anticoagulation therapy vs. no extension of therapy in patients based on their risk of a further unprovoked VTE. Methods A Markov patient-level simulation model was developed, which adopted a lifetime time horizon with monthly time cycles and was from a UK National Health Service (NHS)/Personal Social Services (PSS) perspective. Results Base-case model results suggest that treating patients with a predicted 1 year VTE risk of 17.5% or higher may be cost-effective if decision makers are willing to pay up to £20 000 per quality adjusted life year (QALY) gained. However, probabilistic sensitivity analysis shows that the model was highly sensitive to overall parameter uncertainty and caution is warranted in selecting the optimal decision rule on cost-effectiveness grounds. Univariate sensitivity analyses indicate variables such as anticoagulation therapy disutility and mortality risks were very influential in driving model results. Conclusion This represents the first economic model to consider the use of a decision rule for restarting therapy for unprovoked VTE patients. Better data are required to predict long-term bleeding risks during therapy in this patient group.

Radiographic localisation of the entheses of the equine stifle.

REASON FOR PERFORMING STUDY: Injury to the tendons and ligaments of the equine stifle is a common cause of lameness in horses. Individual radiographic localisation of each tendon and ligament of the stifle has not been previously reported or demonstrated in multiple radiographic projections. OBJECTIVE: To create a series of radiographs identifying the origins and/or insertions of the tendons and ligaments of the equine stifle. STUDY DESIGN: Descriptive study of radiographic anatomy. METHODS: The location of all entheses were determined by gross dissection. The proximal tibia and fibula, distal femur, patella and menisci were isolated from one horse and used as a template. A series of 4 radiographs was obtained with each enthesis identified with barium paste. The radiographic landmarks for each enthesis were described and the best projection(s) for evaluation of each structure of interest identified. RESULTS: Forty-eight radiographic images were produced that demonstrated the best radiographic projections to define each enthesis. CONCLUSIONS: Radiography is the imaging modality most frequently used to evaluate the equine stifle. The images presented here will serve as a guide for evaluating radiographs of the equine stifle, particularly identifying avulsions and enthesopathies of ligamentous and tendinous origins and insertions.

A participatory approach to the development of a co-produced and co-delivered information programme for users of services and family members: the EOLAS programme (paper 1).

OBJECTIVE: The EOLAS programme is a peer and clinician-led mental health information programme on recovery from mental health difficulties, specifically for people with a diagnosis of schizophrenia spectrum or bipolar disorders, their family members and significant others. METHOD: This article, the first of a two part series, outlines the background to and the rationale behind the EOLAS programme, and traces the participatory process used to inform the development and implementation of the pilot phase of the project. The aims of the programme, and the overarching principles that guided its development, delivery and evaluation, including the set-up of the project steering group are outlined and discussed. Findings Two separate programmes, one for family members and one for service users were designed. In addition, participant and facilitator handbooks were developed for each programme, including a training programme for facilitators. CONCLUSION: Central to a recovery oriented service is the involvement of service users and families in the design and delivery of services. EOLAS is one potential model for achieving this aim.

Recurrent focal segmental glomerulosclerosis in the renal allograft: single center experience in the era of modern immunosuppression.

FSGS is an important cause of ESRD and tends to recur in allografts (rFSGS). Older series suggest recurrence rates of 30-60%. In the modern era of transplant immunosuppression, recurrence rates are unknown. There are also few data regarding prevalence of known genetic mutations in adult FSGS patients who undergo transplantation. Recently, FSGS has been subdivided into histological variants, which may predict renal outcomes; there is little information on patterns of recurrence and outcomes in these variants. Finally, treatment for rFSGS relies upon up-titrating calcineurin inhibitors and plasmapheresis. Insufficient information exists on the use of these regimens for rFSGS in the era of modern immunosuppression. We conducted a retrospective chart review involving all renal transplant recipients at Columbia University Medical Center from December 1999 to March 2007. Those with biopsy confirmed primary FSGS were included and information regarding baseline characteristics, histologic variants, genetics, treatment, and clinical outcomes were collected. FSGS recurred in 23% of patients. Those with collapsing histology on native kidney biopsy, tended to recur with the same histology. No known genetic mutations were identified among those with recurrence. Plasmapheresis resulted in complete or partial remission in 75% of those with recurrence. Recurrent FSGS resulted in a trend toward the combined outcome of ESRD or death compared to those without recurrence (27% vs. 12%). Modern immunosuppression does not reduce the rate of rFSGS, known genetic mutations are uncommon in such adult patients, collapsing FSGS tends to recur with the same histology, and plasmapheresis may be helpful in the treatment of recurrence.

Increased blocking activity of combined tachykinin NK1- and NK2-receptor antagonists on tachykinergic bronchomotor responses in the guinea-pig.

1. The present study compared the effect of the administration of tachykinin NK1- and NK2-receptor antagonists alone and in combination on exogenous and endogenous tachykinin-induced contractions using three different guinea-pig airway preparations: isolated bronchus, isolated perfused lung and in vivo. 2. In the isolated bronchi, the tachykinin NK1-receptor antagonist CP 99994 (0.01-1 microM) produced concentration-dependent inhibition of contractions induced the tachykinin NK1-receptor agonists substance P (SP) and [Met-OMe11] SP ([Met-OMe11]SP), whereas the tachykinin NK2-receptor antagonist SR 48968 (0.1 microM) had no effect. SR 48968 (0.001-0.01 microM) concentration-dependently inhibited contractions induced by the tachykinin NK2-receptor agonists neurokinin A (NKA) and [beta-Ala8]-neurokinin A (4-10) ([betaAla8]-NKA) whereas CP 99994 (0.1 microM) did not inhibit the contractions. The contractile activity of capsaicin, an agent that releases endogenous tachykinins from sensory C-fibres, was inhibited in a concentration dependent manner by SR 48968 (0.001-0.03 microM) but not by CP 99994 (0.1 microM). Combination of CP 99994 and SR 48968 caused increased inhibitory effects on the concentration-response curves to SP, [Met-OMe1l]SP, NKA, [beta-Ala8]-NKA and capsaicin. 3. In isolated perfused lungs, SR 48968 concentration (0.01-10 microM) dependently inhibited NKA-, [beta-Ala8]-NKA- and capsaicin-induced bronchoconstriction whereas CP 99994 (30 microM) had no effect on SP-, NKA-, [beta-Ala8]-NKA- and capsaicin-induced bronchoconstriction. Combination of inactive concentrations of CP 99994 and SR 48968 produced an increased inhibitory effect on all previous stimuli-induced bronchoconstriction. 4. In in vivo guinea-pig studies, intravenous and oral pretreatment with SR 48968 (0.01-1 mg kg(-1) i.v. and 0.1-3 mg kg(-1) p.o., respectively), but not with CP 99994 (1 mg kg(-1) i.v. and 0.3-30 mg kg(-1) p.o., respectively), produced a dose-dependent inhibition of the bronchoconstrictor responses induced by NKA, [beta-Ala8]-NKA and capsaicin. CP 99994 intravenously (0.3 mg kg(-1)) and orally (3-10 mg kg(-1)) inhibited SP-induced bronchoconstriction only. Intravenous and oral low dose combinations of CP 99994 and SR 48968 produced an increased inhibition of SP-, NKA-, [beta-Ala8]-NKA- and capsaicin-induced bronchoconstriction, respectively. The present data indicate that combined tachykinin NK1- and NK2-receptor antagonist treatment compared with single antagonist treatment, using CP 99994 and SR 48968, produced an augmented blockade of tachykinin NK1-, NK2- and capsaicin-mediated contractions in guinea pig airways. These findings support the hypothesis that a dual NK1- and NK2-receptor antagonist may provide an advantage over single activity tachykinin NK1- or NK2-receptor antagonists in pulmonary obstructive diseases.

HIV-associated nephropathy: an urban epidemic.

Human immunodeficiency virus-associated nephropathy (HIVAN) is the most common form of chronic renal disease in HIV-1-seropositive patients. Over 85% of cases of HIVAN occur in African-American patients and it is the third leading cause of ESRD in blacks age 20 to 64. Changes in incidence rates of HIVAN have coincided with changes in AIDS incidence rates. The demographics of the AIDS/HIV-1 epidemic indicate that the risk pool for HIVAN will continue to grow and that urban Nephrology centers will continue to see high rates of HIVAN. In addition, improvements in survival rates of HIV-1-seropositive patients on hemodialysis and improved treatment of HIVAN with highly active antiretroviral therapy (HAART) and angiotensin-converting enzyme (ACE)-inhibitors will result in an increased prevalence of HIVAN in the end-stage renal disease (ESRD) and pre-ESRD patient populations.

Discovery of a new class of p38 kinase inhibitors.

The MAP kinase p38 has been implicated in cytokine signaling, and its inhibitors are potentially useful for the treatment of arthritis and osteoporosis. Novel small-molecule inhibitors of p38 kinase were derived from a combinatorial chemistry effort and exhibit activity in the nanomolar range. Very steep structure-activity relationships are observed within this class.

1-Phenyl-5-pyrazolyl ureas: potent and selective p38 kinase inhibitors.

Inhibitors of the MAP kinase p38 are potentially useful for the treatment of arthritis and osteoporosis. Several 2,3-dichlorophenyl ureas were identified as small-molecule inhibitors of p38 by a combinatorial chemistry effort. Optimization for cellular potency led to the discovery of a new class of potent and selective p38 kinase inhibitors, exemplified by the 1-phenyl-5-pyrazolyl urea 7 (IC50 = 13 nM).

Precise genetic mapping and haplotype analysis of the familial dysautonomia gene on human chromosome 9q31.

Familial dysautonomia (FD) is an autosomal recessive disorder characterized by developmental arrest in the sensory and autonomic nervous systems and by Ashkenazi Jewish ancestry. We previously had mapped the defective gene (DYS) to an 11-cM segment of chromosome 9q31-33, flanked by D9S53 and D9S105. By using 11 new polymorphic loci, we now have narrowed the location of DYS to <0.5 cM between the markers 43B1GAGT and 157A3. Two markers in this interval, 164D1 and D9S1677, show no recombination with the disease. Haplotype analysis confirmed this candidate region and revealed a major haplotype shared by 435 of 441 FD chromosomes, indicating a striking founder effect. Three other haplotypes, found on the remaining 6 FD chromosomes, might represent independent mutations. The frequency of the major FD haplotype in the Ashkenazim (5 in 324 control chromosomes) was consistent with the estimated DYS carrier frequency of 1 in 32, and none of the four haplotypes associated with FD was observed on 492 non-FD chromosomes from obligatory carriers. It is now possible to provide accurate genetic testing both for families with FD and for carriers, on the basis of close flanking markers and the capacity to identify >98% of FD chromosomes by their haplotype.

Neural and pancreatic influences on net hepatic glucose uptake and glycogen synthesis.

The role of the liver nerves in the disposition of peripherally administered glucose was examined in seven hepatic innervated (HI) and nine hepatic denervated (HD) 42-h-fasted conscious dogs. After a 40-min basal period, there was a 4-h experimental period during which the hepatic glucose load was increased twofold via peripheral glucose infusion. Somatostatin was infused to suppress pancreatic endocrine secretion, and insulin and glucagon were infused intraportally to produce a fourfold increase in insulin and a gradual decrease (approximately 25%) in glucagon. The area under the curve of net hepatic glucose uptake (NHGU) during the glucose infusion period totaled 483 +/- 82 and 335 +/- 32 mg/kg in HD and HI, respectively (P < 0.05). The area under the curve of the hepatic fractional extraction of glucose was 27% greater in HD (P < 0.05). Net hepatic lactate output was similar in the two groups, and net hepatic glycogen synthesis was 3.8 +/- 0.8 vs. 2.7 +/- 0.5 mg.kg dog wt-1.min-1 in HD and HI, respectively (P = 0.13). The direct pathway of glycogen synthesis was responsible for 54-58% of net hepatic glycogen synthesis in both HI and HD (n = 6 for both). In summary 1) NHGU in response to peripheral glucose infusion was approximately 44% greater in HD than in HI, 2) net hepatic glycogen synthesis was enhanced by 41% in HD although the probability of this change was 0.13, and 3) the contribution of the direct pathway to glycogen synthesis was the same in HD and HI. These data are consistent with a role for the liver nerves in regulating the magnitude of NHGU in response to glucose administration. They also indicate that the absence of liver nerves may reduce glycogen turnover during glucose infusion.

Pharmacological characterization of histamine H3 receptors in isolated guinea pig pulmonary artery and ileum.

We characterized the histamine H3 receptors involved in the modulation of electrical field stimulated neurogenic contraction of guinea pig pulmonary artery sympathetic, and guinea pig ileum parasympathetic preparations. Simultaneous measures of electrical field stimulation-evoked 3H overflow and tension in [3H]norepinephrine-loaded pulmonary artery were sensitive to tetrodotoxin (300 nM) and insensitive to hexamethonium (100 microM). Only the contractile response was inhibited by prazosin (100 nM). (R)-alpha-Methylhistamine's inhibition of the pulmonary artery contraction and 3H overflow were dose-dependently antagonized by thioperamide (30-100 nM). (R)-alpha-Methylhistamine also inhibited the neurogenic contractions of the isolated ileum (pD2 = 8.2). In the pulmonary artery, the relative potency of the histamine H3 receptor antagonists vs. (R)-alpha-methylhistamine inhibition of neurogenic contractions (pD2 = 7.1) was thioperamide (pA2 = 8.6 +/- 0.1) > burimamide (pA2 = 7.6 +/- 0.2) > impromidine (pA2 = 6.9 +/- 0.02). Similarly, the relative potency of histamine H3 receptor antagonists in the isolated ileum was thioperamide > burimamide > or = impromidine, with pA2 estimates of 8.7 +/- 0.1, 7.3 +/- 0.1 and 7.1 +/- 0.1, respectively. Antagonist potencies suggest a predominant histamine H3A-like receptor population on postganglionic sympathetic neurons innervating the pulmonary artery and parasympathetic neurons innervating the ileum longitudinal muscle.

The human gene for neurotrophic tyrosine kinase receptor type 2 (NTRK2) is located on chromosome 9 but is not the familial dysautonomia gene.

The neurotrophic tyrosine kinase receptor type 2 (NTRK2) gene is a member of the trk family of tyrosine protein kinases, which encode receptors for the nerve growth factor-related proteins known as neurotrophins. The neurotrophins and their receptors have long been considered candidate genes for familial dysautonomia (FD), a hereditary sensory neuropathy resulting from the congenital loss of both sensory and autonomic neurons. The DYS gene has recently been mapped to human chromosome 9q31-q33, and therefore we set out to determine the chromosomal localization of the candidate gene NTRK2. A mouse trkB probe was hybridized to both somatic cell hybrids containing human chromosome 9 and a human chromosome 9 flow-sorted cosmid library. The human homologue of trkB, NTRK2, was assigned to chromosome 9. To localize the NTRK2 gene further, a dinucleotide repeat polymorphism was identified within a cosmid that contains NTRK2 exon sequences. This marker was genotyped in the CEPH reference pedigrees and places the NTRK2 gene near D9S1 on the proximal long arm of human chromosome 9. The NTRK2 gene is located approximately 22 cm proximal to DYS and shows several recombinants in disease families. Therefore, the NTRK2 gene can now be excluded as a candidate gene for familial dysautonomia.

Peripherin gene is linked to keratin 18 gene on human chromosome 12.

Peripherin is a neuron-specific intermediate filament (IF) protein, found primarily in phylogenetically old regions of the nervous system. Whereas other neuronal IF genes have only two to three introns and are scattered in the genome, the peripherin gene (PRPH) has a complex intron-exon structure like nonneuronal IF genes that are clustered in tandem arrays, e.g., those encoding the keratins. We used a cosmid containing the human peripherin gene (PRPH) to determine its chromosomal location in relationship to nonneuronal IF genes. Using a rodent-human mapping panel, we localized the PRPH gene to human chromosome 12. Since a cluster of keratin genes maps to 12q12-13, polymorphic markers were developed for PRPH and for one of the keratin genes presumed to be in the cluster, keratin 18 (KRT18). Both markers were typed in CEPH reference families. Pairwise and multipoint analyses of the CEPH data revealed that KRT18 is tightly linked to DNA markers D12S4, D12S22, D12S90, D12S96 and D12S103, which lie between D12S18 and D12S8, with odds greater than 1000:1. These markers are physically located at 12q11-13, thus supporting the fine localization of KRT18 in or near the group of type II keratins in this region. Furthermore, linkage analysis showed that the peripherin gene (PRPH) is tightly linked to KRT18 (Z = 15.73, theta = 0.013), and therefore appears to be in close proximity to the cluster.

Recombinant human IL-10 prevents the onset of diabetes in the nonobese diabetic mouse.

The role of IL-10 in the pathogenesis of autoimmune diabetes mellitus was assessed in the nonobese diabetic (NOD) mouse. In these studies the effect of IL-10 was determined on three parameters of diabetes: The development of hyperglycemia, the development of insulitis, and the production of insulin by beta cells. Initial experiments investigated the effect of anticytokine antibodies on the development of disease. These results indicated that monoclonal anti-IFN-gamma antibody greatly reduced the incidence of hyperglycemia in female NOD mice, while anti-IL-4, IL-5, and IL-10 were ineffective. In subsequent studies, daily subcutaneous administration of IL-10, a known potent inhibitor of IFN-gamma production by TH1 T cells, to 9 and 10-week-old NODs was shown to delay the onset of disease and significantly reduce the incidence of diabetes. Histopathology performed on pancreatic tissue demonstrated that treatment with IL-10 reduced the severity of insulitis, prevented cellular infiltration of islet cells, and promoted normal insulin production by beta cells. Taken together these results indicate IL-10 suppresses the induction and progression of autoimmune pathogenesis associated with diabetes mellitus and suggest a potential therapeutic role for this cytokine in this autoimmune disease.

Comparison of continuous single layer polypropylene anastomosis with double layer and stapled anastomoses in elective colon resections.

The documented leak rate of the continuous single layer polypropylene (CSLP) anastomosis in elective colon resection is 0-6 per cent. It is more cost effective than stapling (S), and should be faster and easier to perform than the double-layer (DL) technique. However, there have been no reported series comparing the outcome of the CSLP anastomosis with the DL and S techniques. We reviewed the charts of 100 patients with elective colon resections. Eighty-four had data sufficient for analysis. There were 44 CSLP, 21 DL, and 19 S. The groups were comparable with respect to 12 preoperative variables. Proportionately more large-small bowel anastomoses were performed in the S group, and no patient in the S group was actively taking steroids. Clinical outcome was assessed. All leaks were clinically apparent and documented with contrast enema or laparotomy. The leak rate for the CSLP was 6.8 per cent (3/44). Two of the three patients with leaks were taking steroids. There were two leaks in the DL group (9.5%), one of which was taking steroids, and no leaks in the S group. The difference in leak rate between the three groups was not statistically significant. The average cost for CSLP at our institution is $4.00 compared with $8.00 and $35.00 for the DL and S, respectively. We conclude that the CSLP is a reasonable and safe alternative to DL and S anastomoses.