Comparable outcomes of in-cement revision and uncemented modular stem revision for Vancouver B2 periprosthetic femoral fracture at 5 years.

INTRODUCTION: Periprosthetic femoral fractures (PFF) are detrimental for patients. Vancouver B2 fractures about a cemented stem can be revised to a longer uncemented stem or using an in-cement revision, if the cement mantle is adequate. There are reports documenting the success of both techniques. The aim of this single centre study was to perform a direct comparison of these two procedures. MATERIALS AND METHODS: A retrospective study of consecutive Vancouver B2 PFFs around a cemented stem during 16 years was performed. All study cases were treated either using an in-cement revision or with an uncemented stem revision. Preoperatively, the groups were compared based upon age, gender, ASA, BMI, and Charlson comorbidity score. The outcome measures were surgical time, complications, in-hospital stay, revisions, 1-year readmission rate, and survivorship. RESULTS: After a median of 3.5 years, there were 70 patients in the uncemented and 31 in the in-cement group. There was no difference in any of the preoperative variables. Surgical time was shorter for in-cement revisions by a mean of 45 min (p < 0.001). There was no difference in in-hospital stay, surgical complications or readmissions. Implant survival at 5 years was 93.5% for the in-cement and 94.4% for the uncemented revision (p = 0.946). Patient survivorship at 5 years was 62.5% for the in-cement and 69.8% for the uncemented group (p = 0.094). CONCLUSIONS: This study demonstrates that in-cement revision is a valid treatment option for Vancouver B2 fractures, comparable to uncemented stem revision, if certain criteria are met. There was no difference in revision rate, patient survivorship, complications, readmissions or in-hospital stay.

Incidence of venous thromboembolism after total hip, total knee and hip fracture surgery at Waitemata District Health Board following a peer-reviewed audit.

AIM: The incidence of venous thromboembolism (VTE) following arthroplasty and hip fracture surgery remains an important metric for quality and financial reasons. An audit at our institution between 2006-2010 showed a higher VTE rate than international data did at the time. This study aims to determine rates of DVT and PE in patients undergoing hip and knee arthroplasty and hip fracture surgery at Waitemata District Health Board (Waitemata DHB) between 1 January 2013 and 31 December 2016. METHODS: This study is a retrospective review of all VTE within three months of elective hip or knee replacement or hip fracture surgery. Data were identified for the period between 2013 and 2016 from Waitemata DHB patient databases, including a dedicated VTE database. RESULTS: The current rates of deep vein thrombosis (DVT) and pulmonary embolism (PE) at our institution following hip or knee arthroplasty or hip fracture surgery are 1.5% and 0.6% respectively, a lower rate than 2.3% and 0.9% respectively in 2006-2010. DVTs were significantly more prevalent after hip fracture surgery than after elective hip or knee arthroplasty, and 71% of DVTs were confined to the distal veins. Of the patients undergoing surgery, 93% received post-operative chemoprophylaxis, mainly aspirin or low molecular-weight heparin (LMWH). CONCLUSION: There has been a significant reduction in VTE rates following elective hip and knee joint replacement and hip fracture surgery between the time periods. This occurred over a period when Waitemata DHB introduced a multi-modal, interdisciplinary team approach to VTE prophylaxis utilising enhanced recovery after surgery (ERAS) pathways. These measures may therefore have contributed to the reduction in VTEs.

Hospital readmissions, mortality and potentially inappropriate prescribing: a retrospective study of older adults discharged from hospital.

AIMS: Applying version 2 of the STOPP/START criteria to discharge prescriptions of older adults discharged from a general medical unit, the aim of this study is to assess potentially inappropriate medications (PIMs) and potential prescribing omissions (PPOs) and their association with hospital readmission and mortality. METHODS: Discharge medications, co-morbidities and patient demographics were recorded over an 8-month period for consecutive emergency admissions of patients aged ≥65 years. PIMs and PPOs were identified using version 2 of the STOPP/START criteria. Multivariate analysis for association of PIMs and PPOs with re-admissions and mortality during the follow-up period were assessed using binary logistic regression. RESULTS: Data for 259 patients with a mean age of 77 (65-99, 51% female) were analysed. At discharge, the mean number of co-morbidities and medications per patient were 5.4 (SD: 2.1 range: 0-14) and 9.3 (SD: 4.0 range: 1-31) respectively. During the follow-up period (mean 41.5 months, SD: 2.0 range: 38-46 months), 50.2% of patients had died and the median number of readmissions was two (IQR: 1-4 range: 0-33). Prescription of more than five medications was significantly associated with PIMs and PPOs (OR: 2.75, 95% CI: 1.34-5.62 and OR 3.20, 95% CI: 1.57-6.54 respectively). Presence of a PIM was associated with three or more readmissions (OR: 2.43 95% CI: 1.19-4.98) and PPOs with mortality (OR: 1.88, 95% CI: 1.09-3.27). CONCLUSIONS: Using version 2 of the STOPP/START criteria, the presence of PIMs and/or PPOs in older adults discharged from hospital is significantly associated with repeated hospital admissions and mortality respectively.

Clinical Inquiry: Is megestrol acetate safe and effective for malnourished nursing home residents?

No. Megestrol acetate (MA) is neither safe nor effective for stimulating appetite in malnourished nursing home residents. It increases the risk of deep vein thrombosis (strength of recommendation [SOR]: C, 2 retrospective chart reviews), but isn't associated with other new or worsening events or disorders (SOR: B, single randomized controlled trial [RCT]). Over a 25-week period, MA wasn't associated with increased mortality (SOR: B, single RCT). After 44 months, however, MA-treated patients showed decreased median survival (SOR: B, single case-control study). Consistent, meaningful weight gain was not observed with MA treatment (SOR: B, single case-control study, single RCT, 2 retrospective chart reviews, single prospective case-series).

Gender, ethnicity and smoking affect pain and function in patients with rotator cuff tears.

BACKGROUND: This study is a collation of baseline demographic characteristics of those presenting for rotator cuff repair in New Zealand, and exploration of associations with preoperative function and pain. Data were obtained from the New Zealand Rotator Cuff Registry; a multicentre, nationwide prospective cohort of rotator cuff repairs undertaken from 1 March 2009 until 31 December 2010. METHODS: A total of 1383 patients were included in the study. This required complete demographic information, preoperative Flex-SF (functional score) and pain scores. Following univariate analysis, a multivariate model was used. RESULTS: The average age was 58 years (69% males and 11% smokers). New Zealand Europeans made up 90% and Maori 5%. The average preoperative Flex-SF was significantly lower (poorer function) in those over 65 years, females, smokers and Maori, in the non-dominant patients, using a multivariate model. Average preoperative pain scores were significantly worse (higher scores) in females, Maori, Polynesians, smokers, using a multivariate model. CONCLUSION: This is the largest reported prospective cohort of patients presenting for rotator cuff surgery. Results can be used to understand the effect of rotator cuff tears on the different patients, for example Maori patients who are under-represented, present younger, with more pain and poorer function.

Altered load transfer in the pelvis in the presence of periprosthetic osteolysis.

Periprosthetic osteolysis in the retroacetabular region with cancellous bone loss is a recognized phenomenon in the long-term follow-up of total hip replacement. The effects on load transfer in the presence of defects are less well known. A validated, patient-specific, 3D finite element (FE) model of the pelvis was used to assess changes in load transfer associated with periprosthetic osteolysis adjacent to a cementless total hip arthroplasty (THA) component. The presence of a cancellous defect significantly increased (p < 0.05) von Mises stress in the cortical bone of the pelvis during walking and a fall onto the side. At loads consistent with single leg stance, this was still less than the predicted yield stress for cortical bone. During higher loads associated with a fall onto the side, highest stress concentrations occurred in the superior and inferior pubic rami and in the anterior column of the acetabulum with larger cancellous defects.

Can new doctors be prepared for practice? A review.

BACKGROUND: The transition from medical student to junior doctor is an important period of change. Research shows junior doctors often experience high levels of stress, and consequently burnout. Understanding how to prepare for the transition may allow individuals who are likely to struggle to be identified and assisted. The aim of this paper is to systematically review the literature on preparedness for practice in newly qualified junior doctors. METHODS: This was a systematic review of literature concerning the transition from student to junior doctor, published in the last 10 years, and that measured or explored one or more factors affecting preparedness. RESULTS: Nine papers were included in this review. These varied in design and methodological quality. Most used survey methodology (n = 7). Six found knowledge and skills, particularly deficiencies in prescribing and practical procedures, relevant in terms of preparedness. Five looked at personal traits, with high levels of neuroticism and low confidence deemed to be important. Medical school and workplace factors, including early clinical experience and shadowing, positively affected preparedness. A lack of senior support proved detrimental. The influence of demographics was inconclusive. DISCUSSION: The studies reviewed indicate that both personal and organisational factors are pertinent to managing the transition from student to junior doctor. Further prospective studies, both qualitative and quantitative, drawing on theories of change, are required to identify what precise factors would make a difference to this transition.

Veterans residing in self-governed recovery homes for substance abuse: sociodemographic and psychiatric characteristics.

OBJECTIVE: Veterans commonly experience both psychiatric and substance abuse problems following their reintegration into the community postwar. The present study describes a sample of veterans residing in self-governed recovery homes. METHODS: A subsample of 24 veterans within a large national study were examined using demographic data and psychiatric and substance abuse measures. Participants were evaluated at baseline and at a one-year follow-up. RESULTS: Abstinence rates for the veteran subsample were high. Additionally, results suggested that participants experienced a reduction in anxiety and depression over time. CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: The psychiatric and substance use improvements of this veteran subsample provide incentive for further research of this at-risk population as residents of self-governed recovery homes.

CD8+ T-cell expansion and maintenance after recombinant adenovirus immunization rely upon cooperation between hematopoietic and nonhematopoietic antigen-presenting cells.

We have recently reported that CD8(+) T-cell memory maintenance after immunization with recombinant human adenovirus type 5 (rHuAd5) is dependent upon persistent transgene expression beyond the peak of the response. In this report, we have further investigated the location and nature of the cell populations responsible for this sustained response. The draining lymph nodes were found to be important for primary expansion but not for memory maintenance, suggesting that antigen presentation through a nonlymphoid source was required. Using bone marrow chimeric mice, we determined that antigen presentation by nonhematopoietic antigen-presenting cells (APCs) was sufficient for maintenance of CD8(+) T-cell numbers. However, antigen presentation by this mechanism alone yielded a memory population that displayed alterations in phenotype, cytokine production and protective capacity, indicating that antigen presentation through both hematopoietic and nonhematopoietic APCs ultimately defines the memory CD8(+) T-cell response produced by rHuAd5. These results shed new light on the immunobiology of rHuAd5 vectors and provide evidence for a mechanism of CD8(+) T-cell expansion and memory maintenance that relies upon both hematopoietic and nonhematopoietic APCs.

Persistence of transgene expression influences CD8+ T-cell expansion and maintenance following immunization with recombinant adenovirus.

Previous studies determined that the CD8(+) T-cell response elicited by recombinant adenovirus exhibited a protracted contraction phase that was associated with long-term presentation of antigen. To gain further insight into this process, a doxycycline-regulated adenovirus was constructed to enable controlled extinction of transgene expression in vivo. We investigated the impact of premature termination of transgene expression at various time points (day 3 to day 60) following immunization. When transgene expression was terminated before the maximum response had been attained, overall expansion was attenuated, yielding a small memory population. When transgene expression was terminated between day 13 and day 30, the memory population was not sustained, demonstrating that the early memory population was antigen dependent. Extinction of transgene expression at day 60 had no obvious impact on memory maintenance, indicating that maintenance of the memory population may ultimately become independent of transgene expression. Premature termination of antigen expression had significant but modest effects on the phenotype and cytokine profile of the memory population. These results offer new insights into the mechanisms of memory CD8(+) T-cell maintenance following immunization with a recombinant adenovirus.

T-cell immunity generated by recombinant adenovirus vaccines.

Recombinant adenovirus vaccines show great promise for generating protective immunity against infectious agents and tumors. Our studies have identified several interesting biological features of the adenovirus vector that influence the T-cell response. Notably, we have demonstrated that following immunization with adenovirus vaccines, the transgene antigen remains available to the system for a longer period than would be expected, resulting in a T-cell population with a sustained effector phenotype. The implications of these observations with regards to the utility of adenovirus vaccines are discussed.

On the role of CD4+ T cells in the CD8+ T-cell response elicited by recombinant adenovirus vaccines.

We have investigated the role of CD4(+) T cells in the development of the CD8(+) T-cell response after immunization with recombinant adenovirus (rAd). In the absence of CD4(+) T cells, the "unhelped" CD8(+) T-cell population exhibited a reduction in primary expansion and long-term survival that appeared to be due to inadequate priming of naïve T cells. There were few functional or phenotypic differences between the helped and unhelped CD8(+) T-cell populations with the exception of O-glycosylated CD43, a marker of effector cells, which was augmented on the unhelped CD8(+) T-cell population. In some cases, the unhelped CD8(+) T-cell population exhibited reduced ability to control virus infection; however, this appeared to be a function of the reduced frequency of antigen-specific CD8(+) T cells. Most notably, the unhelped CD8(+) T-cell population exhibited no defect in secondary expansion. These results provide insight into the role of CD4(+) T cells during the primary CD8(+) T-cell response generated by rAd vaccines and identify potential benefits and issues that must be considered when using adenovirus vaccines under conditions where CD4(+) T-cell function may be limiting, such as vaccination of human immunodeficiency virus patients.

The magnitude of the CD8+ T cell response produced by recombinant virus vectors is a function of both the antigen and the vector.

Virus-based recombinant vaccines have proven highly effective at generating protective CD8+ T cell responses. Multiple vector platforms are available, however, little is known about the relative influence of the different vectors on the transgene-specific CD8+ T cell population. To address this question, we compared several characteristics of the CD8+ T cell response elicited by recombinant adenovirus (rAd) and vaccinia virus (rVV). We found that following rAd immunization the transgene-specific CD8+ T cell response peaked around day 12 and was larger and more sustained than the response produced by rVV. In addition, the CD8+ T cell response generated by rAd was directed primarily against the transgene, whereas the CD8+ T cell response produced by rVV principally targeted the vector backbone. In addition, we also observed that transgene selection also impacted on the magnitude of the CD8+ T cell response elicited by both vectors. Despite differences in the magnitude of the anti-transgene CD8+ T cell response, both vectors elicited CD8+ T cell populations with similar cytokine production, functional avidity and cytolytic activity. In addition, plasmid priming prior to immunization with either rAd or rVV only impacted the magnitude of the transgene gene specific CD8+ T cell response. Our study demonstrates that both vector and transgene selection can influence the magnitude of the CD8+ T cell response, but they do not influence functionality.

Intramuscular immunization with a monogenic plasmid DNA tuberculosis vaccine: Enhanced immunogenicity by electroporation and co-expression of GM-CSF transgene.

Plasmid DNA vaccine has been widely explored for tuberculosis immunization but there is a need to develop the ways to improve its immunogenicity. In this study, we have constructed a plasmid DNA vaccine coding for Ag85A alone or for both Ag85A and GM-CSF and investigated the immune adjuvant effects of electroporation and GM-CSF co-expression, alone or in combination, on CD4 and CD8 T cell IFN-gamma responses, CTL activities and immune protection from pulmonary Mycobacterium tuberculosis challenge in a Balb/c mouse model. We have found that use of electroporation allows a single intramuscular (i.m.) DNA injection to be as effective as repeated i.m. DNA injections in activation of both Ag85A-specific CD4 and CD8 T cells. Co-expression of immune-enhancing cytokine GM-CSF by the same plasmid DNA TB vaccine could further enhance T cell activation including CTL activities on top of electroporation. With regard to immune protection from pulmonary M. tb challenge, use of electroporation also allows a single i.m. DNA injection to be as effective as repeated i.m. DNA injections. Co-expression of GM-CSF transgene also moderately enhances immune protection and such effect is more evident for systemic protection. However, GM-CSF expression has little added effect on immune protection by electroporation-aided immunization protocols. Our findings thus will help with the development of future DNA TB immunization strategies.

Evaluation and treatment of the child with febrile seizure.

Up to 5 percent of children in North America and western Europe experience at least one episode of febrile seizure before six years of age. Most of these seizures are self-limited and patients do not require treatment. Continuous therapy after the seizure is not effective in reducing the development of afebrile seizures. Antipyretics are effective in reducing the risk of febrile seizures if given early in the illness. Immediate care for the patient who has had a febrile seizure includes stopping the seizure, if prolonged, and evaluating the patient for the cause of the fever. Bacterial infections are treatable sources of fever but are not usually the cause of the fever that triggers a seizure. The patient must be assessed for these treatable sources. Long-term consequences of febrile seizure are rare in children who are otherwise healthy. Current recommendations do not support the use of continuing or intermittent neuroleptic or benzodiazepine suppressive therapies after a simple febrile seizure.

Recombinant adenovirus vaccines can successfully elicit CD8+ T cell immunity under conditions of extreme leukopenia.

We have examined the efficacy of vaccination with recombinant adenovirus under conditions of extreme leukopenia in lethally irradiated mice reconstituted with autologous bone marrow. The expansion of antigen-specific CD8(+) T cells following immunization of lethally irradiated hosts paralleled the recovery of total CD8(+) T cells. Surprisingly, the numbers of antigen-specific CD8(+) T cells in lethally irradiated mice beyond 6 weeks postimmunization were comparable to the numbers found in nonirradiated controls. CD8(+) T cells elicited in the lethally irradiated hosts were functionally indistinguishable from those elicited in normal hosts. Antigen expression and presentation persisted for a longer period of time in the draining lymph nodes of irradiated mice compared to those of nonirradiated animals, suggesting that antigen presentation mechanisms were intact during the reconstitution period. Experiments employing allogeneic bone marrow demonstrated that radioresistant host antigen-presenting cells were responsible for antigen presentation during the process of immune reconstitution. These results demonstrate clear compatibility of adenovirus vaccines and cytotoxic therapy. Furthermore, these observations provide novel insights into the mechanisms of CD8(+) T cell activation following adenovirus immunization.

The CD8+ T cell population elicited by recombinant adenovirus displays a novel partially exhausted phenotype associated with prolonged antigen presentation that nonetheless provides long-term immunity.

We have previously reported that the CD8+ T cell response elicited by recombinant adenovirus vaccination displayed a delayed contraction in the spleen. In our current study, we demonstrate that this unusual kinetic is a general phenomenon observed in multiple tissues. Phenotypic analysis of transgene-specific CD8+ T cells present 30 days postimmunization with recombinant adenovirus revealed a population with evidence of partial exhaustion, suggesting that the cells had been chronically exposed to Ag. Although Ag expression could no longer be detected 3 wk after immunization, examination of Ag presentation within the draining lymph nodes demonstrated that APCs were loaded with Ag peptide for at least 40 days postimmunization, suggesting that Ag remains available to the system for a prolonged period, although the exact source of this Ag remains to be determined. At 60 days postimmunization, the CD8+ T cell population continued to exhibit a phenotype consistent with partially exhausted effector memory cells. Nonetheless, these CD8+ T cells conferred sterilizing immunity against virus challenge 7-12 wk postimmunization, suggesting that robust protective immunity can be provided by CD8+ T cells with an exhausted phenotype. These data demonstrate that prolonged exposure to Ag may not necessarily impair protective immunity and prompt a re-evaluation of the impact of persistent exposure to Ag on T cell function.

Recent advances in the development of adenovirus- and poxvirus-vectored tuberculosis vaccines.

Tuberculosis vaccine research began with the search for a vaccine that might be better than, and thus could replace, the current Bacillus Calmette Guérin (BCG) vaccine. Over the last fifteen years or so, intense research effort has led to the identification of a number of novel tuberculosis (TB) vaccines which can be divided into 4 categories: genetically modified mycobacteria, protein, plasmid DNA and viral. However, it is increasingly believed that the current BCG vaccine will continue to be used as a childhood vaccine and that more effort should be directed to developing appropriate boosting vaccines. Mounting evidence suggests that recombinant genetic vaccines, particularly recombinant viral vaccines, are effective in boosting immune activation and protection by BCG vaccination. Since modified vaccinia virus Ankara (MVA)- and adenovirus-vectored TB vaccines have been most extensively studied, this review will focus on recent advances in the development and applications of these two viral TB vaccines.

Electroporation enables plasmid vaccines to elicit CD8+ T cell responses in the absence of CD4+ T cells.

In vivo electroporation dramatically enhances plasmid vaccine efficacy. This enhancement can be attributed to increased plasmid delivery and, possibly, to some undefined adjuvant properties. Previous reports have demonstrated CD8(+) T cell priming by plasmid vaccines is strongly dependent upon CD4(+) T cell help. Indeed, the efficacy of a plasmid vaccine expressing Escherichia coli beta-galactosidase was severely attenuated in MHC class II-deficient (C2D) mice. To determine whether electroporation could compensate for the absence of CD4(+) T cell help, C2D mice were immunized by a single administration of plasmid in combination with electroporation using two conditions which differed only by the duration of the pulse (20 or 50 msec). Both conditions elicited robust cellular and humoral responses in wild-type mice, as measured by IFN-gamma ELISPOT, anti-beta-galactosidase ELISA, and protection from virus challenge. In C2D mice, the cellular response produced by the vaccine combined with the 50-msec pulse, as measured by ELISPOT, was identical to the response in wild-type mice. The 20-msec pulse elicited a milder response that was approximately one-fifth that of the response elicited by the 50-msec pulse. By contrast, the 20-msec conditions provided comparable protection in both wild-type and C2D recipients whereas the protection elicited by the 50-msec conditions in C2D mice was weaker than in wild-type mice. Further investigation is required to understand the discordance between the ELISPOT results and outcome of virus challenge in the C2D mice. Nonetheless, using this technique to prime CD8(+) T cells using plasmid vaccines may prove extremely useful when immunizing hosts with limiting CD4(+) T cell function, such as AIDS patients.

Super-activated interferon-regulatory factors can enhance plasmid immunization.

We have been investigating the adjuvant properties of two super-activated interferon-regulatory factors (IRFs), IRF-3(5D) and IRF7/3A, identified in our previous studies of structure-function relationships, for enhancing plasmid vaccines. Intramuscular injection of plasmid cocktails encoding IRF-3(5D) and IRF7/3A molecules elicited cytotoxic T cell responses in over 80% of mice following a single immunization compared to a 20% response-rate using a control cocktail. Most interestingly, greater than 60% of mice immunized with the super-activated IRFs developed antigen-specific antibodies compared to 0% of the mice in the control group. Finally, vaccines which incorporated the super-activated IRFs provided greater protection against challenge with a recombinant vaccinia virus. These results support further investigation of the potential of these agents as adjuvants for genetic immunization.