Footwear fit as a causal factor in diabetes-related foot ulceration: A systematic review.

AIMS: Incorrectly fitting footwear (IFF) poses a risk of trauma to at-risk feet with diabetes. The aim of this systematic review was to summarise and assess the evidence that IFF is a statistically significant cause of ulceration. METHODS: We searched PubMed, Scopus, Web of Science and Google Scholar for English-language peer-reviewed studies reporting the number or percentage of people with diabetes-related foot ulceration (DFU) attributed to wearing IFF and included a physical examination of the footwear worn. Two independent reviewers assessed the risk of bias using the Newcastle-Ottawa scale. RESULTS: 4318 results were retrieved excluding duplicates with 45 studies shortlisted. Ten studies met the inclusion criteria with most rated as fair (n = 6) or good (n = 3). There is some evidence that DFU is significantly associated with IFF, but this is limited: only 3 of 10 included studies found a statistically significant percentage of those with DFU were wearing IFF or inappropriate footwear which included fastening, material, type or fit (15.0%-93.3%). Risk of bias in these three studies ranged from 'fair' to 'poor'. IFF definitions were often unreported or heterogeneous. Only one study reported IFF-related ulcer sites: 70% were at plantar hallux/toes and 10% at plantar metatarsal heads. CONCLUSIONS: There is some evidence that IFF is a cause of DFU, but further research is needed, which defines IFF, and methodically records footwear assessment, ulcer location and physical activity. Researchers need to uncover why IFF is worn and if this is due to economic factors, a need for footwear education or other reasons.

Hotspots: Adherence in home foot temperature monitoring interventions for at-risk feet with diabetes-A narrative review.

BACKGROUND: Home foot temperature monitoring (HFTM) is recommended for those at moderate to high ulcer risk. Where a > 2.2°C difference in temperature between feet (hotspot) is detected, it is suggested that individuals (1) notify a healthcare professional (HCP); (2) reduce daily steps by 50%. We assess adherence to this and HFTM upon detecting a recurrent hotspot. METHODS: PubMed and Google Scholar were searched until 9 June 2023 for English-language peer-reviewed HFTM studies which reported adherence to HFTM, daily step reduction or HCP hotspot notification. The search returned 1030 results excluding duplicates of which 28 were shortlisted and 11 included. RESULTS: Typical adherence among HFTM study participants for >3 days per week was 61%-93% or >80% of study duration was 55.6%-83.1%. Monitoring foot temperatures >50% of the study duration was associated with decreased ulcer risk (Odds Ratio: 0.50, p < 0.001) in one study (n = 173), but no additional risk reduction was found for >80% adherence. Voluntary dropout was 5.2% (Smart mats); 8.1% (sock sensor) and 4.8%-35.8% (infrared thermometers). Only 16.9%-52.5% of participants notified an HCP upon hotspot detection. Objective evidence of adherence to 50% reduction in daily steps upon hotspot detection was limited to one study where the average step reduction was a pedometer-measured 51.2%. CONCLUSIONS: Ulcer risk reduction through HFTM is poorly understood given only half of the participants notify HCPs of recurrent hotspots and the number of reducing daily steps is largely unknown. HFTM adherence and dropout are variable and more research is needed to determine factors affecting adherence and those likely to adhere.

Contralateral foot temperature monitoring during Charcot immobilisation: A systematic review.

AIMS: Contralateral temperature difference (CTD) is a frequently used marker of healing in Charcot neuro-osteoarthropathy (CN). We aimed to determine whether there is a consistent approach to CTD measurement during healing and the decision-making process around cessation of immobilisation. MATERIALS AND METHODS: Medline, Scopus, and Web of Science were searched until February 2022 for peer-reviewed studies using keywords, including (('arthropathy' OR 'osteoarthropathy' OR 'osteopathy' OR 'neuroarthropathy') AND 'Charcot' AND ('temperature')), which returned 789 results excluding duplicates. Included studies monitored CTD in those with active CN to (i) assess the healing process and (ii) assist in determining the transition from immobilisation. RESULTS: Thirty four studies in total (n = 677 participants) were shortlisted and 19 were included after full paper review. Average CTD at presentation varied from 1.6 to 8.0°C with insufficient data to determine if CTD was proportional to severity of Charcot. Evidence of a relationship between CTD and radiographic or scintigraphy-based markers of healing varied depending on the methodology employed. Threshold CTD for the cessation of immobilisation ranged from <1°C to <2°C. Most frequently it was <2°C sustained for 2-3 visits. Temperature was monitored typically every 2-6 weeks using handheld thermometry at CN site(s) after resting the feet for 15 min. Device type, accuracy/reliability, and ambient temperature were rarely reported. CONCLUSIONS: Further research on CTD and radiographic and radiotracer markers is needed involving larger cohorts. Standardisation in reporting of thermometry device type, accuracy and reliability, foot resting times, and ambient temperature controls is essential to facilitate the comparison of studies, meta-analysis, and evaluation of different immobilisation interventions.

Feature selection for unsupervised machine learning of accelerometer data physical activity clusters - A systematic review.

BACKGROUND: Identifying clusters of physical activity (PA) from accelerometer data is important to identify levels of sedentary behaviour and physical activity associated with risks of serious health conditions and time spent engaging in healthy PA. Unsupervised machine learning models can capture PA in everyday free-living activity without the need for labelled data. However, there is scant research addressing the selection of features from accelerometer data. The aim of this systematic review is to summarise feature selection techniques applied in studies concerned with unsupervised machine learning of accelerometer-based device obtained physical activity, and to identify commonly used features identified through these techniques. Feature selection methods can reduce the complexity and computational burden of these models by removing less important features and assist in understanding the relative importance of feature sets and individual features in clustering. METHOD: We conducted a systematic search of Pubmed, Medline, Google Scholar, Scopus, Arxiv and Web of Science databases to identify studies published before January 2021 which used feature selection methods to derive PA clusters using unsupervised machine learning models. RESULTS: A total of 13 studies were eligible for inclusion within the review. The most popular feature selection techniques were Principal Component Analysis (PCA) and correlation-based methods, with k-means frequently used in clustering accelerometer data. Cluster quality evaluation methods were diverse, including both external (e.g. cluster purity) or internal evaluation measures (silhouette score most frequently). Only four of the 13 studies had more than 25 participants and only four studies included two or more datasets. CONCLUSION: There is a need to assess multiple feature selection methods upon large cohort data consisting of multiple (3 or more) PA datasets. The cut-off criteria e.g. number of components, pairwise correlation value, explained variance ratio for PCA, etc. should be expressly stated along with any hyperparameters used in clustering.

In-shoe pressure thresholds for people with diabetes and neuropathy at risk of ulceration: A systematic review.

INTRODUCTION: In-shoe pressure thresholds play an increasingly important role in the prevention of diabetes-related foot ulceration (DFU). The evidence of their effectiveness, methodological consistency and scope for refinement are the subject of this review. METHODS: 1107 records were identified (after duplicate removal) based on a search of five databases for studies which applied a specific in-shoe pressure threshold to reduce the risk of ulceration. 37 full text studies were assessed for eligibility of which 21 were included. RESULTS: Five in-shoe pressure thresholds were identified, which are employed to reduce the risk of diabetes-related foot ulceration: a mean peak pressure threshold of 200 kPa used in conjunction with a 25% baseline reduction target; a sustained pressure threshold of 35 mm Hg, a threshold matrix based on risk, shoe size and foot region, and a 40-80% baseline pressure reduction target. The effectiveness of the latter two thresholds have not been assessed yet and the evidence for the effectiveness of the other in-shoe pressure thresholds is limited, based only on two RCTs and two cohort studies. CONCLUSIONS: The heterogeneity of current measures precludes meta-analysis and further research and methodological standardisation is required to facilitate ready comparison and the further development of these pressure thresholds.

Toe gaps and their assessment in footwear for people with diabetes: a narrative review.

BACKGROUND: Adequate footwear fit is critical in preventing diabetes-related foot ulcers. One important element is the toe gap, the difference between foot length and internal footwear length available to the foot. We summarised the literature on toe gaps in studies assessing footwear worn by people with diabetes, the methods used to measure both foot length and internal footwear length and identify ambiguities which may impact on toe gap assessment in clinical practice, and suggest pragmatic solutions. METHODS: The Google Scholar database was searched to April 2020 for peer-reviewed studies using keywords related to incorrectly fitting or ill-fitting and diabetes, foot and ulcer which returned 979 results. Included studies within this narrative review encompassed toe gap measurement to assess footwear worn by people with diabetes. RESULTS: A total of eight studies were included after full paper review. Toe gap ranges as used in assessments of footwear worn by people with diabetes vary, with a minimum of 1.0-1.6 cm and a maximum of 1.5-2.0 cm, as do methods of measuring internal footwear length. Only three published studies suggested possible measuring devices. CONCLUSIONS: Toe gap ranged as used when assessing footwear fit in people with diabetes vary and a gold standard device for internal footwear length measurement has yet to emerge. International guidelines provide welcome standardisation, but further research is needed to evaluate both the effect of toe gap ranges upon pressure, plantar stress response and ulceration and available measuring devices to facilitate development of toe gap measurement protocols that may further enhance consistency in practical assessments.

FilterK: A new outlier detection method for k-means clustering of physical activity.

In this paper, a new algorithm denoted as FilterK is proposed for improving the purity of k-means derived physical activity clusters by reducing outlier influence. We applied it to physical activity data obtained with body-worn accelerometers and clustered using k-means. We compared its performance with three existing outlier detection methods: Local Outlier Factor, Isolation Forests and KNN using the ground truth (class labels), average cluster and event purity (ACEP). FilterK provided comparable gains in ACEP (0.581 â†’ 0.596 compared to 0.580-0.617) whilst removing a lower number of outliers than the other methods (4% total dataset size vs 10% to achieve this ACEP). The main focus of our new outlier detection method is to improve the cluster purities of physical activity accelerometer data, but we also suggest it may be potentially applied to other types of dataset captured by k-means clustering. We demonstrate our method using a k-means model trained on two independent accelerometer datasets (training n = 90) and re-applied to an independent dataset (test n = 41). Labelled physical activities include lying down, sitting, standing, household chores, walking (laboratory and non-laboratory based), stairs and running. This type of clustering algorithm could be used to assist with identifying optimal physical activity patterns for health.

Prediction of Diabetic Foot Ulceration: The Value of Using Microclimate Sensor Arrays.

BACKGROUND: Accurately predicting the risk of diabetic foot ulceration (DFU) could dramatically reduce the enormous burden of chronic wound management and amputation. Yet, the current prognostic models are unable to precisely predict DFU events. Typically, efforts have focused on individual factors like temperature, pressure, or shear rather than the overall foot microclimate. METHODS: A systematic review was conducted by searching PubMed reports with no restrictions on start date covering the literature published until February 20, 2019 using relevant keywords, including temperature, pressure, shear, and relative humidity. We review the use of these variables as predictors of DFU, highlighting gaps in our current understanding and suggesting which specific features should be combined to develop a real-time microclimate prognostic model. RESULTS: The current prognostic models rely either solely on contralateral temperature, pressure, or shear measurement; these parameters, however, rarely reach 50% specificity in relation to DFU. There is also considerable variation in methodological investigation, anatomical sensor configuration, and resting time prior to temperature measurements (5-20 minutes). Few studies have considered relative humidity and mean skin resistance. CONCLUSION: Very limited evidence supports the use of single clinical parameters in predicting the risk of DFU. We suggest that the microclimate as a whole should be considered to predict DFU more effectively and suggest nine specific features which appear to be implicated for further investigation. Technology supports real-time in-shoe data collection and wireless transmission, providing a potentially rich source of data to better predict the risk of DFU.

Towards a Portable Model to Discriminate Activity Clusters from Accelerometer Data.

Few methods for classifying physical activity from accelerometer data have been tested using an independent dataset for cross-validation, and even fewer using multiple independent datasets. The aim of this study was to evaluate whether unsupervised machine learning was a viable approach for the development of a reusable clustering model that was generalisable to independent datasets. We used two labelled adult laboratory datasets to generate a k-means clustering model. To assess its generalised application, we applied the stored clustering model to three independent labelled datasets: two laboratory and one free-living. Based on the development labelled data, the ten clusters were collapsed into four activity categories: sedentary, standing/mixed/slow ambulatory, brisk ambulatory, and running. The percentages of each activity type contained in these categories were 89%, 83%, 78%, and 96%, respectively. In the laboratory independent datasets, the consistency of activity types within the clusters dropped, but remained above 70% for the sedentary clusters, and 85% for the running and ambulatory clusters. Acceleration features were similar within each cluster across samples. The clusters created reflected activity types known to be associated with health and were reasonably robust when applied to diverse independent datasets. This suggests that an unsupervised approach is potentially useful for analysing free-living accelerometer data.

A fitting problem: Standardising shoe fit standards to reduce related diabetic foot ulcers.

AIMS: Incorrectly fitting shoes are implicated in callus formation and a significant proportion of diabetic foot ulcers, yet remain surprisingly prevalent. We review the current shoe fit guidelines for consistency and discuss ways in which technology may assist us in standardising methods of footwear assessment. METHODS: Narrative review. RESULTS: Incorrectly fitted shoes are implicated in the development of some diabetic foot ulcers yet surprisingly there's no consensus on shoe fit, despite substantial spending on prescription footwear. Suggested toe gaps vary from 6 to 20 mm and measurement methods also vary from Brannock Devices and callipers to manual measurement. CONCLUSIONS: To prevent fit-related foot ulceration, we need to standardise our biomechanical definition of fit. Future research should (1) evaluate the potential use of 3D scanning technology to provide a standardised means of capturing foot morphology; (2) develop a working biomechanical definition of fit, including toe gap through the identification of key physiological markers that capture and predict dynamic foot shape changes during different physical activities and body weight loading conditions; and (3) determine whether changes in dynamic foot shape of those with diabetes differs from those without, impacting on their shoe fitting needs, potentially necessitating specialist footwear at an earlier stage to avoid ulceration.

Common dietary patterns and risk of cancers of the colon and rectum: Analysis from the United Kingdom Women's Cohort Study (UKWCS).

Few prospective cohort studies in the UK have specifically focused on the associations between commonly consumed dietary patterns and colorectal cancer (CRC). The aim of our study was to assess whether red meat, poultry, fish and vegetarian dietary patterns are associated with differences in the incidence of cancers of colon and rectum in the UKWCS. Four common dietary patterns were defined based on a hierarchy of consumption of red meat, poultry and fish for each cohort participant, using a 217-item food frequency questionnaire. Cox proportional hazards regression was used to provide adjusted hazard ratios (HR) and 95% confidence intervals (CI) for CRC. A total of 32,147 women recruited and surveyed between 1995 and 1998 were followed up for a mean of 17.2 years (426,798 person-years). A total of 462 incident CRC cases were documented; 335 colon cancers (172 proximal and 119 distal) and 152 in the rectum. In multivariable-adjusted models, there was no evidence of a reduction in risk of overall CRC (HR = 0.86, 95% CI: 0.66-1.12), colon cancer (HR = 0.77, 95% CI: 0.56-1.05) or rectal cancer (HR = 1.04, 95% CI: 0.66-1.63) when comparing grouped red meat free diets with diets containing red meat. Exploratory analysis suggested a reduced risk of distal colon cancer in grouped red meat free diets (HR = 0.56, 95% CI: 0.34-0.95), though numbers with this outcome were small. These results indicate that a protective association of red meat free diets specifically on distal colon cancer merits confirmation in a larger study.

Does adherence to the World Cancer Research Fund/American Institute of Cancer Research cancer prevention guidelines reduce risk of colorectal cancer in the UK Women's Cohort Study?

Evidence on adherence to diet-related cancer prevention guidelines and associations with colorectal cancer (CRC) risk is limited and conflicting. The aim of this cohort analysis is to evaluate associations between adherence to the World Cancer Research Fund/American Institute of Cancer Research (WCRF/AICR) 2007 recommendations and incident CRC. The UK Women's Cohort Study comprises over 35 372 women who filled in a FFQ at baseline in 1995. They were followed up for CRC incidence for a median of 17·4 years, an individual score linking adherence to eight of the WCRF/AICR recommendations was constructed. Cox proportional hazards regression provided hazard ratios (HR) and 95 % CI for the estimation of CRC risk, adjusting for confounders. Following exclusions, 444 CRC cases were identified. In the multivariate-adjusted model, women within the second and third (highest) categories of the WRCF/AICR score had HR of 0·79 (95 % CI 0·62, 1·00) and 0·73 (95 % CI 0·48, 1·10), respectively, for CRC compared with those in the lowest, reference category. The overall linear trend across the categories was not significant (P=0·17). No significant associations were observed between the WCRF/AICR score and proximal colon, distal colon and rectal cancers separately. Of the individual score components, a BMI within the normal weight range was borderline significantly protective only for rectal cancer in the fully adjusted model. In view of the likely different causes of CRC subtypes, further research is needed to identify the optimal dietary patterns associated with reducing colon and rectal cancer risk, respectively.

The Mediterranean diet and risk of colorectal cancer in the UK Women's Cohort Study.

Background: Evidence from epidemiological studies investigating associations between adherence to the Mediterranean diet and colorectal cancer is inconsistent. The aim of this study is to assess in the UK Women's Cohort Study whether adherence to the Mediterranean dietary pattern is associated with reduced incidence of cancers of the colon and rectum. Method: A total of 35 372 women were followed for a median of 17.4 years. A 10-component score indicating adherence to the Mediterranean diet was generated for each cohort participant, using a 217-item food frequency questionnaire. The Mediterranean diet score ranged from 0 for minimal adherence to 10 for maximal adherence. Cox proportional hazards regression was used to provide adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for colon and rectal cancer risk. Results: A total of 465 incident colorectal cancer cases were documented. In the multivariable adjusted model, the test for trend was positive (HR = 0.88, 95% CI: 0.78 to 0.99; Ptrend = 0.03) for a 2-point increment in the Mediterranean diet score. For rectal cancer, a 2-point increment in the Mediterranean diet score resulted in an HR (95% CI) of 0.69 (0.56 to 0.86), whereas a 62% linear reduced risk (HR 0.38; 95% CI: 0.20 to 0.74; Ptrend < 0.001) was observed for women within the highest vs the lowest category of the MD score. Estimates for an association with colon cancer were weak (Ptrend = 0.41). Conclusions: Findings suggest that women adhering to a Mediterranean dietary pattern may have a lower risk of colorectal cancer, especially rectal cancer.

Randomised, Double-blind, Placebo-controlled Trial of CCR9-targeted Leukapheresis Treatment of Ulcerative Colitis Patients.

BACKGROUND AND AIMS: Ulcerative colitis patients display increased numbers of circulating pro-inflammatory monocyte human leukocyte antigen-DR [HLA-DRhi] monocytes expressing high levels of the gut-homing C-C chemokine receptor 9 [CCR9] and tumour necrosis factor [TNF]-α. The aim of this first-in-human, double-blind, randomised, placebo-controlled trial was to evaluate selective removal of circulating CCR9-expressing monocytes by leukapheresis in patients with moderate to severe ulcerative colitis, with regards to safety, tolerability, and immunological response. METHODS: Patients with ulcerative colitis were treated every second day with leukapheresis during five sessions with a C-C chemokine ligand 25 [CCL25; CCR9 ligand] column or a placebo column. RESULTS: No major safety concerns were raised and the procedure was well tolerated. Pro-inflammatory HLA-DRhi cells decreased significantly in the active treatment group [p = 0.0391] whereas no statistically significant change was seen in the placebo group [p = 0.4688]. There was a significant decrease of HLA-DRhi monocytes in the active group compared with the placebo group when corrected for the imbalance in weight between the groups [p = 0.0105]. Mayo score decreased in the active group [p = 0.0156] whereas the change in the placebo group was not significant [p = 0.1250]. Mayo score ≤ 3 was observed in five out of 14 patients [35.7%] in the active group compared with one out of eight [12.5%] receiving placebo. The number of responders in the active treatment group was eight out of 14 patients [57.1%], whereas in the corresponding placebo group three out of eight patients [37.5%] responded to placebo. A dose-response correlation was observed between the blood volume processed and clinical outcome. CONCLUSION: This clinical induction trial using CCL25-tailored leukapheresis demonstrates a safe and effective removal of activated monocytes with a clinical effect in patients with ulcerative colitis.

Autologous Peripheral Blood Mononuclear Cells as Treatment in Refractory Acute Respiratory Distress Syndrome.

BACKGROUND: Acute respiratory distress syndrome (ARDS) is a devastating disorder. Despite enormous efforts in clinical research, effective treatment options are lacking, and mortality rates remain unacceptably high. OBJECTIVES: A male patient with severe ARDS showed no clinical improvement with conventional therapies. Hence, an emergent experimental intervention was performed. METHODS: We performed intratracheal administration of autologous peripheral blood-derived mononuclear cells (PBMCs) and erythropoietin (EPO). RESULTS: We found that after 2 days of initial PBMC/EPO application, lung function improved and extracorporeal membrane oxygenation (ECMO) support was reduced. Bronchoscopy and serum inflammatory markers revealed reduced inflammation. Additionally, serum concentration of miR-449a, b, c and miR-34a, a transient upregulation of E-cadherin and associated chromatin marks in PBMCs indicated airway epithelial differentiation. Extracellular vesicles from PBMCs demonstrated anti-inflammatory capacity in a TNF-α-mediated nuclear factor-x03BA;B in vitro assay. Despite improving respiratory function, the patient died of multisystem organ failure on day 38 of ECMO treatment. CONCLUSIONS: This case report provides initial encouraging evidence to use locally instilled PBMC/EPO for treatment of severe refractory ARDS. The observed clinical improvement may partially be due to the anti-inflammatory effects of PBMC/EPO to promote tissue regeneration. Further studies are needed for more in-depth understanding of the underlying mechanisms of in vivo regeneration.

Chemokine receptor expression on monocytes from healthy individuals.

Chronic immune mediated inflammation is characterized by continuous chemokine mediated recruitment and activation of pro-inflammatory cells, monocytes in particular. We believe that an evaluation of the recruitment profile of monocytes during healthy condition is essential for the understanding of cellular response in disease. For this, we have established normal reference values and 95% confidence intervals for receptor expression of 20 chemokine receptors on monocyte subsets; classical (CD14+ CD16−), non-classical (CD14+ CD16+) and HLA-DRhi monocytes from 20 healthy controls using flow cytometry. We demonstrate significant differences in the chemokine receptor expression profiles and high correlation between fraction of cells and level of expression. This is the first global approach to provide a platform for comparable evaluation of cell recruitment during normal and under inflammatory conditions. This will be useful when exploring chemokine­chemokine receptor interactions, inhibition of chemokine signaling and selective removal of migrating cells, which are new treatment strategies in immune mediated diseases.

Treatment of inflammatory bowel disease by chemokine receptor-targeted leukapheresis.

Leukapheresis removes circulating leukocytes en route to the target organ. Hitherto unspecific matrixes have been used to remove leukocytes in inflammatory bowel disease (IBD). This report describes a novel selective leukapheresis column based on chemokine-chemokine receptor interaction. We found an increased expression of the gut homing chemokine receptor CCR9 on CD14(+) monocytes and on CD3(+) T lymphocytes from IBD patients. Biologically active CCL25 was coupled to a Sepharose matrix and demonstrated to selectively remove CCR9-expressing cells leaving other cell populations largely unaffected. A patient with active ulcerative colitis, was subjected to CCL25-column leukapheresis. Four days after treatment, he experienced clinical improvement and stable disease improvement ensued. The study illustrates that specific cells can be targeted using high affinity interactions, i.e., CCL25-CCR9 interactions to remove pathogenic gut-homing cells. Leukapheresis using the bCCL25 column should be investigated in a clinical phase I trial of patients with inflammatory bowel disease.

Autoimmunity and cystatin SA1 deficiency behind chronic mucocutaneous candidiasis in autoimmune polyendocrine syndrome type 1.

Patients with the monogenic disease autoimmune polyendocrine syndrome type I (APSI) develop autoimmunity against multiple endocrine organs and suffer from chronic mucocutaneous candidiasis (CMC), a paradoxical complication with an unknown mechanism. We report here that saliva from APSI patients with CMC is defective in inhibiting growth of Candida albicans in vitro and show reduced levels of a salivary protein identified as cystatin SA1. In contrast, APSI patients without CMC express salivary cystatin SA1 and can inhibit C. albicans to the same extent as healthy controls. We evaluated the anti-fungal activity of cystatin SA1 and found that synthesized full length cystatin SA1 efficiently inhibits growth of C. albicans in vitro. Moreover, APSI patients exhibit salivary IgA autoantibodies recognizing myosin-9, a protein expressed in the salivary glands, thus linking autoimmunity to cystatin SA1 deficiency and CMC. This data suggests an autoimmune mechanism behind CMC in APSI and provides rationale for evaluating cystatin SA1 in antifungal therapy.

Increased cell-mediated immune responses in patients with recurrent herpes simplex virus type 2 meningitis.

The clinical picture of herpes simplex virus type 2 (HSV-2) infection includes genital blisters and less frequently meningitis, and some individuals suffer from recurrent episodes of these manifestations. We hypothesized that adaptive and/or innate immune functional deficiencies may be a major contributing factor in susceptibility to recurrent HSV-2 meningitis. Ten patients with recurrent HSV-2 meningitis were studied during clinical remission. For comparison, 10 patients with recurrent genital HSV infections as well as 21 HSV-seropositive and 19 HSV-seronegative healthy blood donors were included. HSV-specific T cell blasting and cytokine secretion were evaluated in whole blood cultures. HSV-2-induced NK cell gamma interferon production, dendritic cell Toll-like receptor (TLR) expression, and TLR agonist-induced alpha interferon secretion were analyzed. Patients with recurrent HSV-2 meningitis had elevated T cell blasting and Th1 and Th2 cytokine production in response to HSV antigens compared to those of patients with recurrent genital infections. A somewhat increased NK cell response, increased dendritic cell expression of TLR3 and -9, and increased TLR-induced alpha interferon responses were also noted. Contrary to our expectation, recurrent HSV-2 meningitis patients have increased HSV-specific adaptive and innate immune responses, raising the possibility of immune-mediated pathology in the development of recurrent HSV2 meningitis.

Unresectable cholangiocarcinoma: comparison of survival in biliary stenting alone versus stenting with photodynamic therapy.

BACKGROUND & AIMS: Photodynamic therapy (PDT) for unresectable cholangiocarcinoma is associated with improvement in cholestasis, quality of life, and potentially survival. We compared survival in patients with unresectable cholangiocarcinoma undergoing endoscopic retrograde cholangiopancreatography (ERCP) with PDT and stent placement with a group undergoing ERCP with stent placement alone. METHODS: Forty-eight patients were palliated for unresectable cholangiocarcinoma during a 5-year period. Nineteen were treated with PDT and stents; 29 patients treated with biliary stents alone served as a control group. Multivariate analysis was performed by using Model for End-Stage Liver Disease score, age, treatment by chemotherapy or radiation, and number of ERCP procedures and PDT sessions to detect predictors of survival. RESULTS: Kaplan-Meier analysis demonstrated improved survival in the PDT group compared with the stent only group (16.2 vs 7.4 months, P<.004). Mortality in the PDT group at 3, 6, and 12 months was 0%, 16%, and 56%, respectively. The corresponding mortality in the stent group was 28%, 52%, and 82%, respectively. The difference between the 2 groups was significant at 3 months and 6 months but not at 12 months. Only the number of ERCP procedures and number of PDT sessions were significant on multivariate analysis. Adverse events specific to PDT included 3 patients with skin phototoxicity requiring topical therapy only. CONCLUSIONS: ERCP with PDT seems to increase survival in patients with unresectable cholangiocarcinoma when compared with ERCP alone. It remains to be proved whether this effect is attributable to PDT or the number of ERCP sessions. A prospective randomized multicenter study is required to confirm these data.