CT in the detection of latent tuberculosis: a systematic review.

AIM: To evaluate the use of computed tomography (CT) and low-dose CT in the detection of latent tuberculosis (TB). MATERIALS AND METHODS: A systematic search of literature in adherence with the PRISMA guidelines was carried out. Quality assessment of the included studies was conducted. RESULTS: The search strategy identified a total of 4,621 studies. Sixteen studies were considered eligible and included in the review. There was high heterogeneity among all studies. CT was identified as much more sensitive for the detection of latent TB in all studies despite chest radiography often being recommended in guidelines to assess patients for latent TB. Low-dose CT showed promising results in four of the studies; however, these results were limited due to small sample sizes. CONCLUSION: CT is much superior to chest radiography consistently identifying additional cases of latent TB. There are limited high-quality publications available using low-dose CT but findings thus far suggest low-dose CT could be used as an alternative to standard-dose CT for the detection of latent TB. It is recommended that a randomised controlled trial investigating low-dose CT should be carried out.

The association between iron deficiency and outcomes: a secondary analysis of the intravenous iron therapy to treat iron deficiency anaemia in patients undergoing major abdominal surgery (PREVENTT) trial.

In the intravenous iron therapy to treat iron deficiency anaemia in patients undergoing major abdominal surgery (PREVENTT) trial, the use of intravenous iron did not reduce the need for blood transfusion or reduce patient complications or length of hospital stay. As part of the trial protocol, serum was collected at randomisation and on the day of surgery. These samples were analysed in a central laboratory for markers of iron deficiency. We performed a secondary analysis to explore the potential interactions between pre-operative markers of iron deficiency and intervention status on the trial outcome measures. Absolute iron deficiency was defined as ferritin <30 µg.l-1 ; functional iron deficiency as ferritin 30-100 µg.l-1 or transferrin saturation < 20%; and the remainder as non-iron deficient. Interactions were estimated using generalised linear models that included different subgroup indicators of baseline iron status. Co-primary endpoints were blood transfusion or death and number of blood transfusions, from randomisation to 30 days postoperatively. Secondary endpoints included peri-operative change in haemoglobin, postoperative complications and length of hospital stay. Most patients had iron deficiency (369/452 [82%]) at randomisation; one-third had absolute iron deficiency (144/452 [32%]) and half had functional iron deficiency (225/452 [50%]). The change in pre-operative haemoglobin with intravenous iron compared with placebo was greatest in patients with absolute iron deficiency, mean difference 8.9 g.l-1 , 95%CI 5.3-12.5; moderate in functional iron deficiency, mean difference 2.8 g.l-1 , 95%CI -0.1 to 5.7; and with little change seen in those patients who were non-iron deficient. Subgroup analyses did not suggest that intravenous iron compared with placebo reduced the likelihood of death or blood transfusion at 30 days differentially across subgroups according to baseline ferritin (p = 0.33 for interaction), transferrin saturation (p = 0.13) or in combination (p = 0.45), or for the number of blood transfusions (p = 0.06, 0.29, and 0.39, respectively). There was no beneficial effect of the use of intravenous iron compared with placebo, regardless of the metrics to diagnose iron deficiency, on postoperative complications or length of hospital stay.

The chevron bunionectomy for moderate to severe hallux valgus deformity: Effects of procedural factors on hallux valgus correction.

BACKGROUND: Effects of procedural factors on chevron bunionectomy outcomes were studied. METHODS: Included were 109 feet with distal chevron osteotomy and preoperative intermetatarsal angle (IMA) greater than 15 degrees. IMA and hallux valgus angles (HVA), release type, fixation, second-digit procedures, and risk factors were evaluated. RESULTS: Eighty-three percent (91/109 feet) had satisfactory outcomes; nine had moderate pain. From preoperative, IMA improved 7.2 and HVA 20.5 degrees. Risk factors or second-digit procedures had no effect. Lateral release improved IMA (p < 0.01), with no difference between open lateral and transarticular release; 86% percent (64/74) were satisfied with open lateral release compared with 83% (19/23) and 66% (8/12) with no release and transarticular release, respectively. Fixation did not affect outcomes. CONCLUSION: Chevron bunionectomy corrected IMA and HVA to normal with few complications. Lateral release increased IMA correction. Transarticular release had lower satisfaction than open lateral release or no release. LEVEL OF EVIDENCE: Level III, retrospective.

Robotic-assisted total knee arthroplasty with the OMNIBot platform: a review of the principles of use and outcomes.

INTRODUCTION: Technology that enables the orthopaedic surgeon to deliver a surgical plan with precision and reproducibility continues to evolve. Robotic TKA represents the next phase of technological development in knee arthroplasty. Multiple propriety robotic platforms are now available for use in TKA, and one such system is the OMNIBotics platform. We conducted a review of this system, reporting its history and principles of use, published outcomes and our own personal experience performing OMNI robotic-assisted TKAs. MATERIALS AND METHODS: A literature review was conducted using the PRISMA guidelines. Thirteen papers were included for the final review. RESULTS: The OMNIBot is an accurate and consistent delivery tool in TKA surgery and compares favourably to instrumented, navigation-assisted and patient-specific cutting guides. The OMNIBot has been shown to be a reliable tool for delivering different alignment philosophies as well as planning and achieving tibio-femoral coronal balancing. The utility of the system is increased when the robot is used in conjunction with a soft-tissue tensioning device-the BalanceBot. Data regarding PROM's are limited, however results to date show reliable outcomes. Survival analysis of RATKA using the OMNIBot is limited to one study which reported 99.26% survivorship at 3 years. We report our own outcomes using the OMNIBot, having performed 766 TKA's using the OMNIBot, since 2014 with 99.48% survivorship at 6 year follow-up. CONCLUSION: The OMNIBot platform is an imageless, passive robotic system available since 2007, with over 30,000 TKA's being performed with its assistance. It has a small physical footprint, is relatively inexpensive and time efficient. Our review demonstrates a high level of precision of the surgical planning, with a modestly improved accuracy compared to conventional and navigation technology. Published outcomes are limited, however demonstrate good short-term PROM's and survivorship data that compare favourably to other robotic TKA cohorts.

Analysis of Wheeled Knee Walker Use following Foot and Ankle Surgery or Injury.

To determine patient satisfaction and safety with wheeled knee walkers, we performed a retrospective, observational, and descriptive study. Inclusion criteria were age ≥18 years, unilateral foot or ankle surgery, non-weightbearing status, and being given the option of using the knee walker. Surveys were sent to eligible patients, and chart review included only those patients who returned surveys. Primary endpoints were occurrence and frequency of falls. Secondary endpoints were patient demographics, comorbidities, knee walker characteristics, duration of use, and patient satisfaction. We also attempted to identify associations between falls and patient characteristics. Eighty participants, 51 females and 29 males, responded adequately to the survey. The mean age of respondents was 55.6 ± 13.0 years and their mean body mass index (BMI) was 30.2 ± 5.9 kg/m2. Most used a steerable, 4-wheeled knee walker. Almost half (46%) had no prior experience with any type of walking aids, and none had experience using a knee walker. Two thirds (66%) did not receive any instruction on usage of the knee walker. Thirty-four (43%) of the 80 respondents fell while using the knee walker; nearly two thirds (62%) of those who fell reported multiple falls. Sixteen (55%) of 29 males compared to 18 (36%) of 50 females reported falling (p = .097). There was no statistical association between falls and age, BMI, or number of comorbidities. Most respondents (91%) who fell still reported satisfaction with the knee walker. Nearly half (43%) experienced falling, and nearly two thirds (64%) of those who fell had multiple falls.

Estimated dates of detectable infection (EDDIs) as an improvement upon Fiebig staging for HIV infection dating.

Accurate methods for determining the duration of HIV infection at the individual level are valuable in many settings, including many critical research studies and in clinical practice (especially for acute infection). Since first published in 2003, the 'Fiebig staging system' has been used as the primary way of classifying early HIV infection into five sequential stages based on HIV test result patterns in newly diagnosed individuals. However, Fiebig stages can only be assigned to individuals who produce both a negative and a positive test result on the same day, on specific pairs of tests of varying 'sensitivity'. Further, in the past 16 years HIV-testing technology has evolved substantially, and three of the five key assays used to define Fiebig stages are no longer widely used. To address these limitations, we developed an improved and more general framework for estimating the duration of HIV infection by interpreting any combination of diagnostic test results, whether obtained on single or multiple days, into an estimated date of detectable infection, or EDDI. A key advantage of the EDDI method over Fiebig staging is that it allows for the generation of a point estimate, as well as an associated credibility interval for the date of first detectable infection, for any person who has at least one positive and one negative HIV test of any kind. The tests do not have to be run on the same day; they do not have to be run during the acute phase of infection and the method does not rely on any special pairing of tests to define 'stages' of infection. The size of the interval surrounding the EDDI (and therefore the precision of the estimate itself) depends largely on the length of time between negative and positive tests. The EDDI approach is also flexible, seamlessly incorporating any assay for which there is a reasonable diagnostic delay estimate. An open-source, free online tool includes a user-updatable curated database of published diagnostic delays. HIV diagnostics have evolved tremendously since that original publication more than 15 years ago, and it is time to similarly evolve the methods used to estimate timing of infection. The EDDI method is a flexible and rigorous way to estimate the timing of HIV infection in a continuously evolving diagnostic landscape.

Finding the Right Assessment Measures for Young People with Intellectual Disabilities Who Display Harmful Sexual Behaviour.

BACKGROUND: Previous studies and national reports have all noted that a significant proportion of the young people who display harmful sexual behaviours have intellectual disabilities. However, research on the topic has been scarce. This study presents a systematic review of the literature relating to clinical instruments specifically developed or adapted for adolescents with intellectual disabilities who display harmful sexual behaviours. METHOD: An electronic search of databases was completed for published articles in English from the earliest possible date to the end of 2013. RESULTS: No published articles met the full search criteria. This confirmed the lack of published clinical measures, apart from two risk assessment instruments. CONCLUSIONS: Given the lack of measures, it is recommended that the focus of future research needs to be on developing or adapting instruments that will offer researchers' and clinicians' empirical as well as clinical data on this all-too-often-overlooked population of vulnerable youth.

Meta-analysis of the influence of lifestyle changes for preoperative weight loss on surgical outcomes.

BACKGROUND: The aim was to investigate whether preoperative weight loss results in improved clinical outcomes in surgical patients with clinically significant obesity. METHODS: This was a systematic review and aggregate data meta-analysis of RCTs and cohort studies. PubMed, MEDLINE, Embase and CINAHL Plus databases were searched from inception to February 2018. Eligibility criteria were: studies assessing the effect of weight loss interventions (low-energy diets with or without an exercise component) on clinical outcomes in patients undergoing any surgical procedure. Data on 30-day or all-cause in-hospital mortality were extracted and synthesized in meta-analyses. Postoperative thromboembolic complications, duration of surgery, infection and duration of hospital stay were also assessed. RESULTS: A total of 6060 patients in four RCTs and 12 cohort studies, all from European and North American centres, were identified. Most were in the field of bariatric surgery and all had some methodological limitations. The pooled effect estimate suggested that preoperative weight loss programmes were effective, leading to significant weight reduction compared with controls: mean difference -7·42 (95 per cent c.i. -10·09 to -4·74) kg (P < 0·001). Preoperative weight loss interventions were not associated with a reduction in perioperative mortality (odds ratio 1·41, 95 per cent c.i. 0·24 to 8·40; I2 = 0 per cent, P = 0·66) but the event rate was low. The weight loss groups had shorter hospital stay (by 27 per cent). No differences were found for morbidity. CONCLUSION: This limited preoperative weight loss has advantages but may not alter the postoperative morbidity or mortality risk.

Modelling of protein turnover provides insight for metabolic demands on those specific amino acids utilised at disproportionately faster rates than other amino acids.

The nitrogen balance is regulated by factors such as diet, physical activity, age, pathogenic challenges, and climatic conditions. A paradigm was developed from published recommended rates of protein intake (g/kg/day) with corresponding rates of endogenous protein turnover and excretion, to extrapolate amino acid balances under various conditions. The average proportions of amino acids in the ingested proteins representing a well-balanced diet were used to assess intake and an average human composition profile from five major high-turnover proteins in the body to assess endogenous protein turnover. The amino acid excretion profiles for urine and sweat were constructed for males and females from published data. The model calculated the nitrogen balances for a range of amino acids to determine the amino acid requirements to support daily exertion. Histidine, serine, glycine, and ornithine were in negative balances in males and females and this potential deficit was greater in the higher body-mass ranges. Conversely, leucine, isoleucine, and valine were conserved during nitrogen flux and resulted in positive balances. The model was run under a scenario of high demand for the synthesis of IgG during a response to an infectious challenge which indicated that these were increased requirements for tyrosine, threonine, and valine. It was concluded that these amino acids represent points of limitation to anabolic metabolism by restriction of their supply at critical times of demand. This would especially occur under conditions of fitness training, maintaining intensive exercise regimes, facilitating responses to pathogenic challenge, or recovery from injury.

HIV incidence in the Estonian population in 2013 determined using the HIV-1 limiting antigen avidity assay.

OBJECTIVES: Estonia has one the highest number of new HIV diagnoses in the European Union, mainly among injecting drug users and heterosexuals. Little is known of HIV incidence, which is crucial for limiting the epidemic. Using a recent HIV infection testing algorithm (RITA) assay, we aimed to estimate HIV incidence in 2013. METHODS: All individuals aged ≥18 years newly-diagnosed with HIV in Estonia January- December 2013, except blood donors and those undergoing antenatal screening, were included. Demographic and clinical data were obtained from the Estonian Health Board and the Estonian HIV-positive patient database. Serum samples were tested for recent infection using the LAg-avidity EIA assay. HIV incidence was estimated based on previously published methods. RESULTS: Of 69,115 tested subjects, 286 (0.41%) were newly-diagnosed with HIV with median age of 33 years (IQR: 28-42) and 65% male. Self-reported routes of HIV transmission were mostly heterosexual contact (n = 157, 53%) and injecting drug use (n = 62, 21%); 64 (22%) were with unknown risk group. Eighty two (36%) were assigned recent, resulting in estimated HIV incidence of 0.06%, corresponding to 642 new infections in 2013 among the non-screened population. Incidence was highest (1.48%) among people who inject drugs. CONCLUSIONS: These high HIV incidence estimates in Estonia call for urgent action of renewed targeted public health promotion and HIV testing campaigns.

HPA axis in major depression: cortisol, clinical symptomatology and genetic variation predict cognition.

The hypothalamic-pituitary-adrenal (HPA) axis has been implicated in the pathophysiology of a variety of mood and cognitive disorders. Neuroendocrine studies have demonstrated HPA axis overactivity in major depression, a relationship of HPA axis activity to cognitive performance and a potential role of HPA axis genetic variation in cognition. The present study investigated the simultaneous roles HPA axis activity, clinical symptomatology and HPA genetic variation play in cognitive performance. Patients with major depression with psychotic major depression (PMD) and with nonpsychotic major depression (NPMD) and healthy controls (HC) were studied. All participants underwent a diagnostic interview and psychiatric ratings, a comprehensive neuropsychological battery, overnight hourly blood sampling for cortisol and genetic assessment. Cognitive performance differed as a function of depression subtype. Across all subjects, cognitive performance was negatively correlated with higher cortisol, and PMD patients had higher cortisol than did NPMDs and HCs. Cortisol, clinical symptoms and variation in genes, NR3C1 (glucocorticoid receptor; GR) and NR3C2 (mineralocorticoid receptor; MR) that encode for GRs and MRs, predicted cognitive performance. Beyond the effects of cortisol, demographics and clinical symptoms, NR3C1 variation predicted attention and working memory, whereas NR3C2 polymorphisms predicted memory performance. These findings parallel the distribution of GR and MR in primate brain and their putative roles in specific cognitive tasks. HPA axis genetic variation and activity were important predictors of cognition across the entire sample of depressed subjects and HR. GR and MR genetic variation predicted unique cognitive functions, beyond the influence of cortisol and clinical symptoms. GR genetic variation was implicated in attention and working memory, whereas MR was implicated in verbal memory.

Rejuvenation of allogenic red cells: benefits and risks.

BACKGROUND AND OBJECTIVES: To review preclinical and clinical studies that have evaluated the effects of red cell rejuvenation in vivo and in vitro and to assess the potential risks and benefits from their clinical use. MATERIALS AND METHODS: A systematic review and narrative synthesis of the intervention of red cell rejuvenation using a red cell processing solution containing inosine, pyruvate, phosphate and adenine. Outcomes of interest in vitro were changes in red cell characteristics including adenosine triphosphate (ATP), 2,3-diphosphoglycerate (2,3-DPG), deformability and the accumulation of oxidized lipids and other reactive species in the red cell supernatant. Outcomes in vivo were 24-h post-transfusion survival and the effects on oxygen delivery, organ function and inflammation in transfused recipients. RESULTS: The literature search identified 49 studies evaluating rejuvenated red cells. In vitro rejuvenation restored cellular properties including 2,3-DPG and ATP to levels similar to freshly donated red cells. In experimental models, in vivo transfusion of rejuvenated red cells improved oxygen delivery and myocardial, renal and pulmonary function when compared to stored red cells. In humans, in vivo 24-h survival of rejuvenated red cells exceeded 75%. In clinical studies, rejuvenated red cells were found to be safe, with no reported adverse effects. In one adult cardiac surgery trial, transfusion of rejuvenated red cells resulted in improved myocardial performance. CONCLUSION: Transfusion of rejuvenated red cells reduces organ injury attributable to the red cell storage lesion without adverse effects in experimental studies in vivo. The clinical benefits of this intervention remain uncertain.

Immunohistopathological characterization and the impact of topical immunomodulatory therapy in oral chronic graft-versus-host disease: A pilot study.

OBJECTIVE: To characterize the immunohistopathological features of oral chronic graft-versus-host disease (cGVHD), and the impact of topical immunomodulatory therapy on the infiltrating cells. MATERIAL AND METHODS: Paired oral cGVHD biopsies obtained before (n = 12) and 1 month after treatment (n = 12) with topical dexamethasone (n = 8) or tacrolimus (n = 4) were characterized by immunohistochemistry using a panel of CD1a, CD3, CD4, CD8, CD20, CD31, CD62E, CD103, CD163, c-kit, and FoxP3. Controls included acute GVHD (aGVHD; n = 3), oral lichen planus (OLP; n = 5), and normal tissues (n = 5). RESULTS: Oral cGVHD specimens prior to treatment were mainly characterized by basal cell squamatization, lichenoid inflammation, sclerosis, apoptosis, and lymphocytic exocytosis. The infiltrating cells in oral cGVHD primarily consisted of CD3+ , CD4+ , CD8+ , CD103+ , CD163+ , and FoxP3+ cells, which were higher than in normal tissues. Topical dexamethasone or tacrolimus reduced neutrophilic exocytosis, basal cell squamatization, and lichenoid inflammation in oral cGVHD, and dexamethasone reduced the number of CD4+ and CD103+ cells. CONCLUSION: The high expression of CD3, CD4, CD8, CD103, CD163, and FoxP3 confirms that oral cGVHD is largely T-cell-driven with macrophage participation. The impact of topical immunomodulatory therapy was variable, reducing histological inflammatory features, but with a weak clinicopathological correlation. Topical dexamethasone reduced the expression of CD4 and CD103, which may offer novel therapeutic targets.

IgG4 Related Disease, A Case of Large Vessel Vasculitis

Aim This report describes a case of large vessel vasculitis highlighting diagnostic and therapeutic challenges. It describes the use of the B cell depleting agent Rituximab in this setting. This is the case of a 50 year old lady with bipolar disorder presenting with lower limb pain. Method PET CT and CT angiography were employed in the diagnosis of a large vessel vasculitic process. Serum IgG4 was elevated. Histological sampling was not clinically feasible. A presumptive diagnosis of IgG4 related disease was made. Results The patient responded well to steroids and later rituximab. A prompt taper of steroids was required due to labile mood and Rituximab proved to be effective in this case as a maintenance therapy. Conclusion This case demonstrates that a combination of clinical findings, laboratory results and radiological imaging may be necessary for diagnosis for IgG4 related disease, especially in the absence of a histological diagnosis. Rituximab was used in this case as a maintenance therapy allowing for a relatively rapidly reducing course of steroids.

Informing etiologic research priorities for squamous cell esophageal cancer in Africa: A review of setting-specific exposures to known and putative risk factors.

Esophageal squamous cell carcinoma (ESCC) is one of the most common cancers in most Eastern and Southern African countries, but its etiology has been understudied to date. To inform its research agenda, we undertook a review to identify, of the ESCC risk factors which have been established or strongly suggested worldwide, those with a high prevalence or high exposure levels in any ESCC-affected African setting and the sources thereof. We found that for almost all ESCC risk factors known to date, including tobacco, alcohol, hot beverage consumption, nitrosamines and both inhaled and ingested PAHs, there is evidence of population groups with raised exposures, the sources of which vary greatly between cultures across the ESCC corridor. Research encompassing these risk factors is warranted and is likely to identify primary prevention strategies.

International cancer seminars: a focus on esophageal squamous cell carcinoma.

The International Agency for Research on Cancer (IARC) and the US National Cancer Institute (NCI) have initiated a series of cancer-focused seminars [Scelo G, Hofmann JN, Banks RE et al. International cancer seminars: a focus on kidney cancer. Ann Oncol 2016; 27(8): 1382-1385]. In this, the second seminar, IARC and NCI convened a workshop in order to examine the state of the current science on esophageal squamous cell carcinoma etiology, genetics, early detection, treatment, and palliation, was reviewed to identify the most critical open research questions. The results of these discussions were summarized by formulating a series of 'difficult questions', which should inform and prioritize future research efforts.

Deriving an optimal threshold of waist circumference for detecting cardiometabolic risk in sub-Saharan Africa.

BACKGROUND: Waist circumference (WC) thresholds derived from western populations continue to be used in sub-Saharan Africa (SSA) despite increasing evidence of ethnic variation in the association between adiposity and cardiometabolic disease and availability of data from African populations. We aimed to derive a SSA-specific optimal WC cut-point for identifying individuals at increased cardiometabolic risk. METHODS: We used individual level cross-sectional data on 24 181 participants aged ⩾15 years from 17 studies conducted between 1990 and 2014 in eight countries in SSA. Receiver operating characteristic curves were used to derive optimal WC cut-points for detecting the presence of at least two components of metabolic syndrome (MS), excluding WC. RESULTS: The optimal WC cut-point was 81.2 cm (95% CI 78.5-83.8 cm) and 81.0 cm (95% CI 79.2-82.8 cm) for men and women, respectively, with comparable accuracy in men and women. Sensitivity was higher in women (64%, 95% CI 63-65) than in men (53%, 95% CI 51-55), and increased with the prevalence of obesity. Having WC above the derived cut-point was associated with a twofold probability of having at least two components of MS (age-adjusted odds ratio 2.6, 95% CI 2.4-2.9, for men and 2.2, 95% CI 2.0-2.3, for women). CONCLUSION: The optimal WC cut-point for identifying men at increased cardiometabolic risk is lower (⩾81.2 cm) than current guidelines (⩾94.0 cm) recommend, and similar to that in women in SSA. Prospective studies are needed to confirm these cut-points based on cardiometabolic outcomes.International Journal of Obesity advance online publication, 31 October 2017; doi:10.1038/ijo.2017.240.

Cytokine responses to exercise and activity in patients with chronic fatigue syndrome: case-control study.

Chronic fatigue syndrome (CFS) is characterized by fatigue after exertion. A systematic review suggested that transforming growth factor (TGF)-ß concentrations are often elevated in cases of CFS when compared to healthy controls. This study attempted to replicate this finding and investigate whether post-exertional symptoms were associated with altered cytokine protein concentrations and their RNA in CFS patients. Twenty-four patients fulfilling Centers for Disease Control criteria for CFS, but with no comorbid psychiatric disorders, were recruited from two CFS clinics in London, UK. Twenty-one healthy, sedentary controls were matched by gender, age and other variables. Circulating proteins and RNA were measured for TGF-ß, tumour necrosis factor (TNF), interleukin (IL)-8, IL-6 and IL-1ß. We measured six further cytokine protein concentrations (IL-2, IL-4, IL-5, IL-10, IL-12p70, and interferon (IFN)-γ). Measures were taken at rest, and before and after both commuting and aerobic exercise. CFS cases had higher TGF-ß protein levels compared to controls at rest (median (quartiles) = 43·9 (19·2, 61·8) versus 18·9 (16·1, 30·0) ng/ml) (P = 0·003), and consistently so over a 9-day period. However, this was a spurious finding due to variation between different assay batches. There were no differences between groups in changes to TGF-ß protein concentrations after either commuting or exercise. All other cytokine protein and RNA levels were similar between cases and controls. Post-exertional symptoms and perceived effort were not associated with any increased cytokines. We were unable to replicate previously found elevations in circulating cytokine concentrations, suggesting that elevated circulating cytokines are not important in the pathophysiology of CFS.