Anomalies in the review process and interpretation of the evidence in the NICE guideline for chronic fatigue syndrome and myalgic encephalomyelitis.

Chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) is a disabling long-term condition of unknown cause. The National Institute for Health and Care Excellence (NICE) published a guideline in 2021 that highlighted the seriousness of the condition, but also recommended that graded exercise therapy (GET) should not be used and cognitive-behavioural therapy should only be used to manage symptoms and reduce distress, not to aid recovery. This U-turn in recommendations from the previous 2007 guideline is controversial.We suggest that the controversy stems from anomalies in both processing and interpretation of the evidence by the NICE committee. The committee: (1) created a new definition of CFS/ME, which 'downgraded' the certainty of trial evidence; (2) omitted data from standard trial end points used to assess efficacy; (3) discounted trial data when assessing treatment harm in favour of lower quality surveys and qualitative studies; (4) minimised the importance of fatigue as an outcome; (5) did not use accepted practices to synthesise trial evidence adequately using GRADE (Grading of Recommendations, Assessment, Development and Evaluations trial evidence); (6) interpreted GET as mandating fixed increments of change when trials defined it as collaborative, negotiated and symptom dependent; (7) deviated from NICE recommendations of rehabilitation for related conditions, such as chronic primary pain and (8) recommended an energy management approach in the absence of supportive research evidence.We conclude that the dissonance between this and the previous guideline was the result of deviating from usual scientific standards of the NICE process. The consequences of this are that patients may be denied helpful treatments and therefore risk persistent ill health and disability.

Generation of Novel Severe Acute Respiratory Syndrome Coronavirus 2 Variants on the B.1.1.7 Lineage in 3 Patients With Advanced Human Immunodeficiency Virus-1 Disease.

The emergence of new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants is of public health concern in case of vaccine escape. Described are 3 patients with advanced human immunodeficiency virus (HIV)-1 and chronic SARS-CoV-2 infection in whom there is evidence of selection and persistence of novel mutations that are associated with increased transmissibility and immune escape.

Occipital nerve blocks in the treatment of headaches: safety and efficacy.

BACKGROUND: Considering current limitations in known treatment options and the significant disability associated with headache disorders, investigation of additional options is needed. Although occipital nerve blocks (ONBs) are currently being utilized frequently in specialty settings, the potential role of ONBs as an alternative to opioids for the management of acute headache episodes in primary and emergency care settings is not yet understood. OBJECTIVE: Our aim was to conduct a systematic literature review of the available evidence regarding the use of ONBs for the management of acute headaches, and then determine its potential for use in the emergency care setting. Techniques, medication selection, adverse reactions, frequency of use, candidates, and measures that can help improve safety were reviewed in order to better evaluate the usefulness of this tool in emergency care. DISCUSSION: Occipital nerve blocks are technically simple procedures that are highly successful in providing dramatic pain relief results. They are also a relatively safe and beneficial alternative to other headache treatment options. Case reports and research have demonstrated that ONBs can be performed safely in outpatient settings. However, due to the paucity of literature on the use of ONBs in emergency care settings, it can only be speculated that the same outcomes can be achieved. CONCLUSIONS: Interest in the use of ONBs in acute care settings is increasing. Current evidence supports that ONBs can be delivered safely in an outpatient setting by providers who have been trained in and have practiced this procedure. Although additional research is needed, current evidence supports that ONBs can be useful in treating acute headaches in an emergency care setting.

Gene expression profiles predictive of outcome and age in infant acute lymphoblastic leukemia: a Children's Oncology Group study.

Gene expression profiling was performed on 97 cases of infant ALL from Children's Oncology Group Trial P9407. Statistical modeling of an outcome predictor revealed 3 genes highly predictive of event-free survival (EFS), beyond age and MLL status: FLT3, IRX2, and TACC2. Low FLT3 expression was found in a group of infants with excellent outcome (n = 11; 5-year EFS of 100%), whereas differential expression of IRX2 and TACC2 partitioned the remaining infants into 2 groups with significantly different survivals (5-year EFS of 16% vs 64%; P < .001). When infants with MLL-AFF1 were analyzed separately, a 7-gene classifier was developed that split them into 2 distinct groups with significantly different outcomes (5-year EFS of 20% vs 65%; P < .001). In this classifier, elevated expression of NEGR1 was associated with better EFS, whereas IRX2, EPS8, and TPD52 expression were correlated with worse outcome. This classifier also predicted EFS in an independent infant ALL cohort from the Interfant-99 trial. When evaluating expression profiles as a continuous variable relative to patient age, we further identified striking differences in profiles in infants less than or equal to 90 days of age and those more than 90 days of age. These age-related patterns suggest different mechanisms of leukemogenesis and may underlie the differential outcomes historically seen in these age groups.

Gene expression classifiers for relapse-free survival and minimal residual disease improve risk classification and outcome prediction in pediatric B-precursor acute lymphoblastic leukemia.

To determine whether gene expression profiling could improve outcome prediction in children with acute lymphoblastic leukemia (ALL) at high risk for relapse, we profiled pretreatment leukemic cells in 207 uniformly treated children with high-risk B-precursor ALL. A 38-gene expression classifier predictive of relapse-free survival (RFS) could distinguish 2 groups with differing relapse risks: low (4-year RFS, 81%, n = 109) versus high (4-year RFS, 50%, n = 98; P < .001). In multivariate analysis, the gene expression classifier (P = .001) and flow cytometric measures of minimal residual disease (MRD; P = .001) each provided independent prognostic information. Together, they could be used to classify children with high-risk ALL into low- (87% RFS), intermediate- (62% RFS), or high- (29% RFS) risk groups (P < .001). A 21-gene expression classifier predictive of end-induction MRD effectively substituted for flow MRD, yielding a combined classifier that could distinguish these 3 risk groups at diagnosis (P < .001). These classifiers were further validated on an independent high-risk ALL cohort (P = .006) and retainedindependent prognostic significance (P < .001) in the presence of other recently described poor prognostic factors (IKAROS/IKZF1 deletions, JAK mutations, and kinase expression signatures). Thus, gene expression classifiers improve ALL risk classification and allow prospective identification of children who respond or fail current treatment regimens. These trials were registered at http://clinicaltrials.gov under NCT00005603.

Identification of novel cluster groups in pediatric high-risk B-precursor acute lymphoblastic leukemia with gene expression profiling: correlation with genome-wide DNA copy number alterations, clinical characteristics, and outcome.

To resolve the genetic heterogeneity within pediatric high-risk B-precursor acute lymphoblastic leukemia (ALL), a clinically defined poor-risk group with few known recurring cytogenetic abnormalities, we performed gene expression profiling in a cohort of 207 uniformly treated children with high-risk ALL. Expression profiles were correlated with genome-wide DNA copy number abnormalities and clinical and outcome features. Unsupervised clustering of gene expression profiling data revealed 8 unique cluster groups within these high-risk ALL patients, 2 of which were associated with known chromosomal translocations (t(1;19)(TCF3-PBX1) or MLL), and 6 of which lacked any previously known cytogenetic lesion. One unique cluster was characterized by high expression of distinct outlier genes AGAP1, CCNJ, CHST2/7, CLEC12A/B, and PTPRM; ERG DNA deletions; and 4-year relapse-free survival of 94.7% ± 5.1%, compared with 63.5% ± 3.7% for the cohort (P = .01). A second cluster, characterized by high expression of BMPR1B, CRLF2, GPR110, and MUC4; frequent deletion of EBF1, IKZF1, RAG1-2, and IL3RA-CSF2RA; JAK mutations and CRLF2 rearrangements (P < .0001); and Hispanic ethnicity (P < .001) had a very poor 4-year relapse-free survival (21.0% ± 9.5%; P < .001). These studies reveal striking clinical and genetic heterogeneity in high-risk ALL and point to novel genes that may serve as new targets for diagnosis, risk classification, and therapy.

Sequencing by ligation variation with endonuclease V digestion and deoxyinosine-containing query oligonucleotides.

BACKGROUND: Sequencing-by-ligation (SBL) is one of several next-generation sequencing methods that has been developed for massive sequencing of DNA immobilized on arrayed beads (or other clonal amplicons). SBL has the advantage of being easy to implement and accessible to all because it can be performed with off-the-shelf reagents. However, SBL has the limitation of very short read lengths. RESULTS: To overcome the read length limitation, research groups have developed complex library preparation processes, which can be time-consuming, difficult, and result in low complexity libraries. Herein we describe a variation on traditional SBL protocols that extends the number of sequential bases that can be sequenced by using Endonuclease V to nick a query primer, thus leaving a ligatable end extended into the unknown sequence for further SBL cycles. To demonstrate the protocol, we constructed a known DNA sequence and utilized our SBL variation, cyclic SBL (cSBL), to resequence this region. Using our method, we were able to read thirteen contiguous bases in the 3' - 5' direction. CONCLUSIONS: Combining this read length with sequencing in the 5' - 3' direction would allow a read length of over twenty bases on a single tage. Implementing mate-paired tags and this SBL variation could enable > 95% coverage of the genome.

Perianal dermatofibrosarcoma protuberans: a case report.

A 67-year-old man presented with a perianal lump that had increased in size. On examination he had a 3-cm irregular, mobile, elevated, red, polypoid lump at the edge of the anus at the 8-o'clock position. Biopsy results unexpectedly revealed a spindle cell lesion extending deep into the subcutaneous tissue with occasional mitoses. The lesion was positive for CD34 and negative for epithelial markers, consistent with dermatofibrosarcoma protuberans (DFSP). Magnetic resonance imaging of the pelvis showed the mass extending deep into the ischiorectal space with no involvement of the external or internal anal sphincter. He underwent excision of the lesion with circumferential margins of 1 cm and formation of a skin rotation flap to achieve primary closure. Histology confirmed DFSP. Both the deep and lateral resection margins were involved. He proceeded to have a wider excision of margins, which was free of any remaining tumor. Dermatofibrosarcoma protuberans is a rare lesion. It most commonly occurs on the trunk; the perianal presentation in this case is unique. Surgical excision and preservation of functionality with cosmesis was an issue in this case, as DFSP is a locally aggressive tumor with a high recurrence rate.

Axillary ultrasound-guided core biopsy in breast cancer: identifying higher nodal burden and more aggressive clinicopathological characteristics.

BACKGROUND: Patients with sentinel lymph node (SLN) metastases may not require axillary lymph node dissection (ALND) but it remains unclear if patients with a positive ultrasound-guided axillary core biopsy (ACB) would satisfy such criteria. AIMS: The aim of this study was to assess if breast cancer patients with a positive pre-operative ACB have more aggressive tumour characteristics/higher axillary nodal burden compared to those with a positive SLN. METHODS: Data was extracted from a prospectively maintained breast cancer database between 2012 and 2015. Patients who underwent ALND after either positive ACB or SLN were included and tumour characteristics/nodal burden were compared. RESULTS: One hundred eighty patients underwent ALND, 125/180 after positive ACB and 55/180 after positive SLNB. Patients with positive ACB were more likely to undergo mastectomy (chi-square test; p = 0.03) and have higher tumour grades (Mann-Whitney test; p < 0.01) compared to the SLNB group. Median positive nodes excised during ALND were 2 (1-22) and 1 (1-11) for ACB and SLNB groups respectively (p < 0.001). Fifty-six patients received neoadjuvant chemotherapy (NCT). Of 72/125 patients in the ACB group not receiving NCT, the median number of positive nodes was 4 (range, 1-22). Ten patients within the ACB group satisfied ACOSOG Z011 criteria. CONCLUSION: Breast cancer patients with a positive ACB are more likely to have aggressive tumour characteristics and higher nodal burden compared to those identified as having axillary nodal disease on SLNB, which may affect surgical decision making.

Durable treatment response of relapsing CNS plasmacytoma using intrathecal chemotherapy, radiotherapy, and Daratumumab.

CNS myelomatous involvement is a rare complication of multiple myeloma with dismal outcome. This disease's optimal treatment is unclear. Combined approach of systemic therapy, radiotherapy, and intrathecal injections chemotherapy should be considered and autologous stem cell transplant consolidation is offered to eligible patients. The role of Daratumumab in this disease deserves further evaluation.

Brown bowel syndrome, an unusual cause of sigmoid volvulus.

We report a case of a 79-year-old gentleman who presented to the emergency department with a 5-day history of abdominal pain, constipation, a progressively distending abdomen and new onset feculent vomiting on a background of a recent endoscopic decompression of a sigmoid volvulus. Investigations confirmed the presence of a recurrent sigmoid volvulus. Attempts to reduce this endoscopically failed and laparotomy with sub-total colectomy and ileostomy formation was performed. Histology from the resected specimen identified a distinct pathology, namely intestinal lipofuscinosis also known as brown bowel syndrome. Brown bowel syndrome is a recognized but rare complication of chronic long term malnutrition. It may present in a myriad of ways including atonia and, rarely, massive colonic dilatation, as in our case.

Factors Affecting Concordance between Radiological and Histological Findings in Invasive Lobular Carcinoma - Experience from a National Cancer Centre.

BACKGROUND: Invasive lobular carcinoma (ILC) is characterized by an infiltrative discohesive growth pattern, making it difficult to accurately assess both clinically and by imaging studies. Despite favourable biological characteristics, challenges remain in the surgical treatment of ILC. We aimed to evaluate radiology/histology concordance and identify histological and biological parameters on core biopsies that may predict final tumour histology and guide surgical treatment decisions. PATIENTS AND METHODS: The radiology and histology reports for all newly diagnosed cases of ILC were analysed. The biopsy and resection histological slides for all the surgical cases were reviewed. RESULTS: 75 new cases of ILC were diagnosed over a 2-year period. 48 patients underwent surgery of whom 25% had 2 or more operations. There was discordance between radiological and histological tumour focality and tumour size in 35 and 40%, respectively. The correlation between radiology/histology discordance and E-cadherin expression was statistically significant. However, the correlation between radiology/histology discordance and menopausal status, breast density, pattern of invasion, presence of lobular intraepithelial neoplasia (LIN), hormonal status, and Ki67 were not statistically significant. CONCLUSION: Histological and biological factors in ILC, with the exception of E-cadherin expression, do not seem to play a significant role in radiology/histology discordance. However, larger studies are needed to further corroborate these findings.

Response to the editorial by Dr Geraghty.

This article is written in response to the linked editorial by Dr Geraghty about the adaptive Pacing, graded Activity and Cognitive behaviour therapy; a randomised Evaluation (PACE) trial, which we led, implemented and published. The PACE trial compared four treatments for people diagnosed with chronic fatigue syndrome. All participants in the trial received specialist medical care. The trial found that adding cognitive behaviour therapy or graded exercise therapy to specialist medical care was as safe as, and more effective than, adding adaptive pacing therapy or specialist medical care alone. Dr Geraghty has challenged these findings. In this article, we suggest that Dr Geraghty's views are based on misunderstandings and misrepresentations of the PACE trial; these are corrected.

A randomized comparative trial of tenofovir DF or abacavir as replacement for a thymidine analogue in persons with lipoatrophy.

BACKGROUND: Long-term antiretroviral therapy, while dramatically reducing HIV-related morbidity and mortality, is associated with metabolic and morphological changes. Peripheral fat loss, lipoatrophy, appears most associated with prolonged therapy with thymidine nucleoside analogues. METHODS: A randomized, open-label, comparative study of switching from a thymidine nucleoside analogue to either tenofovir disoproxil fumarate (DF) or abacavir in 105 individuals on successful antiretroviral therapy with clinically evident moderate to severe lipoatrophy. RESULTS: Individuals were randomized to tenofovir DF (52) or abacavir (53). The switch was well tolerated and the majority of patients completed 48 weeks of study. One individual in the tenofovir DF group and three in the abacavir group discontinued due to drug-related adverse events. Both groups similarly maintained virological control. Limb fat mass increased similarly in both groups: mean increases by week 48 of 329 and 483 g in tenofovir DF and abacavir groups, respectively [mean 95% confidence interval for difference, -154.3 (range -492.8 to 184.3)]. This change from baseline was statistically significant in both groups (tenofovir DF, P = 0.01; abacavir, P = 0.0001). Mean total cholesterol, low density lipoprotein cholesterol and triglycerides improved modestly with switching to tenofovir DF but were unchanged with abacavir. The changes in these parameters were significantly greater in the tenofovir DF arm relative to abacavir. CONCLUSIONS: Switching from a thymidine nucleoside analogue to either tenofovir DF or abacavir leads to significant improvement in limb fat mass over 48 weeks. Tenofovir DF may have modest advantages over abacavir for changes in lipids. Peripheral lipoatrophy, when clinically apparent, resolves slowly following treatment switching.

Drug resistance genotypes predict response to amprenavir-containing regimens in highly drug-experienced HIV-1-infected patients.

We have undertaken a study of virological responses to amprenavir-containing antiretroviral regimens, during the expanded access programme within the UK. Ninety-five HIV-1-infected patients were included for which virological and immunological follow-up was available for 75, and baseline drug resistance data available for 51. These were highly drug-experienced patients, having previously received a median of nine antiviral drugs, within all available classes. Eighty-eight percent of patients had a virological response to the new regimen, with a median maximal decline of 1.45 log10 copies/ml, and 34% of patients reached <400 copies/ml on treatment. Although 68% of patients with resistance data had protease inhibitor resistance mutations, only 10% patients had key amprenavir resistance mutations, and virological response was predicted by the number of active drugs utilized in the amprenavir-containing regimen, as determined by the baseline genotypic resistance test. Other independent predictors of viral load decline were a higher baseline viral load and fewer previous antiviral drugs. We conclude that amprenavir can contribute to antiviral efficacy in salvage regimens, and that resistance testing may help to optimize its use in this scenario. New formulations of amprenavir, together with boosted regimens, may enhance the activity in the presence of protease inhibitor-resistant virus.

Ethnicity and discordance in plasma HIV-1 RNA viral load and CD4+ lymphocyte count in a cohort of HIV-1-infected individuals.

BACKGROUND: Guidelines for commencing therapy for HIV infection have been based upon HIV-1 RNA and CD4 lymphocyte thresholds. The influence of confounding factors such as gender, ethnicity and co-infections is unproven. OBJECTIVES: To analyse ethnic discordance in plasma HIV-1 viral load (VL) and CD4+ count and its potential clinical significance in Black and Caucasian groups. STUDY DESIGN: Retrospective, cross-sectional, observational study of 537 antiretroviral nai;ve HIV-1-positive individuals attending two East London clinics. Baseline data were obtained from individuals who registered at the clinic from November 1996 to August 1999. An analysis was performed comparing ethnic differences in plasma HIV-1 VL, CD4+ count, CD8+ count, co-infections, CDC disease category, AIDS-defining illnesses and mode of transmission. RESULTS: Plasma HIV-1 VL was significantly lower in Blacks (4.5 copies/ml versus 4.7 copies/ml; P<0.05) despite lower baseline CD4+ counts and similar rates of disease progression to Caucasian groups. This association remained for patients with less advanced disease after stratification for CD4+ count (CD4+ 200-500, VL 4.5 copies/ml versus 4.7 copies/ml, P<0.01; CD4+ >500, VL 3.4 copies/ml versus 4.3 copies/ml, P<0.001) and disease category (non-AIDS, 4.4 copies/ml versus 4.7 copies/ml; P<0.005). On multivariate analysis, the association persisted following adjustment for gender, age, co-infections, CD4+ count and mode of transmission. CONCLUSIONS: These results suggest that plasma HIV-1 VL is discordantly low in Black compared with Caucasian groups stratified for CD4+ count, in this cohort of antiretroviral nai;ve HIV-1-positive individuals living in London. Although there are a number of possible explanations for this finding, it has considerable clinical relevance for the management of Black HIV-1-infected patients within UK, with significant implications for the decision about when to commence antiretroviral or immune-based therapies.

Osteomyelitis complicating pyomyositis in HIV disease.

Pyomyositis has previously been described in association with human immunodeficiency virus (HIV) and as a discrete entity in HIV seronegative patients from tropical climates (tropical pyomyositis). Pyomyositis and osteomyelitis are usually considered a late complication of advanced HIV disease. We describe a patient with well-controlled HIV and both types of musculoskeletal infection. The case highlights an unusual presentation, the utility of MRI in soft tissue infection and an excellent outcome from prolonged antimicrobial therapy following surgical debridement.

Alternative diagnoses to chronic fatigue syndrome in referrals to a specialist service: service evaluation survey.

OBJECTIVE: To assess the accuracy of diagnoses made by referrers to a chronic fatigue syndrome (CFS) service. DESIGN: Retrospective service evaluation surveys of both rejected referral letters and medical case-notes after full clinical assessment. SETTING: A specialist CFS clinic in London, UK. PARTICIPANTS: In the first survey, we assessed rejected referral letters between March 2007 and September 2008. In the second survey, we ascertained the primary diagnosis made in case-notes of 250 consecutive new patients assessed between April 2007 and November 2008. MAIN OUTCOME MEASURES: Reasons for rejection of referrals and primary diagnosis in those assessed. RESULTS: In the first survey, 154 out of 418 referrals (37%) were rejected. Of these, 77 out of the available 127 referrals (61%) had a likely alternative diagnosis. In the second survey of clinically assessed patients, 107 (43%) had alternative medical/psychiatric diagnoses, while 137 out of 250 (54%) patients received a diagnosis of CFS. The commonest alternative medical diagnoses of those assessed were sleep disorders and the commonest alternative psychiatric diagnosis was depressive illness. Altogether 184 of 377 (49%) patients had alternative diagnoses to CFS. CONCLUSIONS: Half of all the referred patients to a specialist CFS clinic had alternative medical and psychiatric diagnoses. Specialist medical assessment for patients with unexplained, disabling, chronic fatigue needs to incorporate both medical and psychiatric assessments.

Gene expression profiling of adult acute myeloid leukemia identifies novel biologic clusters for risk classification and outcome prediction.

To determine whether gene expression profiling could improve risk classification and outcome prediction in older acute myeloid leukemia (AML) patients, expression profiles were obtained in pretreatment leukemic samples from 170 patients whose median age was 65 years. Unsupervised clustering methods were used to classify patients into 6 cluster groups (designated A to F) that varied significantly in rates of resistant disease (RD; P < .001), complete response (CR; P = .023), and disease-free survival (DFS; P = .023). Cluster A (n = 24), dominated by NPM1 mutations (78%), normal karyotypes (75%), and genes associated with signaling and apoptosis, had the best DFS (27%) and overall survival (OS; 25% at 5 years). Patients in clusters B (n = 22) and C (n = 31) had the worst OS (5% and 6%, respectively); cluster B was distinguished by the highest rate of RD (77%) and multidrug resistant gene expression (ABCG2, MDR1). Cluster D was characterized by a "proliferative" gene signature with the highest proportion of detectable cytogenetic abnormalities (76%; including 83% of all favorable and 34% of unfavorable karyotypes). Cluster F (n = 33) was dominated by monocytic leukemias (97% of cases), also showing increased NPM1 mutations (61%). These gene expression signatures provide insights into novel groups of AML not predicted by traditional studies that impact prognosis and potential therapy.