Chelsea and Westminster Hospital

Liver biopsy remains the gold standard in the assessment of severity of liver disease. Noninvasive tests have gained popularity to predict histology in view of the associated risks of biopsy. However, many models include tests not readily available, and there are limited data from patients with HIV/hepatitis C virus (HCV) coinfection. We aimed to develop a model using routine tests to predict liver fibrosis in patients with HIV/HCV coinfection. A retrospective analysis of liver histology was performed in 832 patients. Liver fibrosis was assessed via Ishak score; patients were categorized as 0-1, 2-3, or 4-6 and were randomly assigned to training (n = 555) or validation (n = 277) sets. Multivariate logistic regression analysis revealed that platelet count (PLT), age, AST, and INR were significantly associated with fibrosis. Additional analysis revealed PLT, age, AST, and ALT as an alternative model. Based on this, a simple index (FIB-4) was developed: age ([yr] x AST [U/L]) / ((PLT [10(9)/L]) x (ALT [U/L])(1/2)). The AUROC of the index was 0.765 for differentiation between Ishak stage 0-3 and 4-6. At a cutoff of <1.45 in the validation set, the negative predictive value to exclude advanced fibrosis (stage 4-6) was 90% with a sensitivity of 70%. A cutoff of >3.25 had a positive predictive value of 65% and a specificity of 97%. Using these cutoffs, 87% of the 198 patients with FIB-4 values outside 1.45-3.25 would be correctly classified, and liver biopsy could be avoided in 71% of the validation group. In conclusion, noninvasive tests can accurately predict hepatic fibrosis and may reduce the need for liver biopsy in the majority of HIV/HCV-coinfected patients.

Angela Joyce on the care of children undergoing BMT for genetic disorders

OBJECTIVE: To explore evidence on the links between patient experience and clinical safety and effectiveness outcomes. DESIGN: Systematic review. SETTING: A wide range of settings within primary and secondary care including hospitals and primary care centres. PARTICIPANTS: A wide range of demographic groups and age groups. PRIMARY AND SECONDARY OUTCOME MEASURES: A broad range of patient safety and clinical effectiveness outcomes including mortality, physical symptoms, length of stay and adherence to treatment. RESULTS: This study, summarising evidence from 55 studies, indicates consistent positive associations between patient experience, patient safety and clinical effectiveness for a wide range of disease areas, settings, outcome measures and study designs. It demonstrates positive associations between patient experience and self-rated and objectively measured health outcomes; adherence to recommended clinical practice and medication; preventive care (such as health-promoting behaviour, use of screening services and immunisation); and resource use (such as hospitalisation, length of stay and primary-care visits). There is some evidence of positive associations between patient experience and measures of the technical quality of care and adverse events. Overall, it was more common to find positive associations between patient experience and patient safety and clinical effectiveness than no associations. CONCLUSIONS: The data presented display that patient experience is positively associated with clinical effectiveness and patient safety, and support the case for the inclusion of patient experience as one of the central pillars of quality in healthcare. It supports the argument that the three dimensions of quality should be looked at as a group and not in isolation. Clinicians should resist sidelining patient experience as too subjective or mood-oriented, divorced from the 'real' clinical work of measuring safety and effectiveness.

This paper is the first in a series of two publications relating to the European Crohn's and Colitis Organisation [ECCO] evidence-based consensus on the diagnosis and management of Crohn's disease and concerns the methodology of the consensus process, and the classification, diagnosis and medical management of active and quiescent Crohn's disease. Surgical management as well as special situations including management of perianal Crohn's disease of this ECCO Consensus are covered in a subsequent second paper [Gionchetti et al JCC 2016].

BACKGROUND: Postal and electronic questionnaires are widely used for data collection in epidemiological studies but non-response reduces the effective sample size and can introduce bias. Finding ways to increase response to postal and electronic questionnaires would improve the quality of health research. OBJECTIVES: To identify effective strategies to increase response to postal and electronic questionnaires. SEARCH STRATEGY: We searched 14 electronic databases to February 2008 and manually searched the reference lists of relevant trials and reviews, and all issues of two journals. We contacted the authors of all trials or reviews to ask about unpublished trials. Where necessary, we also contacted authors to confirm methods of allocation used and to clarify results presented. We assessed the eligibility of each trial using pre-defined criteria. SELECTION CRITERIA: Randomised controlled trials of methods to increase response to postal or electronic questionnaires. DATA COLLECTION AND ANALYSIS: We extracted data on the trial participants, the intervention, the number randomised to intervention and comparison groups and allocation concealment. For each strategy, we estimated pooled odds ratios (OR) and 95% confidence intervals (CI) in a random-effects model. We assessed evidence for selection bias using Egger's weighted regression method and Begg's rank correlation test and funnel plot. We assessed heterogeneity among trial odds ratios using a Chi(2) test and the degree of inconsistency between trial results was quantified using the I(2) statistic. MAIN RESULTS: PostalWe found 481 eligible trials. The trials evaluated 110 different ways of increasing response to postal questionnaires. We found substantial heterogeneity among trial results in half of the strategies. The odds of response were at least doubled using monetary incentives (odds ratio 1.87; 95% CI 1.73 to 2.04; heterogeneity P < 0.00001, I(2) = 84%), recorded delivery (1.76; 95% CI 1.43 to 2.18; P = 0.0001, I(2) = 71%), a teaser on the envelope - e.g. a comment suggesting to participants that they may benefit if they open it (3.08; 95% CI 1.27 to 7.44) and a more interesting questionnaire topic (2.00; 95% CI 1.32 to 3.04; P = 0.06, I(2) = 80%). The odds of response were substantially higher with pre-notification (1.45; 95% CI 1.29 to 1.63; P < 0.00001, I(2) = 89%), follow-up contact (1.35; 95% CI 1.18 to 1.55; P < 0.00001, I(2) = 76%), unconditional incentives (1.61; 1.36 to 1.89; P < 0.00001, I(2) = 88%), shorter questionnaires (1.64; 95% CI 1.43 to 1.87; P < 0.00001, I(2) = 91%), providing a second copy of the questionnaire at follow up (1.46; 95% CI 1.13 to 1.90; P < 0.00001, I(2) = 82%), mentioning an obligation to respond (1.61; 95% CI 1.16 to 2.22; P = 0.98, I(2) = 0%) and university sponsorship (1.32; 95% CI 1.13 to 1.54; P < 0.00001, I(2) = 83%). The odds of response were also increased with non-monetary incentives (1.15; 95% CI 1.08 to 1.22; P < 0.00001, I(2) = 79%), personalised questionnaires (1.14; 95% CI 1.07 to 1.22; P < 0.00001, I(2) = 63%), use of hand-written addresses (1.25; 95% CI 1.08 to 1.45; P = 0.32, I(2) = 14%), use of stamped return envelopes as opposed to franked return envelopes (1.24; 95% CI 1.14 to 1.35; P < 0.00001, I(2) = 69%), an assurance of confidentiality (1.33; 95% CI 1.24 to 1.42) and first class outward mailing (1.11; 95% CI 1.02 to 1.21; P = 0.78, I(2) = 0%). The odds of response were reduced when the questionnaire included questions of a sensitive nature (0.94; 95% CI 0.88 to 1.00; P = 0.51, I(2) = 0%).ElectronicWe found 32 eligible trials. The trials evaluated 27 different ways of increasing response to electronic questionnaires. We found substantial heterogeneity among trial results in half of the strategies. The odds of response were increased by more than a half using non-monetary incentives (1.72; 95% CI 1.09 to 2.72; heterogeneity P < 0.00001, I(2) = 95%), shorter e-questionnaires (1.73; 1.40 to 2.13; P = 0.08, I(2) = 68%), including a statement that others had responded (1.52; 95% CI 1.36 to 1.70), and a more interesting topic (1.85; 95% CI 1.52 to 2.26). The odds of response increased by a third using a lottery with immediate notification of results (1.37; 95% CI 1.13 to 1.65), an offer of survey results (1.36; 95% CI 1.15 to 1.61), and using a white background (1.31; 95% CI 1.10 to 1.56). The odds of response were also increased with personalised e-questionnaires (1.24; 95% CI 1.17 to 1.32; P = 0.07, I(2) = 41%), using a simple header (1.23; 95% CI 1.03 to 1.48), using textual representation of response categories (1.19; 95% CI 1.05 to 1.36), and giving a deadline (1.18; 95% CI 1.03 to 1.34). The odds of response tripled when a picture was included in an e-mail (3.05; 95% CI 1.84 to 5.06; P = 0.27, I(2) = 19%). The odds of response were reduced when "Survey" was mentioned in the e-mail subject line (0.81; 95% CI 0.67 to 0.97; P = 0.33, I(2) = 0%), and when the e-mail included a male signature (0.55; 95% CI 0.38 to 0.80; P = 0.96, I(2) = 0%). AUTHORS' CONCLUSIONS: Health researchers using postal and electronic questionnaires can increase response using the strategies shown to be effective in this systematic review.

Preliminary clinical data indicate that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is associated with neurological and neuropsychiatric illness. Responding to this, a weekly virtual coronavirus disease 19 (COVID-19) neurology multi-disciplinary meeting was established at the National Hospital, Queen Square, in early March 2020 in order to discuss and begin to understand neurological presentations in patients with suspected COVID-19-related neurological disorders. Detailed clinical and paraclinical data were collected from cases where the diagnosis of COVID-19 was confirmed through RNA PCR, or where the diagnosis was probable/possible according to World Health Organization criteria. Of 43 patients, 29 were SARS-CoV-2 PCR positive and definite, eight probable and six possible. Five major categories emerged: (i) encephalopathies (n = 10) with delirium/psychosis and no distinct MRI or CSF abnormalities, and with 9/10 making a full or partial recovery with supportive care only; (ii) inflammatory CNS syndromes (n = 12) including encephalitis (n = 2, para- or post-infectious), acute disseminated encephalomyelitis (n = 9), with haemorrhage in five, necrosis in one, and myelitis in two, and isolated myelitis (n = 1). Of these, 10 were treated with corticosteroids, and three of these patients also received intravenous immunoglobulin; one made a full recovery, 10 of 12 made a partial recovery, and one patient died; (iii) ischaemic strokes (n = 8) associated with a pro-thrombotic state (four with pulmonary thromboembolism), one of whom died; (iv) peripheral neurological disorders (n = 8), seven with Guillain-Barré syndrome, one with brachial plexopathy, six of eight making a partial and ongoing recovery; and (v) five patients with miscellaneous central disorders who did not fit these categories. SARS-CoV-2 infection is associated with a wide spectrum of neurological syndromes affecting the whole neuraxis, including the cerebral vasculature and, in some cases, responding to immunotherapies. The high incidence of acute disseminated encephalomyelitis, particularly with haemorrhagic change, is striking. This complication was not related to the severity of the respiratory COVID-19 disease. Early recognition, investigation and management of COVID-19-related neurological disease is challenging. Further clinical, neuroradiological, biomarker and neuropathological studies are essential to determine the underlying pathobiological mechanisms that will guide treatment. Longitudinal follow-up studies will be necessary to ascertain the long-term neurological and neuropsychological consequences of this pandemic.

Abstract The genetic make-up of an individual contributes to the susceptibility and response to viral infection. Although environmental, clinical and social factors have a role in the chance of exposure to SARS-CoV-2 and the severity of COVID-19 1,2 , host genetics may also be important. Identifying host-specific genetic factors may reveal biological mechanisms of therapeutic relevance and clarify causal relationships of modifiable environmental risk factors for SARS-CoV-2 infection and outcomes. We formed a global network of researchers to investigate the role of human genetics in SARS-CoV-2 infection and COVID-19 severity. Here we describe the results of three genome-wide association meta-analyses that consist of up to 49,562 patients with COVID-19 from 46 studies across 19 countries. We report 13 genome-wide significant loci that are associated with SARS-CoV-2 infection or severe manifestations of COVID-19. Several of these loci correspond to previously documented associations to lung or autoimmune and inflammatory diseases 3–7 . They also represent potentially actionable mechanisms in response to infection. Mendelian randomization analyses support a causal role for smoking and body-mass index for severe COVID-19 although not for type II diabetes. The identification of novel host genetic factors associated with COVID-19 was made possible by the community of human genetics researchers coming together to prioritize the sharing of data, results, resources and analytical frameworks. This working model of international collaboration underscores what is possible for future genetic discoveries in emerging pandemics, or indeed for any complex human disease.

In recent years, there has been an increased focus on placing patients at the center of health care research and evaluating clinical care in order to improve their experience and ensure that research is both robust and of maximum value for the use of medicinal products, therapy, or health services. This paper provides an overview of patients' involvement in clinical research and service evaluation along with its benefits and limitations. We describe and discuss patient-reported outcomes (PROs) and patient-reported outcome measures (PROMs), including the trends in current research. Both the patient-reported experiences measures (PREMs) and patient and public involvement (PPI) initiative for including patients in the research processes are also outlined. PROs provide reports from patients about their own health, quality of life, or functional status associated with the health care or treatment they have received. PROMs are tools and/or instruments used to report PROs. Patient report experiences through the use of PREMs, such as satisfaction scales, providing insight into the patients' experience with their care or a health service. There is increasing international attention regarding the use of PREMS as a quality indicator of patient care and safety. This reflects the ongoing health service commitment of involving patients and the public within the wider context of the development and evaluation of health care service delivery and quality improvement.

CONTEXT: Guidelines for antiretroviral therapy are important for clinicians worldwide given the complexity of the field and the varied clinical situations in which these agents are used. The International AIDS Society-USA panel has updated its recommendations as warranted by new developments in the field. OBJECTIVE: To provide physicians and other human immunodeficiency virus (HIV) clinicians with current recommendations for the use of antiretroviral therapy in HIV-infected adults in circumstances for which there is relatively unrestricted access to drugs and monitoring tools. The recommendations are centered on 4 key issues: when to start antiretroviral therapy; what to start; when to change; and what to change. Antiretroviral therapy in special circumstances is also described. DATA SOURCES AND STUDY SELECTION: A 16-member noncompensated panel was appointed, based on expertise in HIV research and patient care internationally. Data published or presented at selected scientific conferences from mid 2004 through May 2006 were identified and reviewed by all members of the panel. DATA EXTRACTION AND SYNTHESIS: Data that might change previous guidelines were identified and reviewed. New guidelines were drafted by a writing committee and reviewed by the entire panel. CONCLUSIONS: Antiretroviral therapy in adults continues to evolve rapidly, making delivery of state-of-the-art care challenging. Initiation of therapy continues to be recommended in all symptomatic persons and in asymptomatic persons after the CD4 cell count falls below 350/microL and before it declines to 200/microL. A nonnucleoside reverse transcriptase inhibitor or a protease inhibitor boosted with low-dose ritonavir each combined with 2 nucleoside (or nucleotide) reverse transcriptase inhibitors is recommended with choice being based on the individual patient profile. Therapy should be changed when toxicity or intolerance mandate it or when treatment failure is documented. The virologic target for patients with treatment failure is now a plasma HIV-1 RNA level below 50 copies/mL. Adherence to antiretroviral therapy in the short-term and the long-term is crucial for treatment success and must be continually reinforced.

OBJECTIVE: To update recommendations for antiretroviral therapy for adult human immunodeficiency virus type 1 (HIV-1) infection, based on new information and drugs that are available. PARTICIPANTS: A 17-member international physician panel with antiretroviral research and HIV patient care experience initially convened by the International AIDS Society-USA in December 1995. EVIDENCE: Available clinical and basic science data including phase 3 controlled trials; data on clinical, virologic, and immunologic end points; research conference reports; HIV pathogenesis data; and panel expert opinion. Recommendations were limited to therapies available (US Food and Drug Administration approved) in 1999. CONSENSUS PROCESS: The panel assesses new research reports and interim results and regularly meets to consider how the new data affect therapy recommendations. Recommendations are updated via full-panel consensus. Guidelines are presented as recommendations if the supporting evidence warrants routine use in the particular situation and as considerations if data are preliminary or incomplete but suggestive. CONCLUSIONS: The availability of new antiretroviral drugs has expanded treatment choices. The importance of adherence, emerging long-term complications of therapy, recognition and management of antiretroviral failure, and new monitoring tools are addressed. Optimal care requires individualized management and ongoing attention to relevant scientific and clinical information in the field.

In September 2006, members of the Sex, Gender and Pain Special Interest Group of the International Association for the Study of Pain met to discuss the following: (1) what is known about sex and gender differences in pain and analgesia; (2) what are the "best practice" guidelines for pain research with respect to sex and gender; and (3) what are the crucial questions to address in the near future? The resulting consensus presented herein includes input from basic science, clinical and psychosocial pain researchers, as well as from recognized experts in sexual differentiation and reproductive endocrinology. We intend this document to serve as a utilitarian and thought-provoking guide for future research on sex and gender differences in pain and analgesia, both for those currently working in this field as well as those still wondering, "Do I really need to study females?"

1. Eighty-five patients have been studied soon after a ligamentous injury at the foot or ankle. These patients were treated in one of three ways, and in fifty-six patients the results were evaluated six to fifteen months after injury. 2. It is concluded: a) that ligamentous injuries at the foot and ankle frequently produce a proprioceptive deficit affecting the muscles of the injured leg; b) that such a deficit is responsible for the symptom of "giving way" of the foot; and c) that the incidence of both the proprioceptive deficit and the symptom of "giving way" can substantially be reduced by treatment after injury with the coordination exercises described in this study. 3. The mechanism of production of the proprioceptive defect is discussed.

Apart from one post-mortem study, the incidence of adhesions following laparotomy has not been well documented. 1. In a prospective analysis of 210 patients undergoing a laparotomy, who had previously had one or more abdominal operations, we found that 93% had intra-abdominal adhesions that were a result of their previous surgery. This compared with 115 first-time laparotomies in which 10.4% had adhesions. 2. Over a 25-year period, 261 of 28 297 adult general surgical admissions were for intestinal obstruction from adhesions (0.9%). Of 4502 laparotomies, 148 were for adhesive obstruction (3.3%). 3. Over a 13-year period all laparotomies were followed up for an average of 14.5 months (range 0-91 months). From these 2708 laparotomies, 26 developed intestinal obstruction due to postoperative adhesions within 1 year of surgery (1%). Fourteen did so within 1 month of surgery (0.5%). 4. The majority of the operations producing intestinal obstruction were lower abdominal, principally involving the colon. The volume of general surgical work from adhesions is large and the incidence of early intestinal obstruction is high.

This collaborative study suggests that not only is the presence of a codon 12 glycine to valine mutation important for cancer progression but also that it predispose to more aggressive biological behaviour in patients with advanced colorectal cancer.

BACKGROUND: Durable suppression of replication of the human immunodeficiency virus (HIV) depends on the use of potent, well-tolerated antiretroviral regimens to which patients can easily adhere. METHODS: We conducted an open-label, noninferiority study involving 517 patients with HIV infection who had not previously received antiretroviral therapy and who were randomly assigned to receive either a regimen of tenofovir disoproxil fumarate (DF), emtricitabine, and efavirenz once daily (tenofovir-emtricitabine group) or a regimen of fixed-dose zidovudine and lamivudine twice daily plus efavirenz once daily (zidovudine-lamivudine group). The primary end point was the proportion of patients without baseline resistance to efavirenz in whom the HIV RNA level was less than 400 copies per milliliter at week 48 of the study. RESULTS: Through week 48, significantly more patients in the tenofovir-emtricitabine group reached and maintained the primary end point of less than 400 copies of HIV RNA per milliliter than did those in the zidovudine-lamivudine group (84 percent vs. 73 percent, respectively; 95 percent confidence interval for the difference, 4 to 19 percent; P=0.002). This difference excludes the inferiority of the tenofovir DF, emtricitabine, and efavirenz regimen, indicating a significantly greater response with this regimen. Significant differences were also seen in the proportion of patients with HIV RNA levels of less than 50 copies per milliliter (80 percent in the tenofovir-emtricitabine group vs. 70 percent in the zidovudine-lamivudine group; 95 percent confidence interval for the difference, 2 to 17 percent; P=0.02) and in increases in CD4 cell counts (190 vs. 158 cells per cubic millimeter, respectively; 95 percent confidence interval for the difference, 9 to 55; P=0.002). More patients in the zidovudine-lamivudine group than in the tenofovir-emtricitabine group had adverse events resulting in discontinuation of the study drugs (9 percent vs. 4 percent, respectively; P=0.02). In none of the patients did the K65R mutation develop. CONCLUSIONS: Through week 48, the combination of tenofovir DF and emtricitabine plus efavirenz fulfilled the criteria for noninferiority to a fixed dose of zidovudine and lamivudine plus efavirenz and proved superior in terms of virologic suppression, CD4 response, and adverse events resulting in discontinuation of the study drugs. (ClinicalTrials.gov number, NCT00112047.)

1. Introduction The redefinition of neuropathic pain,23 which specifically excludes the concept of “dysfunction,” has left a large group of patients without a valid pathophysiological descriptor for their experience of pain. This group comprises people who have neither obvious activation of nociceptors nor neuropathy (defined as disease or damage of the somatosensory system) but in whom clinical and psychophysical findings suggest altered nociceptive function. Typical such patient groups include those labelled as having fibromyalgia, complex regional pain syndrome (CRPS) type 1, other instances of “musculoskeletal” pain (such as “nonspecific” chronic low-back pain), and “functional” visceral pain disorders (such as irritable bowel syndrome, bladder pain syndrome). The aim of this topical review was to propose, for debate, a third mechanistic descriptor intended for chronic pain characterized by altered nociceptive function. 1.1. Historical review Before developing any argument for a third descriptor to accommodate these patients, it is worthwhile reviewing the history of pain terminology. Traditionally, pain mechanisms have been divided into “nociceptive” and “neuropathic” categories. See Table 1 for the historical overview of these definitions.Table 1.: Historical overview of mechanistic pain terminology.1.2. Implications of the changed definition of “neuropathic pain” In the 2005 iteration, “nociceptive” pain was the norm, the “default” or common sense experience of injury = damage ≤pain, familiar to humans. But it evolved that any pain that was not “nociceptive” might be termed “neuropathic” because the latter descriptor included “dysfunction,” which was taken to include any inferred change in nociceptive function. Although it has always been possible to invoke another category, such as “unknown” or “idiopathic,” that strategy runs a poor third to the other 2, as there is no implication of a putative mechanism. The 2011 redefinition of neuropathic pain makes biological and etymological sense. The note that accompanies this definition is stringent: Neuropathic pain is a clinical description (and not a diagnosis), which requires a demonstrable lesion or a disease that satisfies established neurological diagnostic criteria. This robust definition is not being challenged. However, the note that accompanies the 2011 redefinition of nociceptive pain—pain that arises from actual or threatened damage to nonneural tissue and is due to activation of nociceptors—states: This termis designed to contrast with neuropathic pain. The term is used to describe pain occurring with a normally functioning somatosensory nervous system to contrast with the abnormal function seen in neuropathic pain (emphasis added). This perpetuates the “nociceptive–neuropathic” dichotomy as above, except that now the “default” position is neuropathic pain, so that any pain condition that is not characterized by damage to neuronal tissue may attract the term “nociceptive.” This is not only counterintuitive, as surely “a normally functioning somatosensory nervous system” should be taken as the basis for any contrast, but also it fails to accommodate a large group of patients in whom “activation of nociceptors” cannot be confidently established. 2. Proposals This situation requires clarification. The proposals put forward here, as presented in Table 2, include: (1) Assertion of nociceptive pain (2) Confirmation of definition of neuropathic pain, but not as default (3) Need for a third descriptor. Table 2.: Proposed taxonomy for the classification of pain compared with the existing IASP taxonomy from 2011 (http://www.iasp-pain.org/Taxonomy), changes highlighted.2.1. Assertion of nociceptive pain “Nociceptive pain” is the most common human experience of pain. Therefore, we propose that the current IASP 2011 definition of nociceptive pain be used, but that the note be shortened to: “The term is used to describe pain occurring with a normally functioning somatosensory nervous system.” Nociceptive pain should not be defined as the alternative to neuropathic pain. This common-sense biological position presumes that the tissue was “normal” before the noxious stimulus and that the somatosensory apparatus is also “normal.” 2.2. Confirmation of definition of neuropathic pain, but not as default The new definition of neuropathic pain does not require amendment. However, because it is not as common as nociceptive pain and it does not reflect the usual experience of pain, it should not be the default descriptor. 2.3. Need for a third descriptor Even with these points of clarification, the situation of only 2 descriptors will remain unsatisfactory for those patients in whom “activation of nociceptors” cannot be confidently demonstrated or assumed and who also do not meet the definition of “definite” or “probable” neuropathic pain. Appending “possible” neuropathic pain leaves them in taxonomic limbo. In the current state of knowledge, there are reasons to infer that altered nociceptive function does occur in patients experiencing pain in a regional (or more widespread) distribution, unassociated with frank signs of neuropathy but characterized by hypersensitivity in apparently normal tissues. The similarity of such findings to those in frank neural injury or disease suggests that common mechanism(s) may be relevant. A reasonable inference from the presence of these findings is that there has occurred a change in nociceptive processing, probably in the central nervous system. The latter is supported by the findings of demonstrated changes in cerebral activation,16,19,38,39,45 connectivity,4,14,20,25,33,37,41,50 and even in specific cerebral structures1,5,18,22,24,31,36,44 in certain clinical pain states, when also adjusted for depression or anxiety.5,18,21,22,36 However, in these pain conditions, there is no consistent evidence of a lesion or disease of the somatosensory system as a primary cause of the pain, thus disqualifying the pain from attracting the neuropathic descriptor. 2.4. Proposal for a third descriptor It is proposed that a new term be introduced to describe pain states characterized by clinical and psychophysical findings that suggest altered nociception, despite there being no clear evidence of actual or threatened tissue damage causing the activation of nociceptors or evidence for disease or lesion of the somatosensory system causing the chronic pain. The candidate adjectives for this third descriptor include: (1) “Nociplastic,” from “nociceptive plasticity,” to reflect change in function of nociceptive pathways. (2) “Algopathic,” from “algos” (Greek for pain) plus “pathic” (from Greek “patheia” for suffering), paraphrased as “a pathological perception/sensation of pain not generated by injury.” (3) “Nocipathic,” from “nociceptive pathology,” to denote a pathological (ie, not “normal”) state of nociception. The term is intended for clinical usage and is neither a diagnosis nor a synonym for “central sensitization of nociception,” which is a neurophysiological concept. It may well be that the phenomenon of hypersensitivity occurring in ostensibly normal, uninjured tissue without evidence of neuropathy leads to a clinical inference that sensitization may be the underlying mechanism, so that the term is used as a descriptor for that situation. Such reasoning is no different from the phenomenon of observable tissue damage leading to the inference of activation of nociceptors and applying the term “nociceptive pain,” or from the phenomenon of signs of neuropathy leading to the inference of disease or damage of neural structures and applying the term “neuropathic pain.” 3. Discussion 3.1. Do we need a third mechanistic descriptor? The present IASP terminology does not reflect the current understanding that chronic pain is not necessarily a symptom but can result from altered nociceptive function and thus constitute a condition in itself. Consequently, the pain of some large patient groups suffering from altered nociceptive function is currently classified as “pain of unknown origin.” An argument in favour of continuing to use the current nondescriptors “unknown” or “idiopathic” relies on confusion that might arise out of challenges in defining a new descriptor. However, the inability of the current IASP pain terminology to harmonize with current concepts has resulted in the use of other nondefined descriptors such as “dysfunctional”40 or “pathological”35 pain, which not only give no insight into possible mechanisms but also carry implications that may stigmatize patients.9,10 The use of a third mechanistic descriptor in clinical practice has the potential to confer validity on the patient's experience of pain and to facilitate communication between patients, clinicians, and other stakeholders. Clinicians would be encouraged to screen for signs of altered nociceptive function, thus improving diagnosis and treatment, as patients suffering from altered nociceptive function typically respond better to centrally than peripherally targeted therapies. The term would also facilitate research efforts, by identifying altered nociceptive function as an important area for mechanistic studies, establishment of treatment guidelines and development of new treatment strategies. 3.2. When should the descriptor be used and when not? The descriptor is primarily intended for patients suffering from chronic pain conditions characterized by evidence of altered nociceptive processing, such as those currently labelled as fibromyalgia,22 CRPS,47 nonspecific chronic low-back pain,16 irritable bowel syndrome,39 and other “functional” visceral pain disorders.8,48 In addition, patients suffering initially from nociceptive pain, such as osteoarthritis, may develop alterations in nociceptive processing manifested as altered descending pain inhibition3,28 accompanied by spread of hypersensitivity.2,17,29 These patients would then be considered to have a combination of nociceptive and “nociplastic/algopathic/nocipathic” contributors to their pain. The new descriptor is intended to distinguish patients suffering from conditions where altered nociception has been documented from those where the pain mechanisms are still truly unknown. Therefore, the new descriptor does not apply to patients reporting pain without hypersensitivity. As such, it is neither a synonym for idiopathic pain or pain of unknown origin nor a label awarded by exclusion. 3.3. Problems regarding validity and use of the new descriptor Opponents of a new descriptor may argue that mechanisms implicit in the terms “nociceptive” and “neuropathic” are proven, in contrast to the inference of functional changes in the nervous system, which as yet cannot be confirmed. A nociceptive focus may be visualized by radiology or reflected in some laboratory findings. It is argued that neuropathy can be identified by quantitative sensory testing, nerve conduction studies, intra-epidermal nerve fiber density assessments, or by imaging of the central nervous system. However, despite the fact that pathology can be documented for nociceptive and neuropathic pain, the relationship between that pathology and pain mechanisms remains elusive. The latter is illustrated by the low concordance between the degree of tissue damage/inflammation and pain11 or by the low proportion of people with peripheral nerve injury who develop chronic neuropathic pain.32 Although it is true that no specific structural pathology underlying “nociplastic/algopathic/nocipathic” pain has been found, altered nociceptive processing has been documented by quantitative sensory testing,7,15,27,42,47,48 sensory evoked potentials,12,13,34 and functional magnetic resonance imaging.16,19,38,48 Importantly, these functional changes have in many instances been related to pain severity.1,31,41,43 Therefore, while acknowledging these limitations in the current and the proposed pain terminology, there remains a rationale for using the new descriptor to distinguish patients with altered nociception from patients with pain of unknown origin. One unresolved situation is when a patient with nociceptive pain could be classified as also having “nociplastic/algopathic/nocipathic” pain. Clinicians are faced with a continuum of signs of hypersensitivity in patients with chronic pain. Individual differences in sensitivity to stimuli are marked even in healthy subjects26,30 and no clinically useful method to quantify nociceptor activation exists. Although tests of descending pain inhibition could be used clinically,6 the validity and reliability of these tests in a clinical setting remain to be established.49 Therefore, nociceptive and “nociplastic/algopathic/nocipathic” pain should not be regarded as exclusive categorical labels but rather, pragmatically, as concurrent possible mechanistic contributors to the patient's pain. This would be similar to the concurrence of nociceptive and neuropathic contributors in other situations. 3.4. Is future progress in pain research likely to affect the use of the descriptors? These mechanistic terms are descriptors of putative contributors to the experience of pain, not diagnoses; they are placeholders for current concepts and not “set in concrete.” As our knowledge of pain mechanisms advances, so should pain terminology change. 3.5. Concluding remarks This topical review suggests introducing a third mechanistic pain descriptor to be used in patients with clinically determined altered nociception. If the suggestion is well received, the next step will be to define a set of clinically useful positive classification criteria. The term is mechanistic and thus complementary to, but not synonymous with, the proposed ICD-11 diagnostic term “primary pain.”46 By writing this article, the authors hope to open up a fruitful debate regarding modernization of mechanistic pain terminology. Conflict of interest statement E. Kosek has received consultancy and speaker fees in the past 36 months from Eli Lilly and Company and Orion and has ongoing research collaborations with Eli Lilly and Company and AbbVie. M. Cohen has received consultancy fees from Mundipharma and Pfizer for preparation and presentation of educational material. R. Baron has received grants/research support from Pfizer, Genzyme, Grünenthal, and Mundipharma. He is a member of the EU Project No 633491: DOLOR-isk. A member of the IMI “Europain” collaboration and industry members of this are: AstraZeneca, Pfizer, Esteve, UCB-Pharma, Sanofi Aventis, Grünenthal, Eli Lilly, and Boehringer Ingelheim. German Federal Ministry of Education and Research (BMBF): Member of the ERA_NET NEU-RON/IM-PAIN Project. German Research Network on Neuropathic Pain, NoPain system biology. German Research Foundation (DFG). He has received speaking fees from Pfizer, Genzyme, Grünenthal, Mundipharma, Sanofi Pasteur, Medtronic, Eisai, Lilly, Boehringer Ingelheim, Astellas, Desitin, Teva Pharmaceuticals, Bayer Schering, MSD, and bioCSL. He has been a consultant for Pfizer, Genzyme, Grünenthal, Mundipharma, Allergan, Sanofi Pasteur, Medtronic, Eisai, Lilly, Boehringer Ingelheim, Astellas, Novartis, Bristol-Myers Squibb, Biogenidec, AstraZeneca, Merck, AbbVie, Daiichi Sankyo, Glenmark Pharmaceuticals, and bioCSL. G. F. Gebhart, J. -A. Mico, and A. S.C. Rice have nothing to declare. W. Rief has received consultancy fees from Heel and speaker's fees from Bayer. K. Sluka has been Consultant for DJO, Inc, and Bayer, Inc, received research funding from Medtronic, Inc and royalties from IASP Press.

OBJECTIVE: Although postoperative cognitive dysfunction (POCD) often complicates recovery from major surgery, the pathogenic mechanisms remain unknown. We explored whether systemic inflammation, in response to surgical trauma, triggers hippocampal inflammation and subsequent memory impairment, in a mouse model of orthopedic surgery. METHODS: C57BL/6J, knock out (lacking interleukin [IL]-1 receptor, IL-1R(-/-)) and wild type mice underwent surgery of the tibia under general anesthesia. Separate cohorts of animals were tested for memory function with fear conditioning tests, or euthanized at different times to assess levels of systemic and hippocampal cytokines and microglial activation; the effects of interventions, designed to interrupt inflammation (specifically and nonspecifically), were also assessed. RESULTS: Surgery caused hippocampal-dependent memory impairment that was associated with increased plasma cytokines, as well as reactive microgliosis and IL-1beta transcription and expression in the hippocampus. Nonspecific attenuation of innate immunity with minocycline prevented surgery-induced changes. Functional inhibition of IL-1beta, both in mice pretreated with IL-1 receptor antagonist and in IL-1R(-/-) mice, mitigated the neuroinflammatory effects of surgery and memory dysfunction. INTERPRETATION: A peripheral surgery-induced innate immune response triggers an IL-1beta-mediated inflammatory process in the hippocampus that underlies memory impairment. This may represent a viable target to interrupt the pathogenesis of postoperative cognitive dysfunction.

Cognitive decline following surgery in older individuals is a major clinical problem of uncertain mechanism; a similar cognitive decline also follows severe infection, chemotherapy, or trauma and is currently without effective therapy. A variety of mechanisms have been proposed, and exploring the role of inflammation, we recently reported the role of IL-1β in the hippocampus after surgery in mice with postoperative cognitive dysfunction. Here, we show that TNF-α is upstream of IL-1 and provokes its production in the brain. Peripheral blockade of TNF-α is able to limit the release of IL-1 and prevent neuroinflammation and cognitive decline in a mouse model of surgery-induced cognitive decline. TNF-α appears to synergize with MyD88, the IL-1/TLR superfamily common signaling pathway, to sustain postoperative cognitive decline. Taken together, our results suggest a unique therapeutic potential for preemptive treatment with anti-TNF antibody to prevent surgery-induced cognitive decline.

Cytotoxic T lymphocytes (CTLs) are thought to play a crucial role in the termination of the acute primary HIV-1 syndrome, but clear evidence for this presumption has been lacking. Here we demonstrate positive selection of HIV-1 proviral sequences encoding variants within a CTL epitope in Nef, a gene product critical for viral pathogenicity, during and after seroconversion. These positively selected HIV-1 variants carried epitope sequence changes that either diminished or escaped CTL recognition. Other proviruses had mutations that abolished the Nef epitope altogether. These results provide clear evidence that CTLs exert selection pressure on the viral population in acute HIV-1 infection.

BACKGROUND: The T-20 vs. Optimized Regimen Only Study 2 (TORO 2) compared the efficacy and safety of 24 weeks of treatment with the fusion inhibitor enfuvirtide in combination with an optimized background antiretroviral regimen with the efficacy and safety of the optimized background regimen alone. METHODS: The patients had previous treatment with each of the three classes of antiretroviral drugs, documented resistance to each class, or both and a plasma level of human immunodeficiency virus type 1 (HIV-1) RNA of at least 5000 copies per milliliter. They were randomly assigned in a 2:1 ratio to receive either enfuvirtide (90 mg twice daily) plus a background regimen optimized with the aid of resistance testing (enfuvirtide group) or the background regimen alone (control group). RESULTS: Of the 512 patients who underwent randomization, 335 in the enfuvirtide group and 169 in the control group received at least one dose of study medication and had at least one follow-up measurement of plasma HIV-1 RNA. The median base-line plasma HIV-1 RNA level was 5.1 log10 copies per milliliter in both groups. The median CD4+ cell count was 98.0 cells per cubic millimeter in the enfuvirtide group and 101.5 cells per cubic millimeter in the control group. Patients had a median of seven years of previous treatment and had received a median of 12 antiretroviral drugs. The background regimen comprised a mean of four antiretroviral drugs in both groups. At 24 weeks, the least-squares mean change from base line in the plasma viral load (intention-to-treat, last observation carried forward) was a decrease of 1.429 log10 copies per milliliter in the enfuvirtide group and a decrease of 0.648 log10 copies per milliliter in the control group, a difference of 0.781 log10 copies per milliliter (P<0.001). The mean increase in the CD4+ cell count was greater in the enfuvirtide group (65.5 cells per cubic millimeter) than in the control group (38.0 cells per cubic millimeter, P=0.02). CONCLUSIONS: The addition of enfuvirtide to an optimized background regimen provided significant viral suppression and immunologic benefit over a 24-week period in HIV-1-infected patients who had previously received multiple antiretroviral drugs.