Pathway-based signatures predict patient outcome, chemotherapy benefit and synthetic lethal dependencies in invasive lobular breast cancer.

BACKGROUND: Invasive Lobular Carcinoma (ILC) is a morphologically distinct breast cancer subtype that represents up to 15% of all breast cancers. Compared to Invasive Breast Carcinoma of No Special Type (IBC-NST), ILCs exhibit poorer long-term outcome and a unique pattern of metastasis. Despite these differences, the systematic discovery of robust prognostic biomarkers and therapeutically actionable molecular pathways in ILC remains limited. METHODS: Pathway-centric multivariable models using statistical machine learning were developed and tested in seven retrospective clinico-genomic cohorts (n = 996). Further external validation was performed using a new RNA-Seq clinical cohort of aggressive ILCs (n = 48). RESULTS AND CONCLUSIONS: mRNA dysregulation scores of 25 pathways were strongly prognostic in ILC (FDR-adjusted P < 0.05). Of these, three pathways including Cell-cell communication, Innate immune system and Smooth muscle contraction were also independent predictors of chemotherapy response. To aggregate these findings, a multivariable machine learning predictor called PSILC was developed and successfully validated for predicting overall and metastasis-free survival in ILC. Integration of PSILC with CRISPR-Cas9 screening data from breast cancer cell lines revealed 16 candidate therapeutic targets that were synthetic lethal with high-risk ILCs. This study provides interpretable prognostic and predictive biomarkers of ILC which could serve as the starting points for targeted drug discovery for this disease.

Pain after combat injury in male UK military personnel deployed to Afghanistan.

BACKGROUND: Chronic pain after injury poses a serious health burden. As a result of advances in medical technology, ever more military personnel survive severe combat injuries, but long-term pain outcomes are unknown. We aimed to assess rates of pain in a representative sample of UK military personnel with and without combat injuries. METHODS: We used data from the ADVANCE cohort study (ISRCTN57285353). Individuals deployed as UK armed forces to Afghanistan were recruited to include those with physical combat injuries, and a frequency-matched uninjured comparison group. Participants completed self-reported questionnaires, including 'overall' pain intensity and self-assessment of post-traumatic stress disorder, anxiety, and depression. RESULTS: A total of 579 participants with combat injury, including 161 with amputations, and 565 uninjured participants were included in the analysis (median 8 yr since injury/deployment). Frequency of moderate or severe pain was 18% (n=202), and was higher in the injured group (n=140, 24%) compared with the uninjured group (n=62, 11%, relative risk: 1.1, 95% confidence interval [CI]: 1.0-1.2, P<0.001), and lower in the amputation injury subgroup (n=31, 19%) compared with the non-amputation injury subgroup (n=109, 26%, relative risk: 0.9, 95% CI: 0.9-1.0, P=0.034). Presence of at least moderate pain was associated with higher rates of post-traumatic stress (RR: 3.7, 95% CI: 2.7-5.0), anxiety (RR: 3.2, 95% CI: 2.4-4.3), and depression (RR: 3.4, 95% CI: 2.7-4.5) after accounting for injury. CONCLUSION: Combat injury, but not amputation, was associated with a higher frequency of moderate to severe pain intensity in this cohort, and pain was associated with adverse mental health outcomes.

Chronic pain and cognitive impairment: a cross-sectional study in people living with HIV.

Cognitive impairment and chronic pain are amongst the most prevalent neurological sequelae of HIV infection, yet little is understood about the potential bidirectional relationship between the two conditions. Cognitive dysfunction can occur in chronic pain populations whilst those with cognitive impairment can display modified responses to experimentally induced painful stimuli. To date, this has not been explored in HIV cohorts.This study aimed to identify any contribution of chronic pain to cognitive impairment in HIV and to determine differences in pain characteristics between those with and without cognitive dysfunction.This was an observational cohort study involving people living with HIV (n = 148) in the United Kingdom. Participants underwent validated questionnaire-based measurement of pain severity, interference and symptom quality as well as conditioned pain modulation and quantitative sensory testing. All participants completed a computer-based cognitive function assessment.Fifty-seven participants met the criteria for cognitive impairment and 73 for chronic pain. The cognitive impairment group had a higher prevalence of chronic pain (p = 0.004) and reported more neuropathic symptoms (p = 0.001). Those with chronic pain performed less well in emotional recognition and verbal learning domains. The interaction identified between chronic pain and cognitive dysfunction warrants further exploration to identify causal links or shared pathology.

Lagging-strand replication shapes the mutational landscape of the genome.

The origin of mutations is central to understanding evolution and of key relevance to health. Variation occurs non-randomly across the genome, and mechanisms for this remain to be defined. Here we report that the 5' ends of Okazaki fragments have significantly increased levels of nucleotide substitution, indicating a replicative origin for such mutations. Using a novel method, emRiboSeq, we map the genome-wide contribution of polymerases, and show that despite Okazaki fragment processing, DNA synthesized by error-prone polymerase-α (Pol-α) is retained in vivo, comprising approximately 1.5% of the mature genome. We propose that DNA-binding proteins that rapidly re-associate post-replication act as partial barriers to Pol-δ-mediated displacement of Pol-α-synthesized DNA, resulting in incorporation of such Pol-α tracts and increased mutation rates at specific sites. We observe a mutational cost to chromatin and regulatory protein binding, resulting in mutation hotspots at regulatory elements, with signatures of this process detectable in both yeast and humans.

Chronic pain in critical care survivors: a narrative review.

Chronic pain is an important problem after critical care admission. Estimates of the prevalence of chronic pain in the year after discharge range from 14% to 77% depending on the type of cohort, the tool used to measure pain, and the time point when pain was assessed. The majority of data available come from studies using health-related quality of life tools, although some have included pain-specific tools. Nociceptive, neuropathic, and nociplastic pain can occur in critical care survivors, but limited information about the aetiology, body site, and temporal trajectory of pain is currently available. Older age, pre-existing pain, and medical co-morbidity have been associated with pain after critical care admission. No trials were identified of interventions to target chronic pain in survivors specifically. Larger studies, using pain-specific tools, over an extended follow-up period are required to confirm the prevalence, identify risk factors, explore any association between acute and chronic pain in this setting, determine the underlying pathological mechanisms, and inform the development of future analgesic interventions.

A systematic review of the prevalence of postamputation and chronic neuropathic pain associated with combat injury in military personnel.

ABSTRACT: Combat trauma can lead to widespread tissue damage and limb loss. This may result in chronic neuropathic and post amputation pain, including phantom limb pain (PLP) and residual limb pain (RLP). The military population is distinct with respect to demographic, injury, and social characteristics compared with other amputation and trauma cohorts. We undertook a systematic review of studies of military personnel, with a history of combat injury, that reported a prevalence of any type of postamputation pain or chronic neuropathic pain, identified from Embase and MEDLINE databases.Using the inverse variance method with a random-effects model, we undertook a meta-analysis to determine an overall prevalence and performed exploratory analyses to identify the effect of the type of pain, conflict, and time since injury on prevalence. Pain definitions and types of pain measurement tools used in studies were recorded. Thirty-one studies (14,738 participants) were included. The pooled prevalence of PLP, RLP, and chronic neuropathic pain were 57% (95% CI: 46-68), 61% (95% CI: 50-71), and 26% (95% CI: 10-54), respectively. Between-study heterogeneity was high (I 2 : 94%-98%). Characterisation of duration, frequency, and impact of pain was limited. Factors reported by included studies as being associated with PLP included the presence of RLP and psychological comorbidity. The prevalence of postamputation pain and chronic neuropathic pain after combat trauma is high. We highlight inconsistency of case definitions and terminology for pain and the need for consensus in future research of traumatic injury.

A Comparison of Self-reported Pain Measures Between Sensory Phenotypes in HIV-associated Sensory Neuropathy.

Painful HIV-associated neuropathy (HIV-SN) is a prevalent co-morbidity of HIV infection. Sensory phenotyping, using quantitative sensory testing (QST) could allow for improved stratification to guide personalized treatment. However, previous methods of QST interpretation have demonstrated limited association with self-reported pain measures. This study sought to identify differences in self-reported pain measures between composite QST-derived sensory phenotypes, and to examine any differences in participants reporting multi-site, multi-etiology chronic pain. In this cross-sectional observational study of participants with HIV (n = 133), individuals were allocated to neuropathy and neuropathic pain groups through clinical assessment and nerve conduction testing. They completed symptom-based questionnaires and underwent standardized QST. Participants were assigned, by pre-determined algorithm, to a QST-derived sensory phenotype. Symptoms were compared between sensory phenotypes. Symptom characteristics and Neuropathic Pain Symptom Inventory scores differed between QST-derived sensory phenotypes: 'sensory loss' was associated with more paroxysmal and paraesthetic symptoms compared to 'thermal hyperalgesia' and 'healthy' phenotypes (P = .023-0.001). Those with painful HIV-SN and additional chronic pain diagnoses were more frequently allocated to the 'mechanical hyperalgesia' phenotype compared to those with painful HIV-SN alone (P = .006). This study describes heterogeneous sensory phenotypes in people living with HIV. Differences in self-reported pain outcomes between sensory phenotypes has the potential to guide future stratified trials and eventually more targeted therapy. PERSPECTIVE: This article presents quantitative sensory testing derived phenotypes, thought to reflect differing pathophysiological pain mechanisms and relates them to self-reported pain measures in people with HIV infection. This could help clinicians stratify patients to individualize analgesic interventions more effectively.

Health-related quality of life and pain interference in two patient cohorts with neuropathic pain: breast cancer survivors and HIV patients.

OBJECTIVES: Persistent pain is common in HIV patients and breast cancer (BC) survivors. The aim of this study was to compare two patient groups with neuropathic pain (NP) regarding several psychological variables and Health-related Quality of Life. Although, treatment of pain is always planned individually, the knowledge of the differences and similarities between the patient groups may help us to understand more precisely the targets of the interventions for pain. METHODS: Eighty nine BC and 73 HIV patients with symptoms of neuropathic pain (patients with ≥3/7 in the Douleur Neuropathique four interview part (DN4i)) participated in a cross-sectional study. Patients completed questionnaires about mood (HADS), symptoms of insomnia (ISI), pain catastrophizing (PCS), personality (TIPI), Mental and Physical Health-related Quality of Life (M/PHrQoL, RAND/SF-36), and pain intensity and interference (BPI). Analyses were applied by using t-tests and linear regression to assess associations between the studied factors. RESULTS: HIV patients reported higher anxiety (p<0.001), depressive symptoms (p<0.001), pain catastrophizing (p<0.001) and pain interference (p<0.001), poorer sleep (p<0.001), and lower HrQoL in all dimensions compared with BC survivors. There were significant differences in personality traits extraversion, emotional stability, and agreeableness between the two patient groups. In HIV patients, pain interference (ß=-0.344, p<0.001) and mood (ß=-0.580, p<0.001) and in the BC group, mood (ß=-0.591, p<0.001), extraversion (ß=0.229, p=0.005) and sleep (ß=-0.154, p=0.042) associated with MHrQoL. Pain interference (HIV ß=-0.645, p<0.001, BC ß=-0.491, p<0.001) and age (HIV ß=-0.016, p=0.042 and BC ß=-0.018, p=0.019) associated with PHrQoL in both groups, and catastrophizing in the BC group (ß=-0.303, p<0.001). CONCLUSIONS: HIV patients and BC survivors with neuropathic pain, measured with DN4i, have significant differences in various health-related variables and Health-related Quality of Life with both patient groups reporting low HrQoL. The differences in low HrQoL may reflect the fundamental differences between these diseases, BC survivors in remission and HIV patients living with a chronic disease that is under control. This study brings information about the diversity of different patient populations with symptoms of neuropathic pain, and how neuropathic pain associates with wide range of health-related factors. Interventions to support better coping with the symptoms of neuropathic pain could be tailored more individually if the background disease is taken into account.

Acceptability of psychologically-based pain management and online delivery for people living with HIV and chronic neuropathic pain: a qualitative study.

OBJECTIVES: Chronic neuropathic pain is common in people living with HIV. Psychological treatments can improve quality of life for people with chronic pain in general, and online delivery can increase access to these treatments. However, the acceptability of psychological treatment and online delivery have not been investigated in-depth in people living with HIV and chronic neuropathic pain. Therefore, a qualitative study was undertaken to explore views about a psychological treatment for pain management in this population and to investigate the acceptability of online treatment delivery. METHODS: Qualitative interviews were conducted and analysed using inductive thematic analysis, adopting a critical realist perspective. Twenty-six people living with HIV and chronic neuropathic pain completed semi-structured interviews. Their views about a psychological treatment for pain management and online delivery were explored in-depth. RESULTS: Three themes and 12 subthemes were identified. Theme one represents a desire for a broader approach to pain management, including not wanting to take more pills and having multidimensional goals that were not just focussed on pain relief. Theme two includes barriers to online psychologically-based pain management, including concerns about using the Internet and confidentiality. Theme three describes treatment facilitators, including accessibility, therapist support, social connection, and experiencing success. CONCLUSIONS: A psychological treatment for chronic neuropathic pain management appears acceptable for people living with HIV. Therapist-supported online delivery of cognitive-behavioural pain management may be acceptable for people living with HIV given appropriate development of the treatment to address identified barriers to engagement. These data can inform developments to enhance engagement in online psychologically-informed pain management in people living with HIV and more broadly in remote delivery of psychological treatments.

Feasibility randomized-controlled trial of online acceptance and commitment therapy for painful peripheral neuropathy in people living with HIV: The OPEN study.

BACKGROUND: Neuropathic pain negatively affects quality of life among people living with HIV (PLWH). This study examined the feasibility of conducting a full-scale randomized-controlled trial of online acceptance and commitment therapy ("ACT OPEN") for neuropathic pain in PLWH. METHODS: Using a parallel-groups design, thirty-eight participants were randomized to ACT OPEN or a waitlist control (2:1). Participants completed standard self-report outcome measures at baseline, and two- and five-months post-randomization. Participants were aware of their allocation, but assessment was blinded. RESULTS: Twenty-five participants were randomized to ACT OPEN and 13 to the control (of 133 referrals). ACT OPEN completion was 69% and two-month trial retention was 82%. Treatment credibility and satisfaction scores for ACT OPEN were comparable to scores reported in previous trials of cognitive-behavioural treatments for pain. Four adverse events were reported during the study, including one serious adverse event; all of these were unrelated to the research procedures. Small to moderate effects and 95% confidence intervals suggest that the true effect may favour ACT OPEN for improvements in pain intensity/interference and depression. CONCLUSIONS: A full-scale RCT of online ACT for pain management in PLWH may be feasible with refinements to trial design to facilitate recruitment. SIGNIFICANCE: Research on pain management in people living with HIV has primarily focused on pharmacological treatments with limited success. This is the first study to show the potential feasibility of a psychological treatment based on acceptance and commitment therapy delivered online and tailored for pain management in people with HIV ("ACT OPEN"). ACT OPEN may be a promising treatment in this population and further evaluation in a full-scale randomized-controlled trial appears warranted. TRIAL REGISTRATION: The trial was registered (clinicaltrials.gov; NCT03584412).

Quantitative Assessment and Prognostic Associations of the Immune Landscape in Ovarian Clear Cell Carcinoma.

Ovarian clear cell carcinoma (OCCC) is a rare subtype of epithelial ovarian cancer characterised by a high frequency of loss-of-function ARID1A mutations and a poor response to chemotherapy. Despite their generally low mutational burden, an intratumoural T cell response has been reported in a subset of OCCC, with ARID1A purported to be a biomarker for the response to the immune checkpoint blockade independent of micro-satellite instability (MSI). However, assessment of the different immune cell types and spatial distribution specifically within OCCC patients has not been described to date. Here, we characterised the immune landscape of OCCC by profiling a cohort of 33 microsatellite stable OCCCs at the genomic, gene expression and histological level using targeted sequencing, gene expression profiling using the NanoString targeted immune panel, and multiplex immunofluorescence to assess the spatial distribution and abundance of immune cell populations at the protein level. Analysis of these tumours and subsequent independent validation identified an immune-related gene expression signature associated with risk of recurrence of OCCC. Whilst histological quantification of tumour-infiltrating lymphocytes (TIL, Salgado scoring) showed no association with the risk of recurrence or ARID1A mutational status, the characterisation of TILs via multiplexed immunofluorescence identified spatial differences in immunosuppressive cell populations in OCCC. Tumour-associated macrophages (TAM) and regulatory T cells were excluded from the vicinity of tumour cells in low-risk patients, suggesting that high-risk patients have a more immunosuppressive microenvironment. We also found that TAMs and cytotoxic T cells were also excluded from the vicinity of tumour cells in ARID1A-mutated OCCCs compared to ARID1A wild-type tumours, suggesting that the exclusion of these immune effectors could determine the host response of ARID1A-mutant OCCCs to therapy. Overall, our study has provided new insights into the immune landscape and prognostic associations in OCCC and suggest that tailored immunotherapeutic approaches may be warranted for different subgroups of OCCC patients.

Meta-analysis comparing placebo responses in clinical trials of painful HIV-associated sensory neuropathy and diabetic polyneuropathy.

Background and aims The placebo response has been identified as one factor responsible for the lack of therapeutic trials with positive outcomes in neuropathic pain. Reviews have suggested that certain neuropathic pain conditions, including HIV-associated sensory neuropathy (HIV-SN), exhibit a greater placebo response than other neuropathic aetiologies. If true, such a finding could substantially affect clinical trial design and therapeutic developments for these conditions. This study aimed to identify any difference in placebo response between trials of systemic pharmacological intervention in HIV-SN and a comparable neuropathic condition, diabetic polyneuropathy (DPN) and to identify factors influencing the placebo response. Methods A systematic review search to identify randomised, double-blind studies of systemic pharmacological interventions for painful HIV-SN and DPN published between January 1966 and June 2019 was performed. A meta-analysis of the magnitude of placebo response and the proportion of placebo responders was conducted and compared between the two disease conditions. A meta-regression was used to assess for any study and participant characteristics that were associated with the placebo response. Only studies meeting a methodological quality threshold were included. Results Seventy-five trials were identified. There was no statistically significant difference in the proportion of placebo responders (HIV-SN = 0.35; versus DPN = 0.27, p = 0.129). The difference observed in the magnitude of the placebo response [pain reduction of 1.68 (1.47-1.88) DPN; 2.38 (1.87-2.98) in HIV-SN] was based on only 2 trials of HIV-SN and 35 of DPN. Potential factors influencing the placebo response such as psychological measures, were reported inconsistently. Conclusions We found no statistically significant difference in the placebo response rate between painful HIV-SN and DPN. Too few studies were available that reported the necessary information to clarify potential differences in the magnitude of placebo response or to elucidate parameters that could be contributing such differences. Implications The placebo response is one factor that may contribute to a lack of positive trials in neuropathic pain; some etiologies may display larger responses than others. This meta-analysis found no significant difference in placebo response between trials of HIV-associated sensory neuropathy and painful diabetic polyneuropathy, although limited data were available.

Determining Real Change in Conditioned Pain Modulation: A Repeated Measures Study in Healthy Volunteers.

Conditioned pain modulation (CPM) is a potentially useful biomarker in pain populations; however, a statistically robust interpretation of change scores is required. Currently, reporting of CPM does not consider measurement error. Hence, the magnitude of change representing a "true" CPM effect is unknown. This study determined the standard error of measurement (SEM) and proportion of healthy participants showing a "true" CPM effect with a standard CPM paradigm. Fifty healthy volunteers participated in an intersession reliability study using pressure pain threshold (PPT) test stimulus and contact heat, cold water, and sham conditioning stimuli. Baseline PPTs were used to calculate SEM and >±2 × SEM to determine CPM effect. SEM for PPT was .21 kg/cm2. An inhibitory CPM effect (>+2 SEM) was elicited in 59% of subjects in response to cold stimulus; in 44% to heat. Intrasession and intersession reliability of within-subject CPM response was poor (kappa coefficient <.36). Measurement error is important in determining CPM effect and change over time. Even when using reliable test stimuli, and incorporating measures to limit bias and error, CPM intersession reliability was fair and demonstrated a large degree of within-subject variation. Determining "true" change in CPM will underpin future interrogations of intraindividual differences in CPM. PERSPECTIVE: This study used a distribution-based statistical approach to identify real change in CPM, based on the SEM for the test stimulus. Healthy volunteers demonstrate substantial within-subject variation; CPM effect was paradigm dependent at intrasession testing and unstable to the same paradigm at intersession testing.

A qualitative study of the experience and impact of neuropathic pain in people living with HIV.

Painful distal symmetrical polyneuropathy is common in HIV and is associated with reduced quality of life. Research has not explored the experience of neuropathic pain in people with HIV from a person-centred perspective. Therefore, a qualitative interview study was conducted to more deeply understand the experience and impact of neuropathic pain in this population. Semistructured interviews were conducted with 26 people with HIV and peripheral neuropathic pain symptoms. Interviews explored the impact of pain and participants' pain management strategies. Interviews were transcribed verbatim and analysed using thematic analysis. Four themes and 11 subthemes were identified. Theme 1 reflects the complex characterisation of neuropathic pain, including the perceived unusual nature of this pain and diagnostic uncertainty. Theme 2 centred on the interconnected impacts of pain on mood and functioning and includes how pain disrupts relationships and threatens social inclusion. Theme 3 reflects the struggle for pain relief, including participants' attempts to "exhaust all options" and limited success in finding lasting relief. The final theme describes how pain management is complicated by living with HIV; this theme includes the influence of HIV stigma on pain communication and pain as an unwanted reminder of HIV. These data support the relevance of investigating and targeting psychosocial factors to manage neuropathic pain in HIV.

The Utility of Corneal Nerve Fractal Dimension Analysis in Peripheral Neuropathies of Different Etiology.

Purpose: Quantification of corneal confocal microscopy (CCM) images has shown a significant reduction in corneal nerve fiber length (CNFL) in a range of peripheral neuropathies. We assessed whether corneal nerve fractal dimension (CNFrD) analysis, a novel metric to quantify the topological complexity of corneal subbasal nerves, can differentiate peripheral neuropathies of different etiology. Methods: Ninety patients with peripheral neuropathy, including 29 with diabetic peripheral neuropathy (DPN), 34 with chronic inflammatory demyelinating polyneuropathy (CIDP), 13 with chemotherapy-induced peripheral neuropathy (CIPN), 14 with human immunodeficiency virus-associated sensory neuropathy (HIV-SN), and 20 healthy controls (HCs), underwent CCM for estimation of corneal nerve fiber density (CNFD), CNFL, corneal nerve branch density (CNBD), CNFrD, and CNFrD adjusted for CNFL (ACNFrD). Results: In patients with DPN, CIDP, CIPN, or HIV-SN compared to HCs, CNFD (P = 0.004-0.0001) and CNFL (P = 0.05-0.0001) were significantly lower, with a further significant reduction among subgroups. CNFrD was significantly lower in patients with CIDP compared to HCs and patients with HIV-SN (P = 0.02-0.0009) and in patients with DPN compared to HCs and patients with HIV-SN, CIPN, or CIDP (P = 0.001-0.0001). ACNFrD was lower in patients with CIPN, CIDP, or DPN compared to HCs (P = 0.03-0.0001) and in patients with DPN compared to those with HIV-SN, CIPN, or CIDP (P = 0.01-0.005). Conclusions: CNFrD can detect a distinct pattern of corneal nerve loss in patients with DPN or CIDP compared to those with CIPN or HIV-SN and controls. Translational Relevance: Various peripheral neuropathies are characterized by a comparable degree of corneal nerve loss. Assessment of corneal nerve topology by CNFrD could be useful in differentiating neuropathies based on the pattern of loss.

Pain thresholds and intensities of CRPS type I and neuropathic pain in respect to sex.

BACKGROUND AND AIMS: Healthy women have generally been found to have increased experimental pain perception and chronic pain has a higher prevalence in female as compared to male patients. However, no study has investigated whether pain intensity and pain perception thresholds are distinct or similar between sexes within various chronic pain entities. We investigated whether average pain intensities and pain thresholds assessed using quantitative sensory testing (QST) differed between women and men suffering from three distinct chronic pain conditions: Complex Regional Pain Syndrome (CRPS type I), peripheral nerve injury (PNI) or polyneuropathy (PNP), as compared to paired healthy volunteers. METHODS: QST data of 1,252 patients (669 female, 583 male) with PNI (n = 342), PNP (n = 571) or CRPS (n = 339), and average pain intensity reports from previously published studies were included. Absolute and z-values (adjusted for age and body region) of cold, heat, pressure (PPT) and pinprick pain thresholds were compared in generalized linear models with aetiology, duration of underlying pain disease and average pain intensity as fixed effects. RESULTS: Average pain intensity during the past four weeks did not differ between women and men, in both mean and range. In women absolute pain thresholds for cold, heat and pinprick were lower than in males across all diagnoses (p < .05). However, after z-transformation these differences disappeared except for PPT in CRPS (p = .001). DISCUSSION: Pain thresholds in patients show only minor sex differences. However, these differences mimic those observed in healthy subjects and do not seem to be linked to specific pathophysiological processes. SIGNIFICANCE: Female healthy participants and female patients with neuropathic pain conditions or CRPS I report lower pain thresholds compared to males, but pain intensity is similar and there is no sex difference in the extent to which the thresholds are altered in neuropathic pain or CRPS. Thus, the sex differences observed in various chronic pain conditions mimic those obtained in healthy participants, indicating that these differences are not linked to specific pathophysiological processes and are of minor clinical relevance.

Implementation of a Quality Index for Improvement of Quantification of Corneal Nerves in Corneal Confocal Microcopy Images: A Multicenter Study.

PURPOSE: Corneal confocal microscopy (CCM) is an imaging method to detect loss of nerve fibers in the cornea. The impact of image quality on the CCM parameters has not been investigated. We developed a quality index (QI) with 3 stages for CCM images and compared the influence of the image quality on the quantification of corneal nerve parameters using 2 modes of analysis in healthy volunteers and patients with known peripheral neuropathy. METHODS: Images of 75 participants were a posteriori analyzed, including 25 each in 3 image quality groups (QI 1-QI 3). Corneal nerve fiber length (CNFL) was analyzed using automated and semiautomated software, and corneal nerve fiber density and corneal nerve branch density were quantified using automated image analysis. Three masked raters assessed CCM image quality (QI) independently and categorized images into groups QI 1-QI 3. In addition, statistical analysis was used to compare interrater reliability. Analysis of variance was used for analysis between the groups. Interrater reliability analysis between the image ratings was performed by calculating Fleiss' kappa and its 95% confidence interval. RESULTS: CNFL, corneal nerve fiber density, and corneal nerve branch density increased significantly with QI (P < 0.001, all post hoc tests P < 0.05). CNFL was higher using semiautomated compared with automated nerve analysis, independent of QI. Fleiss kappa coefficient for interrater reliability of QI was 0.72. CONCLUSIONS: The quantification of corneal nerve parameters depends on image quality, and poorer quality images are associated with lower values for corneal nerve parameters. We propose the QI as a tool to reduce variability in quantification of corneal nerve parameters.

Psychosocial factors associated with persistent pain in people with HIV: a systematic review with meta-analysis.

Chronic pain remains a prevalent and disabling problem for people living with HIV in the current antiretroviral treatment era. Psychosocial treatments may have promise for managing the impact of this pain. However, research is needed to identify psychosocial processes to target through such treatments. The current systematic review and meta-analysis examined the evidence for psychosocial factors associated with pain, disability, and quality of life in people living with HIV and persistent pain. Observational and experimental studies reporting on the association between one or more psychosocial factors and one or more pain-related variables in an adult sample of people living with HIV and pain were eligible. Two reviewers independently conducted eligibility screening, data extraction, and quality assessment. Forty-six studies were included in the review and 37 of these provided data for meta-analyses (12,493 participants). "Some" or "moderate" evidence supported an association between pain outcomes in people with HIV and the following psychosocial factors: depression, psychological distress, posttraumatic stress, drug abuse, sleep disturbance, reduced antiretroviral adherence, health care use, missed HIV clinic visits, unemployment, and protective psychological factors. Surprisingly, few studies examined protective psychological factors or social processes, such as stigma. There were few high-quality studies. These findings can inform future research and psychosocial treatment development in this area. Greater theoretical and empirical focus is needed to examine the role of protective factors and social processes on pain outcomes in this context. The review protocol was registered with PROSPERO (CRD42016036329).

Use of Corneal Confocal Microscopy to Evaluate Small Nerve Fibers in Patients With Human Immunodeficiency Virus.

Importance: Objective quantification of small fiber neuropathy in patients with human immunodeficiency virus (HIV)-associated sensory neuropathy (HIV-SN) is difficult but needed for diagnosis and monitoring. In vivo corneal confocal microscopy (IVCCM) can quantify small fiber damage. Objective: To establish whether IVCCM can identify an abnormality in corneal nerve fibers and Langerhans cells in patients with and without HIV-SN. Design, Setting, and Participants: This prospective, cross-sectional cohort study was conducted between July 24, 2015, and September 17, 2015. Twenty patients who were HIV positive were recruited from adult outpatient clinics at Chelsea and Westminster Hospital NHS Foundation Trust in England. These patients underwent IVCCM at Moorfields Eye Hospital NHS Foundation Trust in London, England, and the IVCCM images were analyzed at Weill Cornell Medicine-Qatar in Ar-Rayyan, Qatar. Patients were given a structured clinical examination and completed validated symptom questionnaires and the Clinical HIV-Associated Neuropathy Tool. Results from patients with HIV were compared with the results of the age- and sex-matched healthy control participants (n = 20). All participants were classified into 3 groups: controls, patients with HIV but without SN, and patients with HIV-SN. Main Outcomes and Measures: Comparison of corneal nerve fiber density, corneal nerve branch density, corneal nerve fiber length, corneal nerve fiber tortuosity, and corneal Langerhans cell density between healthy controls and patients with HIV with and without SN. Results: All 40 participants were male, and most (≥70%) self-identified as white. Of the 20 patients with HIV, 14 (70%) had HIV-SN. This group was older (mean [SD] age, 57.7 [7.75] years) than the group without HIV-SN (mean [SD] age, 42.3 [7.26] years) and the controls (mean [SD] age, 53.8 [10.5] years). Corneal nerve fiber density was reduced in patients with HIV compared with the controls (26.7/mm2 vs 38.6/mm2; median difference, -10.37; 95.09% CI, -14.27 to -6.25; P < .001) and in patients with HIV-SN compared with those without (25.8/mm2 vs 30.7/mm2; median difference, -4.53; 95.92% CI, -8.85 to -0.26; P = .03). Corneal nerve branch density and corneal nerve fiber length were reduced in patients with HIV, but no differences were identified between those with neuropathy and without neuropathy (corneal nerve branch density: 95.83/mm2 for the controls vs 72.37/mm2 for patients with HIV; median difference, -24.53; 95.32% CI, -50.62 to -3.13; P = .01; and corneal nerve fiber length: 28.4 mm/mm2 for the controls vs 21.9 mm/mm2 for patients with HIV; median difference, -5.24; 95.09% CI, -8.83 to -1.38; P = .001). Tortuosity coefficient was increased in patients with HIV compared with controls (16.44 vs 13.95; median difference, 2.34; 95.09% CI, 0.31 to 4.65; P = .03) and in those with HIV-SN compared with those without (17.84 vs 14.18; median difference, 4.32; 95.92% CI, 0.68-9.23; P = .01). No differences were identified in corneal Langerhans cell density (19.84 cells/mm2 for the controls vs 41.43 cells/mm2 for patients with HIV; median difference, 9.38; 95% CI, -12.51 to 26.34; P = .53). Conclusions and Relevance: In vivo corneal confocal microscopy could be used in the assessment of HIV-SN, but larger studies are required to confirm this finding.