Optimising plasma clozapine levels to improve treatment response: an individual patient data meta-analysis and receiver operating characteristic curve analysis.

BACKGROUND: Although clozapine is the most efficacious medication for treatment-refractory schizophrenia, not all patients will have an adequate response. Optimising clozapine dose using therapeutic drug monitoring could therefore maximise response. AIMS: Using individual patient data, we undertook a receiver operating characteristic (ROC) curve analysis to determine an optimal therapeutic range for clozapine levels to guide clinical practice. METHOD: We conducted a systematic review of PubMed, PsycINFO and Embase for studies that provided individual participant level data on clozapine levels and response. These data were analysed using ROC curves to determine the prediction performance of plasma clozapine levels for treatment response. RESULTS: We included data on 294 individual participants from nine studies. ROC analysis yielded an area under the curve of 0.612. The clozapine level at the point of optimal diagnostic benefit was 372 ng/mL; at this level, the response sensitivity was 57.3%, and specificity 65.7%. The interquartile range for treatment response was 223-558 ng/mL. There was no improvement in ROC performance with mixed models including patient gender, age or length of trial. Clozapine dose and clozapine concentration to dose ratio did not provide significantly meaningful prediction of response to clozapine. CONCLUSIONS: Clozapine dose should be optimised based on clozapine therapeutic levels. We found that a range between 250 and 550 ng/mL could be recommended, while noting that a level of >350 ng/mL is the most optimal for response. Although some patients may not respond without clozapine levels >550 ng/mL, the benefits should be weighed against the increased risk of adverse drug reactions.

Subjective cognitive changes following premenopausal risk-reducing bilateral salpingo-oophorectomy.

OBJECTIVE: Women at high risk of ovarian cancer are commonly advised to undergo risk-reducing bilateral salpingo-oophorectomy (BSO) prior to natural menopause. Cognitive symptoms during natural menopause transition are frequently reported; however, very few studies have examined cognitive changes following surgical menopause. To address this gap, we explored the cognitive experiences of women within 24 months post BSO. METHODS: This observational cross-sectional sub-study is part of a larger project, the Early Menopause and Cognition Study (EM-COG). We investigated perceived cognitive experiences in Australian women (n = 16) who underwent risk-reducing BSO using qualitative interviews. Thematic analysis was undertaken to identify key themes. RESULTS: Fifteen out of 16 participants (93.75%) reported changes to cognition within 24 months post BSO. The key cognitive symptoms reported were brain fog, memory and retrieval difficulties, slower processing speed as well as attention difficulties. Five participants (31.3%) experienced negative mood symptoms post BSO. CONCLUSION: Findings from this study suggest that women experience subjective cognitive changes within 24 months post BSO. This period could be a vulnerable time for women's cognitive health. While these findings need to be confirmed by a large prospective study, our research indicates that psychoeducation and awareness will be helpful in managing cognitive symptoms after surgical menopause.

Deliberate foreign body ingestion in patients with underlying mental illness: A retrospective multicentre study.

OBJECTIVE: Deliberate foreign body ingestion (DFBI) is characterised by recurrent presentations among patients with mental health conditions, intellectual disabilities and in prisoners. We aimed to profile the characteristics and evaluate the care of such patients in this study. METHODS: Adult patients with an endoscopic record of attempted foreign body retrieval between January 2013 and September 2020 were identified at three Australian hospitals. Those with a documented mental health diagnosis were included and their standard medical records reviewed. Presentation history, demographics, comorbidities and endoscopic findings were recorded and described. RESULTS: A total of 166 admissions were accounted for by 35 patients, 2/3 of which had borderline personality disorder (BPD). Repetitive presentations occurred in more than half of the cohort. There was an increased trend of hospital admissions throughout the years. At least half of the cohort had a documented mental health review during their admission. An average of 3.3 (2.9) foreign bodies were ingested per single episode. Endoscopic intervention was performed in 76.5% of incidents. The combined Length of stay for all patients was 680 days. CONCLUSION: Deliberate foreign body ingestion in mental health patients is a common, recurring and challenging problem that is increasing in frequency and requires collaborative research to further guide holistic management.

Possible substance use disorders among first responders during the COVID-19 era: a quasi-experimental study of personal and residential vulnerability.

Background: During the COVID-19 pandemic possible substance use disorders (SUD) were exacerbated from increased stress and isolation. Experiences of symptomology differ widely by occupations.Objectives: The objectives were to determine if there is a temporal relationship between COVID-19 vulnerability and possible SUDs among first responders, and to examine the association with neighborhood vulnerability.Methods: We conducted an analysis with two distinct cohorts dependent on time of entry: 1) First responders that began counseling prior to COVID-19 and 2) First responders that began counseling after the start of COVID-19. Data were collected at intake from first responders seeking mental health services between 2017 and 2021 at an organization in Dallas/Fort Worth, Texas. The study sample included 195 mostly male (75%) first responders (51% law enforcement officers; 49% emergency medical technicians/firefighters). Bivariate models tested unadjusted relationships between covariates and possible SUD. Adjusted models consisted of a two-level multivariable logistic regression models.Results: Nearly 40% (n = 77) screened positive for a possible SUD. Those beginning counseling after COVID-19 did not have higher odds of SUDs. For every unit increase in neighborhood Severe COVID-19 Health Risk Index at a first responder's residential location there was an increase in the odds of a possible SUD (AOR = 3.14, 95% CI: 1.47, 6.75).Conclusions: Our study highlights the degree to which personal and residential vulnerability to COVID-19 impacted first responders. The increased occupational stress of this population, and an established pattern of maladaptive coping, elucidates the need for preventative and clinical approaches to strengthen the resilience of this population.

Validation of the adapted response to stressful experiences scale.

There is evidence to suggest that resilience may be a protective factor to moderate the experience of mental health symptoms among military personnel. The present study analyzed the validity and reliability of a full-scale and adapted measure of resilience from a sample of 470 U.S. military service Veterans receiving clinical services from a civilian nonprofit agency. Results of an exploratory factor analysis, a two-factor confirmatory factor analysis, and a single-factor confirmatory factor analysis indicated that while the Response to Stressful Experiences Scale (RSES) indicated a fair model fit for the sample, the brief measure of resilience (RSES-4) demonstrated a better factor structure (RMR = .017, GFI = .995, CFI = .994, TLI = .981, RMSEA = .057), criterion and concurrent validity, and acceptable internal consistency.

Evaluation of the proposed anti-N-methyl-d-aspartate receptor encephalitis clinical diagnostic criteria in psychiatric patients.

OBJECTIVE: The gold standard for diagnosing anti-NMDAR encephalitis is demonstration of the antibody in CSF. Clinical diagnostic criteria have been proposed for when this is not available in a timely manner which is evaluated, in this study, for a psychiatric population. METHODS: This study retrospectively assessed the proposed criteria in patients presenting to psychiatric services for the first time with known anti-NMDAR antibody status. Antibody-positive cases were derived from the literature (conception to December 2019) and a state-wide (Queensland, Australia) cohort. Antibody-negative cases were derived from a service-wide (Metro South, Queensland, Australia) cohort of psychiatric cases which underwent antibody testing for routine organic screening. Sensitivity and specificity were calculated at 1 week following admission and the point of discharge. RESULTS: The proposed criteria were applied to 641 cases (500 antibody-positive and 141 antibody-negative), demonstrating a sensitivity which increased from around 19% after 1 week to 49% by the point of discharge. Specificity was 100% at both time points. The mean average time to become positive using the proposed criteria was 19.5 days compared to 34.9 days for return of antibody testing. CONCLUSIONS: High specificity of the proposed criteria, seen in this study, suggests that cases which are positive can be considered for expedited commencement of treatment. However, if clinical suspicion is high despite criteria being negative, it is essential to test CSF for anti-NMDAR antibody.

Hepatitis C virus infection inhibits a Src-kinase regulatory phosphatase and reduces T cell activation in vivo.

Among human RNA viruses, hepatitis C virus (HCV) is unusual in that it causes persistent infection in the majority of infected people. To establish persistence, HCV evades host innate and adaptive immune responses by multiple mechanisms. Recent studies identified virus genome-derived small RNAs (vsRNAs) in HCV-infected cells; however, their biological significance during human HCV infection is unknown. One such vsRNA arising from the hepatitis C virus (HCV) E2 coding region impairs T cell receptor (TCR) signaling by reducing expression of a Src-kinase regulatory phosphatase (PTPRE) in vitro. Since TCR signaling is a critical first step in T cell activation, differentiation, and effector function, its inhibition may contribute towards HCV persistence in vivo. The effect of HCV infection on PTPRE expression in vivo has not been examined. Here, we found that PTPRE levels were significantly reduced in liver tissue and peripheral blood mononuclear cells (PBMCs) obtained from HCV-infected humans compared to uninfected controls. Loss of PTPRE expression impaired antigen-specific TCR signaling, and curative HCV therapy restored PTPRE expression in PBMCs; restoring antigen-specific TCR signaling defects. The extent of PTPRE expression correlated with the amount of sequence complementarity between the HCV E2 vsRNA and the PTPRE 3' UTR target sites. Transfection of a hepatocyte cell line with full-length HCV RNA or with synthetic HCV vsRNA duplexes inhibited PTPRE expression, recapitulating the in vivo observation. Together, these data demonstrate that HCV infection reduces PTPRE expression in the liver and PBMCs of infected humans, and suggest that the HCV E2 vsRNA is a novel viral factor that may contribute towards viral persistence.

Knockout of MCT1 results in total absence of spermatozoa, sex hormones dysregulation, and morphological alterations in the testicular tissue.

Lactate is a key metabolite for the normal occurrence of spermatogenesis. In the testis, lactate is produced by the Sertoli cells and transported to germline cells. Monocarboxylate transporters (MCTs) are key players in that process. Among the family of MCTs, MCT1 is at least partly responsible for lactate uptake by the germ cells. We aimed to perform a first assessment of the role of MCT1 in male reproductive potential. Mct1 conditional knockout (cKO) mice were used for morphometric evaluation, testicular morphology, and sperm parameter assessment. Serum steroid hormones levels were also measured. cKO animals showed a decrease in gonadosomatic index, testis weight, and seminiferous tubular diameters. Deletion of MCT1 also causes morphological changes in the organization of the seminiferous tubules and on Sertoli cell morphology. These changes resulted in failure of spermatogenesis with depletion of germ cells and total absence of spermatozoa. MCT1 cKO animals presented also hormonal dysregulation, with a decrease in serum 17ß-estradiol levels. In conclusion, MCT1 is pivotal for male reproductive potential. Absence of MCT1 results in maintenance of undifferentiated spermatogonia pool and compromised sperm production.

Ventral striatal regulation of CREM mediates impulsive action and drug addiction vulnerability.

Impulsivity, a multifaceted behavioral hallmark of attention-deficit/hyperactivity disorder (ADHD), strongly influences addiction vulnerability and other psychiatric disorders that incur enormous medical and societal burdens yet the neurobiological underpinnings linking impulsivity to disease remain poorly understood. Here we report the critical role of ventral striatal cAMP-response element modulator (CREM) in mediating impulsivity relevant to drug abuse vulnerability. Using an ADHD rat model, we demonstrate that impulsive animals are neurochemically and behaviorally more sensitive to heroin and exhibit reduced Crem expression in the nucleus accumbens core. Virally increasing Crem levels decreased impulsive action, thus establishing a causal relationship. Genetic studies in seven independent human populations illustrate that a CREM promoter variant at rs12765063 is associated with impulsivity, hyperactivity and addiction-related phenotypes. We also reveal a role of Crem in regulating striatal structural plasticity. Together, these results highlight that ventral striatal CREM mediates impulsivity related to substance abuse and suggest that CREM and its regulated network may be promising therapeutic targets.

A national Health and Work Strategy: a search for evidence.

BACKGROUND: The Health and Safety Executive's new Health and Work Strategy is based on an up-to-date assessment of workplace health priorities. Rather than replicating traditional prioritization approaches, a broader assessment of health and work priorities was carried out using a range of stakeholders. AIMS: To develop a set of health priorities for further research and intervention activity. METHODS: Four exercises were carried out, including internal prioritization, two external web-hosted questionnaire studies of younger workers and occupational health professionals, focus groups and tele-depth interviews with workplace health and safety professionals. RESULTS: The highest rated internal priorities (weighted priority scores) were identified as mesothelioma (70), lung cancer (69.25), chronic obstructive pulmonary disease (COPD; 69), musculoskeletal disorders (MSDs; 66.25), hearing loss (65.75), stress (65.5), asthma (64.5) and hand-arm vibration syndrome (61.5). Using the three highest ranked criteria developed by occupational health professionals ((i) the preventability of the condition, (ii) the impact of the condition and (iii) the number of workers affected), mesothelioma, lung cancer, COPD, MSDs, hearing loss, stress and asthma were identified as the top seven priorities. Generic issues identified included ageing and work, obesity, newer technologies, and ethnicity and cultures of workforces. Apprentices identified stress, depression, anxiety, musculoskeletal and respiratory disorders, fatigue and workload as important workplace health considerations. CONCLUSIONS: This process identified a number of expected and new areas of health research interest. We believe the findings reflect the real world requirements of work as assessed by occupational health and safety practitioners and workers.

Molecular epidemiology of Clostridioides (previously Clostridium) difficile isolates from a university hospital in Minas Gerais, Brazil.

The molecular epidemiology of 38 non-duplicate toxigenic Clostridioides (previously Clostridium) difficile isolates from inpatients from a hospital in Brazil during a 6-year period (2012-2017) were investigated by multilocus sequence typing (MLST) and ribotyping. These isolates were classified into 20 sequence types (ST), six (30%) of which were novel, revealing a high diversity in a single hospital. Classic hypervirulent strains ST1/RT027 and ST11/RT078 were not identified, while ST42 (almost all RT106) was the most common type, being detected in 11 (28.9%) strains. Noteworthy, six (15.8%) isolates were classified into five STs from clade 2, four of which were new ST and RT. Our study suggests that possible hypervirulent strains other than ST1/RT027 might be inadvertently circulating in Brazilian hospitals and highlights the importance of permanent surveillance on circulating strains in a national scale.

Two Distinct Patterns of Clostridium difficile Diversity Across Europe Indicating Contrasting Routes of Spread.

Background: Rates of Clostridium difficile infection vary widely across Europe, as do prevalent ribotypes. The extent of Europe-wide diversity within each ribotype, however, is unknown. Methods: Inpatient diarrheal fecal samples submitted on a single day in summer and winter (2012-2013) to laboratories in 482 European hospitals were cultured for C. difficile, and isolates the 10 most prevalent ribotypes were whole-genome sequenced. Within each ribotype, country-based sequence clustering was assessed using the ratio of the median number of single-nucleotide polymorphisms between isolates within versus across different countries, using permutation tests. Time-scaled Bayesian phylogenies were used to reconstruct the historical location of each lineage. Results: Sequenced isolates (n = 624) were from 19 countries. Five ribotypes had within-country clustering: ribotype 356, only in Italy; ribotype 018, predominantly in Italy; ribotype 176, with distinct Czech and German clades; ribotype 001/072, including distinct German, Slovakian, and Spanish clades; and ribotype 027, with multiple predominantly country-specific clades including in Hungary, Italy, Germany, Romania, and Poland. By contrast, we found no within-country clustering for ribotypes 078, 015, 002, 014, and 020, consistent with a Europe-wide distribution. Fluoroquinolone resistance was significantly more common in within-country clustered ribotypes (P = .009). Fluoroquinolone-resistant isolates were also more tightly clustered geographically with a median (interquartile range) of 43 (0-213) miles between each isolate and the most closely genetically related isolate, versus 421 (204-680) miles in nonresistant pairs (P < .001). Conclusions: Two distinct patterns of C. difficile ribotype spread were observed, consistent with either predominantly healthcare-associated acquisition or Europe-wide dissemination via other routes/sources, for example, the food chain.

Patient and Strain Characteristics Associated With Clostridium difficile Transmission and Adverse Outcomes.

Background: No study has used whole-genome sequencing (WGS) to investigate risk factors for Clostridium difficile (CD) transmission between cases, or assessed the impact of recent acquisition on patient outcome. Methods: This 20 month retrospective cohort study included consecutive cytotoxin-positive diarrheal samples, which underwent culture, ribotyping, and WGS (Illumina). Sequenced isolates were compared using single nucleotide variants (SNVs). Independent predictors of acquisition from another case, onward transmission, 120-day recurrence, and 30-day mortality were identified using logistic regression with backwards elimination. Results: Of 660 CD cases, 640 (97%) were sequenced, of which 567 (89%) shared a ribotype with a prior case, but only 227 (35%) were ≤2 SNVs from a prior case, supporting recent acquisition. Plausible (<2 SNVs) recent ward-based acquisition from a symptomatic case was more frequent in certain ribotypes; 64% (67/105) for ribotype-027 cases, compared with 11% (6/57) for ribotype-078. Independent risk factors (adjusted P < .05) for CD acquisition included older age, longer inpatient duration, and ribotype; these factors, and male sex, increased onward transmission. Patients with a plausible donor had a greater risk of recurrence (adjusted P = .001) and trended towards greater 30-day mortality (adjusted P = .06). Ribotype had no additional mortality or recurrence impact after adjusting for acquisition (P > .1). Conclusions: Greater transmission of certain lineages suggests CD may have different reservoirs and modes of transmission. Acquiring CD from a recent case is associated with poorer clinical outcomes. Clinical characteristics associated with increased healthcare-associated CD transmission could be used to target preventative interventions.

Refining the psychiatric syndrome of anti-N-methyl-d-aspartate receptor encephalitis.

OBJECTIVE: To review the psychiatric symptoms of anti-N-methyl-d-aspartate (NMDA) receptor encephalitis, in an attempt to differentiate the presentation from a primary psychiatric disorder. METHOD: A systematic literature review of PubMed and EMBASE of all published cases of anti-NMDA receptor encephalitis was performed from inception to January 2018. RESULTS: There were 706 cases of anti-NMDA receptor encephalitis identified. Cases were typically young (mean age 22.6 years, SD 14.8), female (F : M ratio 3.5 : 1) and presented with significant behavioural disturbance. Reported behaviour was most commonly severe agitation and aggression, abnormal speech, and catatonia. Psychosis occurred in 45.8% of cases. Investigation results were inconsistent (MRI abnormal in 35.6%, EEG abnormal in 83.0%) and non-specific. Psychiatric treatment often required multiple psychotropics, and there may be increased risk of significant side-effects such as neuroleptic malignant syndrome. Prognosis was usually good; however, cognitive and behavioral symptoms remained prominent during recovery, and psychiatrist involvement was required in this period. CONCLUSION: The presentation of anti-NMDA receptor encephalitis is variable. However, there are often psychiatric features which are atypical to a primary psychiatric illness, such as severe agitation, speech abnormalities, and catatonia, which may help early identification.

Underestimation of spirometry if recommended testing guidance is not followed.

Background: Lung function measured at work is used to make important employment decisions. Improving its quality will reduce misclassification and allow more accurate longitudinal interpretation over time. Aims: To assess the amount by which lung function (forced expiratory volume in 1 second [FEV1] and forced vital capacity [FVC]) values will be underestimated if recommended spirometry testing guidance is not followed. Methods: Lung function was measured in a population of workers. Knowledge of the final reproducible FEV1 and FVC for each worker allowed estimation of the underestimates that would have occurred if less forced manoeuvres than recommended had been performed. Results: A total of 667 workers (661 males, mean age 43 years, range 18-66) participated. Among them, 560 (84%) achieved reproducible results for both FEV1 and FVC; 470 (84%) of these did so after three technically acceptable forced expiratory manoeuvres, a cumulative total of 533 after four, 548 after five, 557 after six, 559 after seven and 560 after eight blows. If only one (or first two) technically acceptable blow(s) had been performed, mean underestimates were calculated for FEV1 of 115.1 ml (35.4 ml) and for FVC of 143.4 ml (42.3 ml). Conclusions: In this study, reproducible spirometry was achievable in most workers. Not adhering to standards underestimates lung function by clinically significant amounts.

Correlation between restriction endonuclease analysis and PCR ribotyping for the identification of Clostridioides (Clostridium) difficile clinical strains.

Restriction endonuclease analysis (REA) and PCR ribotyping are two typing systems that have been frequently utilized for molecular epidemiologic characterization of Clostridioides (Clostridium) difficile. To correlate typing data obtained from each method, we performed both REA and PCR ribotyping on a large and diverse set of historical and contemporary C. difficile infection clinical isolates. Eighty isolates were selected from each reference laboratory in the United States (Microbiology Reference Laboratory, Hines VA Medical Center) and United Kingdom (Clostridium difficile Network for England and Northern Ireland laboratory, University of Leeds). The 160 isolates were assigned to 82 unique ribotypes and 51 unique REA groups (116 unique REA types). In general, concordance between typing methods was good. Dendrogram analysis of PCR ribotype band patterns demonstrated close genetic relationships among strain types with discordant REA and ribotype assignments. While REA typing was more discriminatory, several REA types in this study were further discriminated by PCR ribotyping, indicating that discriminatory value of these typing methods may be strain dependent. These data will assist with molecular epidemiologic surveillance of strains identified by these two commonly used C. difficile typing systems.

Contribution to Clostridium Difficile Transmission of Symptomatic Patients With Toxigenic Strains Who Are Fecal Toxin Negative.

Background: The role of symptomatic patients who are toxigenic strain positive (TS+) but fecal toxin negative (FT-) in transmission of Clostridium difficile is currently unknown. Methods: We investigated the contribution of symptomatic TS+/FT- and TS+/FT+ patients in C. difficile transmission in 2 UK regions. From 2-step testing, all glutamate dehydrogenase (GDH)-positive specimens, regardless of fecal toxin result, from Oxford (April 2012 through April 2013) and Leeds (July 2012 through April 2013) microbiology laboratories underwent culture and whole-genome sequencing (WGS), using WGS to identify toxigenic strains. Plausible sources for each TS+/FT+ case, including TS+/FT- and TS+/FT+ patients, were determined using WGS, with and without hospital admission data. Results: A total of 1447 of 12772 (11%) fecal samples were GDH positive, 866 of 1447 (60%) contained toxigenic C. difficile, and fecal toxin was detected in 511 of 866 (59%), representing 235 Leeds and 191 Oxford TS+/FT+ cases. TS+/FT+ cases were 3 times more likely to be plausibly acquired from a previous TS+/FT+ case than a TS+/FT- patient. Fifty-one of 265 (19%) TS+/FT+ cases diagnosed >3 months into the study were genetically related (≤2 single-nucleotide polymorphisms) to ≥1 previous TS+/FT+ case or TS+/FT- patient: 27 (10%) to only TS+/FT+ cases, 9 (3%) to only TS+/FT- patients, and 15 (6%) to both. Only 10 of 265 (4%) were genetically related to a previous TS+/FT+ or TS+/FT- patient and shared the same ward simultaneously or within 28 days. Conclusions: Symptomatic TS+/FT- patients were a source of C. difficile transmission, although they accounted for less onward transmission than TS+/FT+ cases. Although transmission from symptomatic patients with either fecal toxin status accounted for a low overall proportion of new cases, both groups should be infection control targets.

Comparison of Control of Clostridium difficile Infection in Six English Hospitals Using Whole-Genome Sequencing.

BACKGROUND: Variation in Clostridium difficile infection (CDI) rates between healthcare institutions suggests overall incidence could be reduced if the lowest rates could be achieved more widely. METHODS: We used whole-genome sequencing (WGS) of consecutive C. difficile isolates from 6 English hospitals over 1 year (2013-14) to compare infection control performance. Fecal samples with a positive initial screen for C. difficile were sequenced. Within each hospital, we estimated the proportion of cases plausibly acquired from previous cases. RESULTS: Overall, 851/971 (87.6%) sequenced samples contained toxin genes, and 451 (46.4%) were fecal-toxin-positive. Of 652 potentially toxigenic isolates >90-days after the study started, 128 (20%, 95% confidence interval [CI] 17-23%) were genetically linked (within ≤2 single nucleotide polymorphisms) to a prior patient's isolate from the previous 90 days. Hospital 2 had the fewest linked isolates, 7/105 (7%, 3-13%), hospital 1, 9/70 (13%, 6-23%), and hospitals 3-6 had similar proportions of linked isolates (22-26%) (P ≤ .002 comparing hospital-2 vs 3-6). Results were similar adjusting for locally circulating ribotypes. Adjusting for hospital, ribotype-027 had the highest proportion of linked isolates (57%, 95% CI 29-81%). Fecal-toxin-positive and toxin-negative patients were similarly likely to be a potential transmission donor, OR = 1.01 (0.68-1.49). There was no association between the estimated proportion of linked cases and testing rates. CONCLUSIONS: WGS can be used as a novel surveillance tool to identify varying rates of C. difficile transmission between institutions and therefore to allow targeted efforts to reduce CDI incidence.

Improved Survival Among all Interferon-α-Treated Patients in HCV-002, a Veterans Affairs Hepatitis C Cohort of 2211 Patients, Despite Increased Cirrhosis Among Nonresponders.

BACKGROUND: As the era of interferon-alpha (IFN)-based therapy for hepatitis C ends, long-term treatment outcomes are now being evaluated. AIM: To more fully understand the natural history of hepatitis C infection by following a multisite cohort of patients. METHODS: Patients with chronic HCV were prospectively enrolled in 1999-2000 from 11 VA medical centers and followed through retrospective medical record review. RESULTS: A total of 2211 patients were followed for an average of 8.5 years after enrollment. Thirty-one percent of patients received HCV antiviral therapy, 15 % with standard IFN/ribavirin only, 16 % with pegylated IFN/ribavirin, and 26.7 % of treated patients achieved sustained virologic response (SVR). Cirrhosis developed in 25.8 % of patients. Treatment nonresponders had a greater than twofold increase in the hazard of cirrhosis and hepatocellular carcinoma, compared to untreated patients, whereas SVR patients were only marginally protected from cirrhosis. Nearly 6 % developed hepatocellular carcinoma, and 27.1 % died during the follow-up period. Treated patients, regardless of response, had a significant survival benefit compared to untreated patients (HR 0.58, CI 0.46-0.72). Improved survival was also associated with college education, younger age, lower levels of alcohol consumption, and longer duration of medical service follow-up-factors typically associated with treatment eligibility. CONCLUSIONS: As more hepatitis C patients are now being assessed for all-oral combination therapy, these results highlight that patient compliance and limiting harmful behaviors contribute a significant proportion of the survival benefit in treated patients and that the long-term clinical benefits of SVR may be less profound than previously reported.

Recommendations for spinal rehabilitation professionals regarding sexual education needs and preferences of people with spinal cord dysfunction: a mixed-methods study.

STUDY DESIGN: Mixed-methods study using comprehensive survey and semi-structured interviews. OBJECTIVES: Compare the experiences of sexual education during rehabilitation for people with non-traumatic spinal cord dysfunction (SCDys) and traumatic spinal cord injury (SCI), determine preferences for the delivery of this information and provide recommendations for spinal rehabilitation professionals. SETTING: Community, Australia. METHODS: Adults completed survey (traumatic SCI n=115; SCDys=39) or were interviewed (SCDys: n=21). Survey included questions regarding sexual education during rehabilitation, participant satisfaction with this and preferred modes for receiving such information. These themes were also explored during interviews. RESULTS: No difference between SCI and SCDys regarding satisfaction or preferred modes of presentation (all P>0.05). People with SCDys were less likely to report receiving sexuality education during rehabilitation (SCDys n=11, 30%; SCI n=61, 53%; P=0.03). Interviews suggested that this may be gendered, as only two women recalled receiving sexual education, whereas men often received this as part of continence management. Overall, only 18% were satisfied or very satisfied with sexual education and information received, and 36% were dissatisfied or very dissatisfied. Preferred modes for receiving sexuality information included sexuality counsellor (n=97), recommended internet sites (n=77), peer support workers (n=76), staff discussion (n=67), written information (n=67) and DVD (n=58). These preferences were confirmed during interviews, although women expressed a strong preference for written information sheets. CONCLUSION: There was very low satisfaction with sexuality education during rehabilitation. Our findings highlight the scope and directions for improving the sexual education and information given to people with both SCDys and SCI during rehabilitation.