Quality of life and patient-perceived symptoms in patients with psoriasis undergoing proactive or reactive management with the fixed-dose combination Cal/BD foam: A post-hoc analysis of PSO-LONG.

BACKGROUND: Psoriasis has important physical and psychosocial effects that extend beyond the skin. Understanding the impact of treatment on health-related quality of life (HRQoL) and patient-perceived symptom severity in psoriasis is key to clinical decision-making. OBJECTIVES: This post hoc analysis of the PSO-LONG trial data assessed the impact of long-term proactive or reactive management with fixed-dose combination calcipotriene 50 µg/g and betamethasone dipropionate 0.5 mg/g (Cal/BD) foam on patient-reported outcomes (PROs) in patients with psoriasis vulgaris. METHODS: Five hundred and twenty-one patients from the Phase 3, randomized, double-blind PSO-LONG trial were included. An initial 4-week, open-label phase of fixed-dose combination Cal/BD foam once daily (QD) was followed by a 52-week maintenance phase, at the start of which patients were randomized to a proactive management arm (Cal/BD foam twice weekly) or reactive management arm (vehicle foam twice weekly). Patient-perceived symptom severity and HRQoL were assessed using the Psoriasis Symptom Inventory (PSI), the Dermatology Life Quality Index (DLQI) and the EuroQol-5D for psoriasis (EQ-5D-5L-PSO). RESULTS: Statistically and clinically significant improvements were observed across all PRO measures. The mean difference (standard deviation) from baseline to Week 4 was -8.97 (6.18) for PSI, -6.02 (5.46) for DLQI and 0.11 (0.15) for EQ-5D-5L-PSO scores. During maintenance, patients receiving reactive management had significantly higher DLQI (15% [p = 0.007]) and PSI (15% [p = 0.0128]) and a numerically lower EQ-5D-5L-PSO mean area under the curve score than patients receiving proactive management (1% [p = 0.0842]). CONCLUSIONS: Cal/BD foam significantly improved DLQI, EQ-5D-5L-PSO and PSI scores during the open-label and maintenance phases. Patients assigned to proactive management had significantly better DLQI and PSI scores and numerically better EQ-5D-5L-PSO versus reactive management. Additionally, baseline flare was associated with worse PROs than the start of a relapse, and patients starting a relapse also had worse PROs than patients in remission.

The association between heart diseases and suicide: a nationwide cohort study.

OBJECTIVE: To assess the association between specific heart diseases and suicide. DESIGN: Nationwide retrospective cohort study. PARTICIPANTS: A total of 7 298 002 individuals (3 640 632 males and 3 657 370 females) aged ≥15 years and living in Denmark during 1980-2016. MAIN OUTCOME MEASURES: Incidence rate ratios (IRR) with 95% confidence intervals. In multivariate analysis, we adjust for sex, period, age group, living status, income level, Charlson Comorbidity Index, psychiatric disorders prior to heart disease and self-harm prior to heart disease. RESULTS: Excess suicide rate ratios were found for following disorders: heart failure (IRR: 1.48; 95% CI: 1.38-1.58); cardiomyopathy (IRR: 1.41; 95% CI: 1.16-1.70); acute myocardial infarction (IRR: 1.28; 95% CI: 1.21-1.36); cardiac arrest with successful resuscitation (IRR: 4.75; 95% CI: 3.57-6.33); atrial fibrillation and flutter (IRR: 1.42; 95% CI: 1.32-1.52); angina pectoris (IRR: 1.19; 95% CI: 1.12-1.26); and ventricular tachycardia (IRR: 1.53; 95% CI: 1.20-1.94). A higher rate of suicide was noted during the first 6 months after the diagnosis of heart failure (IRR: 2.38; 95% CI: 2.04-2.79); acute myocardial infarction (IRR: 2.24; 95% CI: 1.89-2.66); atrial fibrillation and flutter (IRR: 2.70; 95% CI: 2.30-3.18); and angina pectoris (IRR: 1.83; 95% CI: 1.53-2.19) when compared to later. CONCLUSION: Several specific disorders were found to be associated with elevated rates of suicide. Additionally, we found temporal associations with higher suicide rates in the first time after diagnosis. Our results underscore the importance of being attentive towards psychological distress in individuals with heart disease.

Association between body mass index and sperm quality and sperm DNA integrity. A large population study.

This study aimed to analyse whether the functional quality of spermatozoa is associated with body mass index (BMI). Semen samples were obtained from 1824 men undergoing fertility evaluation/treatment. Semen analysis was performed using World Health Organization (WHO) criteria, and morphology was evaluated with the motile sperm organelle morphology examination (MSOME). The percentages of sperm DNA fragmentation (using TdT (terminal deoxynucleotidyl transferase)-mediated dUTP nick-end labelling (TUNEL) assays), sperm chromatin packaging/underprotamination (using chromomycin A3/CMA3 ), mitochondrial damage (using MitoTracker Green) and apoptosis (using annexin V) were also assessed. At least 200 spermatozoa were examined in each evaluation. The following BMI values were used as cut-off points: ≤24.9 kg/m2 , 25-29.9 kg/m2 (overweight) and ≥30 kg/m2 (obese). High BMI negatively affects sperm concentration, vitality, motility and morphology (p < .05). Conversely, high BMI does not seem to be associated with impaired sperm DNA integrity, as assessed by DNA fragmentation, sperm protamination and sperm apoptosis (p > .05). However, increased BMI is associated with increased mitochondrial damage in spermatozoa (p < .05). In conclusion, given the adverse consequences of obesity and the possible effect of male BMI on assisted reproduction technology (ART) outcomes, the benefits of weight reduction should be discussed when counselling couples interested in fertility treatment.

Biallelic ß-carotene oxygenase 2 knockout results in yellow fat in sheep via CRISPR/Cas9.

The recently emerged CRISPR/Cas9 approach represents an efficient and versatile genome editing tool for producing genetically modified animals. Β-carotene oxygenase 2 (BCO2) is a key enzyme in the progress of ß-carotene metabolism and is associated with yellow adipose tissue color in sheep. We have recently demonstrated targeted multiplex mutagenesis in sheep and have generated a group of BCO2-disrupted sheep by zygote injection of the CRISPR/Cas9 components. Here, we show that biallelic modification of BCO2 resulted in yellow fat, compared with the fat color in monoallelic individuals and wild types (snow-flower white). We subsequently characterized the effects of gene modifications at genetic levels employing sequencing and Western blotting, highlighting the importance of the BCO2 gene for the determination of fat color in sheep. These results indicate that genetic modification via CRISPR/Cas9 holds great potential for validating gene functions as well as for generating desirable phenotypes for economically important traits in livestock.

Beneficial Immune Effects of Myeloid-Related Proteins in Kidney Transplant Rejection.

Acute rejection is a risk factor for inferior long-term kidney transplant survival. Although T cell immunity is considered the main effector in clinical acute rejection, the role of myeloid cells is less clear. Expression of S100 calcium-binding protein A8 (S100A8) and S100A9 was evaluated in 303 biopsies before and after transplantation from 190 patients. In two independent cohorts of patients with acute rejection (n = 98 and n = 11; mostly cellular rejections), high expression of S100 calcium-binding protein A8 (S100A8) and A9 (S100A9) was related to improved graft outcome. Mechanisms of action of the S100 molecules were investigated. In the graft and peripheral blood cells, S100A8 and S100A9 expression correlated with myeloid-derived suppressor markers. In line with this finding, recombinant S100A8 and S100A9 proteins inhibited maturation and the allogeneic T cell stimulatory capacity of dendritic cells. S100A9 enhanced the production of reactive oxygen species by macrophages, which suppressed T cell activity at low concentrations in the form of hydrogen peroxide. Intragraft S100A8 and S100A9 expression linked to reduced expression of T cell immunity and tissue injury markers and higher expression of immune regulatory molecules. This study sheds new light on the importance of myeloid cell subsets in directing the outcome of T cell-mediated acute rejection.

Pulse photodynamic therapy reduces inflammation without compromising efficacy in the treatment of multiple mild actinic keratoses of the face and scalp: a randomized clinical trial.

BACKGROUND: The main side-effects of photodynamic therapy (PDT) for actinic keratoses (AKs) are post-treatment erythema and oedema, and pain during illumination. Severe erythema after PDT enhances the down time associated with the treatment. OBJECTIVES: To evaluate in a randomized intraindividual study whether pulse-PDT and corticosteroid pulse-PDT would reduce treatment-induced erythema compared with conventional PDT. METHODS: Twenty-two patients with multiple mild AKs on the face and scalp were treated with methyl aminolaevulinate (MAL)-PDT in three similar areas. Two areas were incubated with MAL for 30 min (pulse-PDT) and one area was incubated with MAL for 3 h (conventional PDT). All areas were illuminated with red light after 3 h. In one of the pulse-PDT areas a superpotent corticosteroid was applied before and just after PDT (S-pulse-PDT). RESULTS: Pulse-PDT significantly reduced PDT-induced erythema (P = 0·020), and erythema was even further reduced by S-pulse-PDT (P < 0·001). The complete lesion response rate 3 months after PDT did not differ significantly between the three treated areas. CONCLUSIONS: Pulse-PDT and S-pulse-PDT reduced erythema 24 h after treatment of multiple mild AKs on the face and scalp. The use of a short MAL application time and topical corticosteroid did not affect the efficacy of PDT and may be an easy way to make PDT treatment of large visible areas more acceptable.

Defining "intermittent UVR exposure".

BACKGROUND: Cutaneous malignant melanoma (CMM) has been associated with "intermittent UVR exposure", which in previous studies has mainly been assessed by retrospective questionnaire data. Further, there is no uniform definition of the term "intermittent UVR exposure". OBJECTIVES: We aimed to define and quantify "intermittent UVR exposure" by an objective measure. METHODS: A broad study population of adults and children had data collected during a summer period. Data were personal UVR dosimetry measurements, from which the number of "intermittent days" was derived, sun behaviour diaries and retrospective questionnaires. Two definitions of intermittent UVR exposure were tested: (1) days when UVR dose exceeded 3 times individual average daily UVR dose, and (2) days when UVR dose exceeded individual constitutive skin type. Measures of nevi and lentigines were used as surrogates for CMM. RESULTS: Using the first definition based solely on UVR dosimetry data we found 1241 "intermittent days" out of a total of 17 277 days (7.2%) among 148 participants. The numbers for nevi and lentigo density were significantly predicted by the number of intermittent days (R(2) = 0.15 and R(2) = 0.40, p < 0.001). The corresponding numbers for prediction of nevi and lentigo density by retrospective questionnaire data was lower (R(2) = 0.11, R(2) = 0.26, p < 0.001). CONCLUSIONS: We introduce a well-defined objective measure of intermittent UVR exposure. This measure may provide a better prediction of solar skin damage and CMM than retrospective questionnaire data.

[Telephone enquiries on the topic of malignant hyperthermia: Evaluation of the content and subsequent diagnostic results at the MH Center Leipzig]. / Telefonische Anfragen zum Thema maligne Hyperthermie: Auswertung der Inhalte und der resultierenden Diagnostikergebnisse am MH-Zentrum Leipzig.

BACKGROUND: Malignant hyperthermia (MH) is an autosomal dominant metabolic myopathy. The in vitro contracture test (IVCT) is still considered to be the gold standard for diagnosing a disposition for MH. However, advances in genetic testing for MH disposition have supplemented or even replaced the invasive procedure of the IVCT. Information about MH can be obtained by either contacting the hotline for MH as a nationwide 24 h/7 days a week service or one of the regional MH centers. METHODS: The protocols of telephone conversations concerning MH at the MH Center University Leipzig were retrospectively analyzed. Data were collected from January 2011 to March 2015. Additionally, the results of the IVCT and genetic testing evolving from the counseling interviews were examined. RESULTS: A total of 205 telephone calls were documented during the period in question and an IVCT was performed as a consequence of 112 of the telephone calls. The IVCT resulted in 27 individuals being identified as MH susceptible which was subsequently diagnosed in 15 individuals with known familial MH disposition and 12 individuals were identified as new index patients. In 24 individuals a total of 13 different mutations were detected and of these 4 mutations were causative concerning MH. Of the 205 telephone calls 131 were private and 74 of medical professional origin. Among the private enquiries MH disposition within the family was a frequent reason for contacting the MH Center (61.8%). Conversations relating to MH-like symptoms during general anesthesia were carried out with 35.1% of medical doctors and with 22.9% of private callers. Advice about neuromuscular symptoms of unknown genesis was given to 15.3% of private individuals and to 24.3% of medical doctors. Overall MH topics were discussed with 23% (N = 17) of the medical profession and approximately half of these were anesthesiologists (N = 8). Not a single call was documented for the treatment of a suspected MH crisis. CONCLUSION: Private individuals and families affected by a MH disposition often showed good compliance with respect to counseling and diagnostics for MH and contacted the MH center more often than medical doctors. A more comprehensive cooperation with the medical profession is preferable and necessary to obtain a systematic and broad synopsis of characteristic and uncharacteristic signs and symptoms of MH. The telephone conversations analyzed as well as the diagnostic results (IVCT and genetic testing) underline that MH disposition is still a current and relevant topic.

siRNA mediated knockdown of tissue factor expression in pigs for xenotransplantation.

Acute vascular rejection (AVR), in particular microvascular thrombosis, is an important barrier to successful pig-to-primate xenotransplantation. Here, we report the generation of pigs with decreased tissue factor (TF) levels induced by small interfering (si)RNA-mediated gene silencing. Porcine fibroblasts were transfected with TF-targeting small hairpin (sh)RNA and used for somatic cell nuclear transfer. Offspring were analyzed for siRNA, TF mRNA and TF protein level. Functionality of TF downregulation was investigated by a whole blood clotting test and a flow chamber assay. TF siRNA was expressed in all twelve liveborn piglets. TF mRNA expression was reduced by 94.1 ± 4.7% in TF knockdown (TFkd) fibroblasts compared to wild-type (WT). TF protein expression in PAEC stimulated with 50 ng/mL TNF-α was significantly lower in TFkd pigs (mean fluorescence intensity TFkd: 7136 ± 136 vs. WT: 13 038 ± 1672). TF downregulation significantly increased clotting time (TFkd: 73.3 ± 8.8 min, WT: 45.8 ± 7.7 min, p < 0.0001) and significantly decreased thrombus formation compared to WT (mean thrombus coverage per viewing field in %; WT: 23.5 ± 13.0, TFkd: 2.6 ± 3.7, p < 0.0001). Our data show that a functional knockdown of TF is compatible with normal development and survival of pigs. TF knockdown could be a valuable component in the generation of multi-transgenic pigs for xenotransplantation.

Light protection of the skin after photodynamic therapy reduces inflammation: an unblinded randomized controlled study.

BACKGROUND: Photodynamic therapy (PDT) is followed by significant inflammation. Protoporphyrin (Pp)IX is still formed in the skin after PDT and patients are sensitive to daylight 24-48 h after treatment. Exposure to daylight after PDT may therefore increase inflammation. OBJECTIVES: To investigate whether protection with inorganic sunscreen, foundation or light-blocking plaster after PDT can reduce inflammation caused by daylight-activated PpIX. METHODS: On the right arm of 15 subjects with sun-damaged skin, four identical squares (3 × 3 cm) were given conventional PDT treatment. Immediately after red-light illumination the squares were either left unprotected or protected by inorganic sunscreen [sun protection factor (SPF) 50], foundation (SPF50) or light-blocking plaster. The skin was then illuminated with artificial daylight for 2 h and afterwards covered for 24 h. Fluorescence and erythema (inflammation) were measured with a fluorescence camera and a reflectance meter. RESULTS: PpIX was significantly reduced after artificial daylight illumination (P < 0·0004), except on the square protected with light-blocking silver plaster, where it had increased (P = 0·09). The increased erythema 24 h after treatment was reduced by 19% with the sunscreen (P = 0·29), by 27% with the foundation (P = 0·10) and by 44% with the silver plaster (P = 0·002). CONCLUSIONS: Artificial daylight exposure after conventional PDT increases skin erythema. Light-blocking plaster gives more effective protection against post-PDT daylight exposure than inorganic sunscreen and foundation. In practice such full protection can be achieved by use of sun-blocking clothes or daylight avoidance for 24 h.

Topical corticosteroid reduces inflammation without compromising the efficacy of photodynamic therapy for actinic keratoses: a randomized clinical trial.

BACKGROUND: Photodynamic therapy (PDT) is an effective and established treatment for actinic keratoses (AK) and nonmelanoma skin cancer. The main side-effects of PDT are post-treatment erythema and oedema, and pain during illumination. Severe erythema after PDT enhances the down time associated with the treatment. OBJECTIVES: To evaluate in a randomized intraindividual study whether use of a topical corticosteroid just before and just after PDT would reduce treatment-induced erythema compared with conventional PDT. METHODS: Twenty-two patients with multiple AKs in the face and scalp were treated with methyl aminolaevulinate PDT in two symmetrical areas. One area was randomized to superpotent corticosteroid (clobetasol propionate) before and just after PDT. Objective and visual erythema, protoporphyrin IX (PpIX) fluorescence and pain were evaluated. RESULTS: Topical corticosteroid significantly reduced PDT-induced erythema (P = 0·012). The complete lesion response rate 3 months after PDT, and PpIX fluorescence prior to illumination did not differ significantly between the two treated areas. CONCLUSIONS: Superpotent corticosteroid before and just after PDT reduced the erythema 24 h after treatment of multiple AKs on the face and scalp. The use of topical corticosteroid did not affect the efficacy of PDT and may be an easy way to make PDT treatment of large visible areas more acceptable.

UVR exposure and vitamin D in a rural population. A study of outdoor working farmers, their spouses and children.

BACKGROUND: Living and working in the countryside may result in excessive UVR exposure, with increased risk of skin cancer. Some sun exposure is, however, recommended, since vitamin D production is UVB-dependent. OBJECTIVES: To examine UVR exposure and vitamin D levels in a rural population of outdoor working male farmers, their indoor working spouses and their children, expected to receive high UVR exposure. METHODS: Prospective, cohort study. During the summer 2009 daily, personal UVR exposure and sun behaviour were recorded by dosimetry and diaries (17 403 days). Vitamin D was measured at the end of summer and the following winter. RESULTS: Risk behaviour (= exposure of shoulders/upper body to the sun), beach days, sunscreen use and sunburns were infrequent. Farmers and boys had the highest daily UVR exposure (both 1.5 SED per day), likewise on work days. On non-work days the UVR exposure was even higher (up to 2.0 SED per day). Farmers, girls and boys had a higher chronic UVR exposure than the spouses, who had more intermittent high UVR exposure. Vitamin D levels did not differ between family members. At the end of summer 16% of the participants were vitamin D insufficient, the following winter, 61%. Some UVR exposure variables correlated positively, but weakly, with vitamin D levels. CONCLUSIONS: UVR exposure was generally high among this study population, however, vitamin D levels still dropped below the recommended level during winter for most participants. Differences in UVR exposure between the groups did not result in differences in vitamin D levels.

Gene knockout and knockin by zinc-finger nucleases: current status and perspectives.

Zinc-finger nucleases (ZFNs) are engineered site-specific DNA cleavage enzymes that may be designed to recognize long target sites and thus cut DNA with high specificity. ZFNs mediate permanent and targeted genetic alteration via induction of a double-strand break at a specific genomic site. Compared to conventional homology-based gene targeting, ZFNs can increase the targeting rate by up to 100,000-fold; gene disruption via mutagenic DNA repair is similarly efficient. The utility of ZFNs has been shown in many organisms, including insects, amphibians, plants, nematodes, and several mammals, including humans. This broad range of tractable species renders ZFNs a useful tool for improving the understanding of complex physiological systems, to produce transgenic animals, cell lines, and plants, and to treat human disease.

Laparoscopic-Assisted ERCP in Gastric Bypass Patients-No Stones Left Unturned: A Single Center Retrospective Cohort Study.

PURPOSE: The long-term need for biliary duct intervention following Roux-en-Y gastric bypass surgery (RYGB) is uncertain. We investigated the rate of laparoscopic assisted retrograde cholangiopancreatography (LAERCP) following RYGB. Also, the pre-LAERCP diagnostic workup together with the true rate of choledocholithiasis in patients with or without prior cholecystectomy was investigated. MATERIALS AND METHODS: Retrospective cohort study of RYGB and LAERCP performed at the Hospital South West Jutland, University Hospital of Southern Denmark, from 1 January 2013 to 31 May 2022. RESULTS: One percent of patients (n = 13) with a history of RYGB (n = 1363) underwent LAERCP at our facility during a median follow-up of 60.6 months. The stone extraction rate was 66.7% in patients with in situ gallbladder and 12.5% in patients with prior cholecystectomy. Cannulation of the common bile duct was achieved in 96.7% of cases. Postoperative complications were observed in 22.6% of the cases. CONCLUSION: Approximately 1% of RYGB patients needed LAERCP during a median follow-up of 5 years. In patients with a history of cholecystectomy, the LAERCP rate of stone extraction was very low (12.5%).

Determinants of personal ultraviolet-radiation exposure doses on a sun holiday.

BACKGROUND: A great number of journeys to sunny destinations are sold to the Danish population every year. We suspect that this travel considerably increases personal annual ultraviolet-radiation (UVR) exposure doses. This is important because such exposure is the main cause of skin cancer, and studies have shown a correlation between intermittent solar UVR exposure and malignant melanoma. OBJECTIVES: To prospectively monitor the behaviour of a group of sun seekers during a winter sun holiday and to study the impact of behaviour on personal UVR exposure doses. METHODS: In this observational study 25 Danish sun seekers were closely monitored by on-site investigators for 6 days during a winter sun holiday in the Canary Islands, thus avoiding the possible recall bias of retrospective studies with questionnaires. The volunteers recorded their location, clothing and sunscreen use in diaries, and their UVR doses were measured by personal UVR dosimeters worn on the wrist. This resulted in 3450 half-hour registrations during 150 participation days. RESULTS: On average, each volunteer received a total UVR dose of 57 standard erythema doses over 6 days, which is 43% of the annual UVR dose of a Danish indoor worker. Their exposed body area, sunscreen use and percentage of body with sunscreen application were positively correlated with their personal UVR doses, and there was also a strong relationship between location and UVR doses received. CONCLUSIONS: The behaviour of the volunteers had a major impact on their personal UVR doses. Our results emphasize the importance of changing the behaviour of sun seekers with protanning attitudes to reduce their personal annual UVR exposure doses, and possibly their risk of skin cancer.

Single-session ERCP in patients with previous Roux-en-Y gastric bypass using percutaneous-assisted transprosthetic endoscopic therapy: a case series.

Endoscopic retrograde cholangiopancreatography (ERCP) remains technically challenging following Roux-en-Y gastric bypass (RYGB). Various techniques have been described to access the excluded stomach. We describe our experience using percutaneous-assisted transprosthetic endoscopic therapy (PATENT) to perform antegrade ERCP. Balloon enteroscopy was used to access the excluded stomach. Direct retrograde percutaneous endoscopic gastrostomy (RPEG) was performed and an esophageal self-expandable metal stent (SEMS) was deployed within the gastrostomy tract. A duodenoscope was advanced through the SEMS and antegrade ERCP was performed. Following ERCP, a gastrostomy tube was placed through the SEMS to maintain patency. Five patients underwent successful antegrade ERCP using PATENT. All patients had a diagnosis of sphincter of Oddi dysfunction. Biliary sphincterotomy was performed in all patients and liver enzymes normalized in four patients with preprocedural elevations. In conclusion, antegrade ERCP employing PATENT is feasible and can be performed during a single endoscopic session in patients with previous RYGB.

Validation of self-reported erythema: comparison of self-reports, researcher assessment and objective measurements in sun worshippers and skiers.

BACKGROUND: Most epidemiological data of sunburn related to skin cancer have come from self-reporting in diaries and questionnaires. We thought it important to validate the reliability of such data. OBJECTIVE: To validate the quality of self-reported erythema by sun worshippers and skiers, and to validate the ability to determine erythema visually compared with objectively measured erythema. METHODS: The skin in a group of sun worshippers in Tenerife and of skiers in Austria was closely monitored over a week. The participants used a diary to record any erythema assessed on different skin sites and underwent a twice daily skin examination by researchers who assessed erythema on the same sites. Lastly, the erythema assessment was validated by objective measurements. RESULTS: We found that the participants' agreed with researchers' assessment of erythema in only 57-61% of cases, and that the researchers detected up to 28% more of the objectively measured erythema than the participants did. We also found that, even for the trained eye (researchers), it was difficult to detect an increase in erythema as only 71-91% of those cases with an increase >15 in measured erythema percentage were detected in the evening. Possibly, detection was impeded by a simultaneous increase in pigmentation. CONCLUSION: Self-assessment of erythema from diaries is unreliable. Erythema is considerably underestimated and possibly neglected. Even for the trained eye, it can be difficult to detect erythema.

No need for rescue medication (NNR) as an easily interpretable efficacy outcome measure in analgesic trials: validation in an individual-patient meta-analysis of dental pain placebo-controlled trials of naproxen.

WHAT IS KNOWN AND OBJECTIVE: In analgesic trials, pain relief is often assessed using a pain-relief score. We aimed to assess, through a meta-analysis, whether absence of need for rescue medication (NNR) is a reliable outcome measure in the evaluation of acute pain relief. METHODS: Individual-patient meta-analysis of placebo-controlled trials of single-dose naproxen sodium 220 or 440 mg in dental pain. Efficacy estimates were based on NNR and compared with the more commonly used 50% maximum total pain relief score (50% TOTPAR). The trials included were the full set of trials sponsored by one manufacturer. RESULTS AND DISCUSSION: Need for rescue medication and 50% TOTPAR gave comparable estimates of efficacy of naproxen sodium (220 and 440 mg) relative to placebo in dental pain at both 8 and 12 h after dosing. WHAT IS NEW AND CONCLUSION: No need for rescue medication is a reliable outcome measure for use in acute pain trials. As it is more readily understandable than 50% TOTPAR, it should be the preferred primary outcome measure in acute pain trials.

Cortical plasticity after cochlear implantation.

The most dramatic progress in the restoration of hearing takes place in the first months after cochlear implantation. To map the brain activity underlying this process, we used positron emission tomography at three time points: within 14 days, three months, and six months after switch-on. Fifteen recently implanted adult implant recipients listened to running speech or speech-like noise in four sequential PET sessions at each milestone. CI listeners with postlingual hearing loss showed differential activation of left superior temporal gyrus during speech and speech-like stimuli, unlike CI listeners with prelingual hearing loss. Furthermore, Broca's area was activated as an effect of time, but only in CI listeners with postlingual hearing loss. The study demonstrates that adaptation to the cochlear implant is highly related to the history of hearing loss. Speech processing in patients whose hearing loss occurred after the acquisition of language involves brain areas associated with speech comprehension, which is not the case for patients whose hearing loss occurred before the acquisition of language. Finally, the findings confirm the key role of Broca's area in restoration of speech perception, but only in individuals in whom Broca's area has been active prior to the loss of hearing.