Fazirsiran for Liver Disease Associated with Alpha1-Antitrypsin Deficiency.

BACKGROUND: Alpha1-antitrypsin (AAT) deficiency results from carriage of a homozygous SERPINA1 "Z" mutation (proteinase inhibitor [PI] ZZ). The Z allele produces a mutant AAT protein called Z-AAT, which accumulates in hepatocytes and can lead to progressive liver disease and fibrosis. This open-label, phase 2 trial investigated the safety and efficacy of fazirsiran, an RNA interference therapeutic, in patients with liver disease associated with AAT deficiency. METHODS: We assigned adults with the PI ZZ genotype and liver fibrosis to receive fazirsiran at a dose of 200 mg (cohorts 1 [4 patients] and 2 [8 patients]) or 100 mg (cohort 1b [4 patients]) subcutaneously on day 1 and week 4 and then every 12 weeks. The primary end point was the change from baseline to week 24 (cohorts 1 and 1b) or week 48 (cohort 2) in liver Z-AAT concentrations, which were measured by means of liquid chromatography-mass spectrometry. RESULTS: All the patients had reduced accumulation of Z-AAT in the liver (median reduction, 83% at week 24 or 48). The nadir in serum was a reduction of approximately 90%, and treatment was also associated with a reduction in histologic globule burden (from a mean score of 7.4 [scores range from 0 to 9, with higher scores indicating a greater globule burden] at baseline to 2.3 at week 24 or 48). All cohorts had reductions in liver enzyme concentrations. Fibrosis regression was observed in 7 of 15 patients and fibrosis progression in 2 of 15 patients after 24 or 48 weeks. There were no adverse events leading to trial or drug discontinuation. Four serious adverse events (viral myocarditis, diverticulitis, dyspnea, and vestibular neuronitis) resolved. CONCLUSIONS: In this small trial, fazirsiran was associated with a strong reduction of Z-AAT concentrations in the serum and liver and concurrent improvements in liver enzyme concentrations. (Funded by Arrowhead Pharmaceuticals; AROAAT-2002 ClinicalTrials.gov number, NCT03946449.).

Ego Depletion as a Measure of Emotion Processing Deficits among MUS Patients.

Previous studies have found a link between emotion processing deficits and medically unexplained physical symptoms (MUS). The majority of previous studies have used self-report measures of emotional processing, with the majority focusing on alexithymia, and have produced inconsistent and contradictory results. In the present study, we investigated the role of emotion-processing deficits in MUS by assessing emotion regulation performance and the effects of performance on ego depletion. Participants with high or low levels of self-reported MUS watched emotion-evoking videos under instructions to allow or suppress their emotional reactions, and then performed an anagram task to measure their effort and perseverance. Contrary to the research with self-report measures, experimental analysis of emotion-processing revealed that MUS is correlated with the inability to regulate negative emotions. Unexpected self-regulatory tendencies of the participants with high symptom levels were discussed.

The Utian Quality of Life (UQOL) Scale: development and validation of an instrument to quantify quality of life through and beyond menopause.

OBJECTIVE: Quality of life (QOL) is an outcome variable requiring measurement in clinical care or pivotal regulatory trial research. Current menopause QOL measures are mostly life phase or disease symptom inventories or scores. Believing that QOL should refer more to "sense of well-being," we have developed the Utian QOL scale (UQOL) that is strongly based on perception of sense of well-being as distinct from menopausal symptoms. DESIGN: A pool of items sampling various aspects of well-being was developed. Peri- and postmenopausal women (n = 327) responded to the items, and their responses were subjected to a factor analysis. Four factors emerged, each representing a QOL domain. The resulting 23-item instrument was validated in a geographically and socioeconomically diverse sample of peri- and postmenopausal women using the Short Form-36, an established, frequently used QOL inventory. QOL domains were subjected to confirmatory factor analyses, formal item analysis was completed, and the measure was assessed for reliability and validity, including a second sample of women (n = 270). RESULTS: Women (n = 597; mean age, 52.9 years) from 12 communities across the United States completed the measure. The UQOL seems to reflect four components of QOL: occupational QOL, health QOL, emotional QOL, and sexual QOL. The questionnaire and scoring system are presented. CONCLUSION: We are reporting on the process of validating an instrument for quantifying sense of well-being in a perimenopausal population. Substantial reliability and validity estimates for the scale and its subscales support the UQOL as a valuable new tool for use in clinical research and practice.

The role of perceived sleep norms in subjective sleep appraisals and sleep-related illness behavior.

The present investigation sought to extend extant research on subjective sleep complaints by examining their relation to perceived sleep norms. Results from two studies showed that individuals' distress and illness behavior in response to symptoms of fatigue and non-restorative sleep was influenced by their perceptions of peer norms for those symptoms. Individuals who believed they experienced a greater degree of fatigue and non-restorative sleep than their peers reported more distress arising from those symptoms, and were also more likely to seek social support and medical treatment for them. Furthermore, participants who scored higher in neuroticism were more likely to believe they experienced worse fatigue and non-restorative sleep than their peers, and thus reported higher symptom-related distress, and higher likelihood of engaging in illness behaviors. These results provide preliminary evidence of the clinical relevance of perceived norms in the way individuals respond to and manage sleep related problems.

Family experience in a regional participant contact registry for research on intellectual disability.

Participant recruitment is one of the most significant challenges in research on intellectual disability (ID). One potential solution is to develop a participant contact registry, which allows the researcher to contact participants directly rather than recruiting through multiple schools or service agencies. The authors describe the development of one such registry and results of a survey of registry families. Results suggest that families joined the registry to help others, they hope research in the ID field improves the daily lives of individuals with ID and their families, and they find research participation to be a positive experience. However, logistic concerns can be an important barrier to their research participation, and they would like more information about the research study both before and after participating.

Somatoform, factitious, and related diagnoses in the national hospital discharge survey: addressing the proposed DSM-5 revision.

BACKGROUND: The DSM-5 working group on the somatoform (SFD) and factitious (FD) disorders has recommended substantial revisions of these categories. The recommendations are based, in part, on anecdotal evidence that the diagnoses are infrequently used. OBJECTIVE: To assess the assignment rates for SFD, FD, and related diagnoses among general medical inpatients. METHOD: The National Hospital Discharge Survey was queried for instances of SFD and FD, along with related diagnoses identifying medical cases in which psychological factors play a role. Diagnoses of major depression and generalized anxiety disorder were queried for comparison purposes. RESULTS: The target diagnoses were assigned far less frequently than published prevalence and recognition rates suggest. Nearly half of the assigned target diagnoses were generic diagnoses (esp. physiological malfunction due to psychological factors) other than SFD or FD. However, the apparent degree of underassignment of the target diagnoses was not dramatically greater than the underassignment observed for major depression and generalized anxiety disorder. CONCLUSION: The results provide empirical support for the impression that physicians do not assign SFD and FD diagnoses in recognized cases, but do not strongly support the assertion that these diagnoses are uniquely problematic.

Physician-based estimates of medically unexplained symptoms: a comparison of four case definitions.

BACKGROUND: Medically unexplained symptoms (MUS) are considered a common occurrence in medical settings, although definitions, methodologies and resulting prevalence rates for MUS vary widely between studies. OBJECTIVES: The objective of the present study was to characterize physicians' estimates of MUS, including clinically significant MUS, and to demonstrate in a single study how estimates vary based on the definition used. METHODS: Two hundred and thirteen physicians completed an online questionnaire regarding the number of patients who present to their clinic with MUS. To reduce memory biases, participants reported on the number of patient seen in their most recent clinic day who met increasingly restrictive case definitions for MUS. Weekly estimates were also obtained. RESULTS: The least restrictive definition yielded an estimate of 11%. When certainty criteria were added to the definition of MUS, the estimate decreased considerably to 4%. Approximately 3% of patients were estimated to have chronic MUS that affected their daily functioning or caused significant distress (i.e. psychologically significant MUS), and only half of these, 1.5%, were assigned a diagnosis of somatoform disorder or factitious disorder. The proportion of MUS cases accounted for by malingering was 18%. CONCLUSIONS: The present study documents significantly lower estimates of MUS than chart review studies. However, our results suggest that a significant proportion of the total number of patients who present with MUS have abnormal illness behaviour associated with significant impairment or distress. Despite physicians' recognizing significant distress and dysfunction in these cases, formal diagnoses of somatoform or factitious disorder are rarely assigned.

In vivo evaluation of DIAGNOdent for the quantification of occlusal dental caries.

The accurate diagnosis of non-cavitated occlusal caries is generally considered problematic. Induced fluorescence quantified by the DIAGNOdent device (KaVo) gives a reading from 0-99, which may help in the caries diagnostic process. There is some controversy around the implication of increased severity of decay with increased DIAGNOdent readings. This in vivo study assessed the correlation of depth and volume of decay as it was removed by traditional rotary handpieces with DIAGNOdent readings and determined sensitivities/specificities of the device at different cut-off points. Included in the current study were 31 patients providing 60 permanent molar and premolar occlusal surfaces suspected of dentinal decay. DIAGNOdent readings were recorded, along with lesion depth (as measured by periodontal probe) and volume measurements (as calculated from measuring the mass of a polyvinyl siloxane impression of the cavity, divided by the material's calculated density). Clinical detection of decay at the DEJ was used as the gold-standard to calculate an appropriate cut-off. Pearson correlation coefficients indicated that DIAGNOdent readings were weakly correlated with lesion depth (r = 0.47) and lesion volume (also r = 0.47). An appropriate cut-off point for the sample in the current study was calculated between 35 and 40; a more specific cut-off point could not be determined due to the sample size distribution. It was concluded that the DIAGNOdent device should be used as an adjunct in the caries diagnosis and treatment planning process.

The A, B, C's of factitious disorder: a response to Turner.

The fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-V) is being prepared, but little attention has been accorded the category of factitious disorder, despite its presence in the manual for almost 30 years. Among relevant articles that have appeared, Turner's publication advocates retention of the category, but with new criteria. In the current paper, we reject Turner's reformulation but use the identified diagnostic dilemmas to illuminate the phenomenology of factitious disorder. We also offer a reconceptualization of the diagnosis that should better inform the preparations for DSM-V.

Tooth bleaching and pit and fissure stain.

PURPOSE: To investigate if tooth whitening had any effect on the shade of occlusal pit and fissure stains and whether reservoirs in bleaching trays affected bleaching of occlusal pit and fissure stains. METHODS: 96 extracted molars were randomly divided into three paired groups for whitening using a 10% carbamide peroxide solution (Opalescence) or a 22% carbamide peroxide solution (Nite White Excel 3), or tap water for a control. One of each pair utilized reservoirs in their custom bleaching trays. Three dentists evaluated the shade of a specified occlusal area of pit and fissure stain twice before bleaching and twice after bleaching. RESULTS: Pit and fissure stain showed significant lightening of shade for either of the bleaching systems (P < 0.0005) but not the control (P = 0.816). There was no significant difference in pit and fissure stain shade lightening following treatment between those groups utilizing reservoirs in the custom trays and those without reservoirs (P = 0.658).

DIAGNOdent measurements and correlation with the depth and volume of minimally invasive cavity preparations.

In this clinical study, DIAGNOdent (KaVo) was used to assess previously diagnosed carious lesions in the pits and fissures of first and second molars. The measurements from this device were correlated with the depth and volume of the cavity preparations that resulted from minimal intervention to remove occlusal carious lesions. Twenty-five patients, 18 years of age and older, who were previously scheduled for an occlusal restoration due to caries, were recruited and enrolled in this clinical study. These patients had 48 qualifying teeth without previous restorations, sealants or other carious lesions. The occlusal surface of each study tooth was cleaned utilizing ProphyFlex2 (KaVo). Two dentists separately traced the pit and fissure system of each tooth using DIAGNOdent for two 15-second periods each. The peak reading of each of the four measurements was recorded. An impression of the occlusal surface of each tooth was recorded with a polyvinyl siloxane bite registration material. The carious lesions were removed with an air abrasion unit employing a 0.015-inch nozzle opening utilizing minimal operative intervention. A low viscosity polyvinyl siloxane was used to take an impression of the cavity preparation impression, using the bite registration impression to form the occlusal surface of the preparation impression. The preparation impression volume was calculated from its weight, using the known density of the impression material. The greatest depth of the preparation was measured. The Pearson correlation coefficient was used to investigate any relationship between depth or volume of the preparation impression and the DIAGNOdent measurements. The correlation for preparation volume and maximum DIAGNOdent measurement was 0.191 (p = 0.189). Other logical subsets of cases also did not result in any statistically significant correlations between the DIAGNOdent readings and the depth or volume of the final cavity preparations.

Should a dental explorer be used to probe suspected carious lesions? Yes--an explorer is a time-tested tool for caries detection.

The caries rate is dropping worldwide, a fact that appears to have no relationship to whether dentists in the affected countries use an explorer to probe suspected carious lesions. Questions have been raised about this procedure on the basis of the purported inaccuracy of its contribution to caries diagnosis, its possible spread of infective plaque from other teeth in the mouth or the damage it can cause to pits and fissures. Longterm randomized clinical trials are necessary in these areas of question, trials that use endpoints that are clear and meaningful to clinical dentists. Until the time comes that facts emerge from acceptable long-term clinical trials, dentists should feel comfortable using the dental explorer to probe suspected carious lesions.

Treatment decisions and conservation of tooth structure.

New technology is becoming available to help establish an early diagnosis of incipient and hidden pit and fissure caries, and microdentistry techniques are being developed to follow the principles of minimal intervention. Following the accurate diagnosis of suspected lesions, early intervention can be in the form of chemotherapeutics to promote remineralization or conservative intervention to minimize tooth structure loss. Patient risk factors should have a role in developing and individualized treatment program. The life cycle of a restored molar is used in this article to illustrate the long-term value of early diagnosis, preventive therapy, and conservative intervention to preserve tooth structure and to extend the retention of healthy teeth.

The Utian Quality of Life (UQOL) Scale: development and validation of an instrument to quantify quality of life through and beyond menopause.

OBJECTIVE: Quality of life (QOL) is an outcome variable requiring measurement in clinical care or pivotal regulatory trial research. Current menopause QOL measures are mostly life phase or disease symptom inventories or scores. Believing that QOL should refer more to "sense of well-being," we have developed the Utian QOL scale (UQOL) that is strongly based on perception of sense of well-being as distinct from menopausal symptoms. DESIGN: A pool of items sampling various aspects of well-being was developed. Peri- and postmenopausal women (n = 327) responded to the items, and their responses were subjected to a factor analysis. Four factors emerged, each representing a QOL domain. The resulting 23-item instrument was validated in a geographically and socioeconomically diverse sample of peri- and postmenopausal women using the Short Form-36, an established, frequently used QOL inventory. QOL domains were subjected to confirmatory factor analyses, formal item analysis was completed, and the measure was assessed for reliability and validity, including a second sample of women (n = 270). RESULTS: Women (n = 597; mean age, 52.9 years) from 12 communities across the United States completed the measure. The UQOL seems to reflect four components of QOL: occupational QOL, health QOL, emotional QOL, and sexual QOL. The questionnaire and scoring system are presented. CONCLUSION: We are reporting on the process of validating an instrument for quantifying sense of well-being in a perimenopausal population. Substantial reliability and validity estimates for the scale and its subscales support the UQOL as a valuable new tool for use in clinical research and practice.

Early treatment of incipient carious lesions: a two-year clinical evaluation.

BACKGROUND: The purpose of this study was to quantify conservation of tooth structure and evaluate the efficacy of early treatment of questionable carious lesions in pits and fissures of posterior teeth using air abrasion followed by placement of preventive resin restorations. METHODS: Ninety-three patients with 223 questionably carious teeth, mainly with darkly stained pits and fissures, were recruited from general dentistry clinics. After baseline evaluation, each tooth was randomly assigned to either an early treatment or control group. The authors used air abrasion to investigate the pits and fissures of teeth in the early treatment group. The teeth were sealed and restored with a flowable resin-based composite. All teeth in both groups were examined at six-month intervals to clinically evaluate the quality of the restorations and the caries status of the control teeth. RESULTS: After two years, two of the 113 restorations in the early treatment group required further treatment because of penetrating stain at a margin. In the control group, 14 teeth required treatment because of caries. The mean weight of the impression material--a surrogate measure of volume of removed tooth structure--in preparations that extended into dentin in the early treatment group was 0.0260 grams compared with 0.0281 g in the control group. There was no statistically significant difference between the impression weights (P = .390). CONCLUSION: After two years of a proposed five-year study, the authors concluded that conservation of tooth structure was not substantiated by early treatment. CLINICAL IMPLICATIONS: Treating questionable carious lesions early may not conserve tooth structure.