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Introduction: Cystic fibrosis (CF) is a life-limiting genetic disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) is a CFTR modulator (CFTRm) that targets the underlying cause of CF. Based on safety and efficacy demonstrated in clinical trials, ELX/TEZ/IVA is approved in the US for the treatment of CF in people aged ≥ 2 years who have ≥ 1 F508del-CFTR mutation or a CFTR mutation that is responsive to ELX/TEZ/IVA based on in vitro data. While ELX/TEZ/IVA demonstrated unprecedented improvements in lung function and dramatic reductions in pulmonary exacerbations (PEx) and associated hospitalizations in clinical trials, a limited number of studies have examined the impact of ELX/TEZ/IVA on healthcare resource utilization (HCRU) and associated costs in a real-world setting. The aim of this retrospective study was to evaluate changes in PEx, HCRU, and associated non-CFTRm healthcare costs following initiation of ELX/TEZ/IVA among people with CF aged ≥ 12 years in the US., Methods: We evaluated the rates of PEx, HCRU, and associated costs before and after initiation of ELX/TEZ/IVA in people with CF aged ≥ 12 years using data from the Merative MarketScan® Commercial Claims and Encounters Database and the Merative Multi-State Medicaid Database from April 21, 2019 to December 31, 2020. Because the study period included time following the onset of the COVID-19 pandemic, we limited our primary analysis to the period prior to the pandemic (October 21, 2019 to March 12, 2020). Outcomes following the onset of the pandemic (March 13 to December 31, 2020) were examined in an exploratory analysis., Results: In both commercially insured and Medicaid-insured people with CF, ELX/TEZ/IVA was associated with reductions in PEx, hospitalizations, and associated costs prior to the COVID-19 pandemic, and these reductions were maintained following the onset of the pandemic., Conclusions: These findings suggest that ELX/TEZ/IVA reduces the burden and costs associated with PEx and hospitalizations in people with CF., (© 2023. The Author(s).)

Elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) was shown to be safe and efficacious in people with cystic fibrosis (CF) with ≥ 1 F508del-CFTR allele in Phase 3 clinical trials. ELX/TEZ/IVA treatment led to improved lung function, with increases in percent predicted forced expiratory volume in 1 second (ppFEV 1 ) and Cystic Fibrosis Questionnaire-Revised respiratory domain score. Here, we evaluated the impact of ELX/TEZ/IVA on the rate of lung function decline over time by comparing changes in ppFEV 1 in participants from the Phase 3 trials with a matched group of people with CF from the US Cystic Fibrosis Foundation Patient Registry not eligible for cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapy. Participants treated with ELX/TEZ/IVA had on average no loss of pulmonary function over a 2-year period (mean annualized rate of change in ppFEV 1 , +0.39 percentage points [95% CI, -0.06 to 0.85]) compared with a 1.92 percentage point annual decline (95% CI, -2.16 to -1.69) in ppFEV 1 in untreated controls. ELX/TEZ/IVA is the first CFTR modulator therapy shown to halt lung function decline over an extended time period., (Copyright © 2022. Published by Elsevier B.V.)

Background: Postsecondary education can provide opportunities for students from traditionally hidden populations like those who have experienced foster care or homelessness. To assist these students, campus support programs (CSPs) provide a wide range of services and activities., Objective: Evidence of the impact of CSPs is limited, and little is known about how students who were involved in CSPs fare at or after graduation. This study seeks to address these gaps in knowledge. Methods: This mixed-methods study surveyed 56 young people involved in a CSP for college students who have experienced foster care, relative care, or homelessness. Participants completed surveys at graduation, 6 months post-graduation, and one-year post-graduation., Results: At graduation, over two-thirds of the students felt completely (20.4%) or fairly (46.3%) prepared for life after graduation. Most felt completely (37.0%) or fairly confident (25.9%) that they would get a job after graduation. Six months after graduation, 85.0% of the graduates were employed, with 82.2% working at least full-time. 45% of the graduates were enrolled in graduate school. These numbers were similar a year after graduation. Post-graduation, participants described areas of their lives that were going well, obstacles and hardships faced, changes they would like to see in their lives, and post-graduation needs. Across these areas themes were present in the areas of finances, work, relationships, and resilience., Conclusions: Institutions of higher education and CSP should assist students with a history of foster care, relative care, and homelessness to ensure that after graduation, they have adequate money, employment, and support., Competing Interests: Conflict of InterestThe authors have no relevant financial or non-financial interests to disclose. Partial financial support was received from a private donor who wishes to remain anonymous. The study was approved by Florida State University institutional review board., (© The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2023, Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.)

The onset of the Coronavirus disease (COVID-19) pandemic forced higher education institutions to abruptly transition to remote services and online learning. Students with a foster care background are a subgroup of students who have been particularly hard hit by the pandemic, as were the campus-based programs (CSPs) designed to support them. The purpose of this study was to learn about the impact of the pandemic on CSPs and CSP participants. Focus groups were conducted with CSP administrators and separately with CSP students from two- and four-year colleges in California. The first theme that emerged from the data focused on challenges exacerbated by the pandemic, with six subthemes zeroing in on breaks in social connections, academic disruptions, technology woes, gaps in basic needs, employment challenges, and the toll on mental health. The second theme described participants' responses, including their creative and collaborative actions. Administrators quickly adapted service delivery, formed partnerships with new units and organizations to ensure students' needs were met, and found creative ways to stay connected with students during a time of pervasive isolation. Students talked about their own efforts to access resources, connect with peers, and use of strategies to manage challenges such as burnout and depression. A second subtheme highlighted the ways participants displayed resilience, such as creating boundaries to manage their own self-care and leaning on each other for support. The findings from this study increase our understanding of the experiences students faced during the pandemic and shed light on implications moving forward to support students with foster care histories in higher education., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 Elsevier Ltd. All rights reserved.)

Recent federal laws and state policies reflect the government's investment in improving education and employment outcomes for youth with foster care histories. However, little research has assessed the roles of these programs using national data. Drawing on data from the National Youth in Transitions Database (NYTD) ( n = 7797), this study examines the roles that state-level policies and programs, youth-level participation in programs and services, and youth characteristics play in youths' connection to employment and education ("connectedness") at age 21. Results from multilevel regression analyses find that foster youth in states with widely available tuition waiver programs increases the odds of connectedness to school. The amount of time youth spend in extended foster care, as well as receipt of postsecondary education aid and services, also increases connectedness. Study findings underscore the importance of material and relational supports in supporting foster youths' connection to employment and education in early adulthood.

Families who foster offer essential care for children and youth when their own parents are unable to provide for their safety and well-being. Foster caregivers face many challenges including increased workload, emotional distress, and the difficulties associated with health and mental health problems that are more common in children in foster care. Despite these stressors, many families are able to sustain fostering while maintaining or enhancing functioning of their unit. This qualitative study applied an adaptational process model of family resilience that emerged in previous studies to examine narratives of persistent, long-term, and multiple fostering experiences. Data corroborated previous research in two ways. Family resilience was again described as a transactional process of coping and adaptation that evolves over time. This process was cultivated through the activation of 10 family strengths that are important in different ways, during varied phases., (© 2016 Family Process Institute.)

Child welfare agencies have adopted assessment tools and instruments to inform the level of risk and guide the agency's level of intervention with the family. Actuarial assessments may be more uniform but inflexible with respect to practice wisdom whereas clinical or consensus-based assessments are more comprehensive and intuitive but lack objectivity. The purpose of the current study is to compare clinical and actuarial methods of risk assessment used by child welfare workers to make decisions about substantiation and services. The current study examined the (1) association between clinical and actuarial dimensions, (2) association between actuarial dimensions and outcomes, (3) association between clinical dimensions and outcomes, (4) caseworker primary use of actuarial dimensions, and (5) caseworker supplementary use of actuarial dimensions. Findings indicated that the actuarial may not be solely predictive of agency intensity with respect to case decision and service provision. Our findings suggest that dual-measurement does inform intensity, and we speculate from these findings that the measures may be involved with decision-making in a complex way. This study may be best viewed as a means by which researchers begin to parse how decisions are made; with this information, instruments may be better tailored to facilitate clinical, critical thought., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Social workers are at risk for experiencing burnout and secondary traumatic stress (STS) as a result of the nature of their work and the contexts within which they work. Little attention has been paid to the factors within a social worker's control that may prevent burnout and STS and increase compassion satisfaction. Empathy, which is a combination of physiological and cognitive processes, may be a tool to help address burnout and STS. This article reports on the findings of a study of social workers (N = 173) that explored the relationship between the components of empathy, burnout, STS, and compassion satisfaction using the Empathy Assessment Index and the Professional Quality of Life instruments. It was hypothesized that higher levels of empathy would be associated with lower levels of burnout and STS, and higher levels of compassion satisfaction. Findings suggest that components of empathy may prevent or reduce burnout and STS while increasing compassion satisfaction, and that empathy should be incorporated into training and education throughout the course of a social worker's career.

Adolescents, and especially male adolescents, make up a disproportionately smaller portion of maltreatment reports compared to younger children. This study used the National Child Abuse and Neglect Data System to better understand the characteristics of adolescents reported to Child Protective Services (CPS), to examine whether these characteristics changed over time, and to determine whether certain child or CPS report characteristics predicted CPS involvement. Although adolescents were the focal group, younger children were also analyzed for comparison. Between 2005 and 2010, reports of neglect and the proportion of children of Hispanic and unknown racial/ethnic origins increased. Concurrently, the proportion of cases resulting in CPS involvement declined. Although race/ethnicity predicted CPS involvement, this pattern was not consistent across all age groups or races/ethnicities. The type of alleged maltreatment did not typically predict CPS involvement; however, allegations of sexual abuse among school-aged children and adolescents, particularly among girls, were more likely to result in CPS involvement. These findings can assist child welfare professionals in determining appropriate services tailored to families and developing prevention programs targeting adolescents.

Vector surveillance for infectious diseases is labor intensive and constantly threatened by budget decisions. We report on outcomes of an undergraduate research experience designed to build surveillance capacity for West Nile Virus (WNV) in Montana (USA). Students maintained weekly trapping stations for mosquitoes and implemented assays to test for WNV in pools of Culex tarsalis. Test results were verified in a partnership with the state health laboratory and disseminated to the ArboNET Surveillance System. Combined with prior surveillance data, Cx. tarsalis accounted for 12% of mosquitoes with a mean capture rate of 74 (±SD = 118) Cx. tarsalis females per trap and a minimum infection rate of 0.3 infected mosquitoes per 1000 individuals. However, capture and infection rates varied greatly across years and locations. Infection rate, but not capture rate, was positively associated with the number of WNV human cases (Spearman's rho = 0.94, p < 0.001). In most years, detection of the first positive mosquito pool occurred at least a week prior to the first reported human case. We suggest that undergraduate research can increase vector surveillance capacity while providing effective learning opportunities for students.

Although schools have been trying to address bullying by utilizing different approaches that stop or reduce the incidence of bullying, little remains known about what specific intervention strategies are most successful in reducing bullying in the school setting. Using the social-ecological framework, this paper examines school-based disciplinary interventions often used to deliver consequences to deter the reoccurrence of bullying and aggressive behaviors among school-aged children. Data for this study are drawn from the School-Wide Information System (SWIS) with the final analytic sample consisting of 1,221 students in grades K - 12 who received an office disciplinary referral for bullying during the first semester. Using Kaplan-Meier Failure Functions and Multi-level discrete time hazard models, determinants of the probability of a student receiving a second referral over time were examined. Of the seven interventions tested, only Parent-Teacher Conference (AOR = 0.65, p < .01) and Loss of Privileges (AOR = 0.71, p < .10) were significant in reducing the rate of the reoccurrence of bullying and aggressive behaviors. By using a social-ecological framework, schools can develop strategies that deter the reoccurrence of bullying by identifying key factors that enhance a sense of connection between the students' mesosystems as well as utilizing disciplinary strategies that take into consideration student's microsystem roles.

Objective: To assess the safety, tolerability, and efficacy of spliceosomal peptide P140 (IPP-201101; sequence 131-151 of the U1-70K protein phosphorylated at Ser140), which is recognized by lupus CD4+ T cells, in the treatment of patients with systemic lupus erythematosus (SLE)., Methods: An open-label, dose-escalation phase II study was conducted in two centers in Bulgaria. Twenty patients (2 male and 18 female) with moderately active SLE received 3 subcutaneous (SC) administrations of a clinical batch of P140 peptide at 2-week intervals. Clinical evaluation was performed using approved scales. A panel of autoantibodies, including antinuclear antibodies, antibodies to extractable nuclear antigens (U1 RNP, SmD1, Ro/SSA, La/SSB), and antibodies to double-stranded DNA (anti-dsDNA), chromatin, cardiolipin, and peptides of the U1-70K protein, was tested by enzyme-linked immunosorbent assay (ELISA). The plasma levels of C-reactive protein, total Ig, IgG, IgG subclasses, IgM, IgA, and IgE, and of the cytokines interleukin-2 and tumor necrosis factor alpha were measured by ELISA and nephelometry., Results: IgG anti-dsDNA antibody levels decreased by at least 20% in 7 of 10 patients who received 3 x 200 microg IPP-201101 (group 1), but only in 1 patient in the group receiving 3 x 1,000 microg IPP-201101 (group 2). Physician's global assessment of disease activity scores and scores on the SLE Disease Activity Index were significantly decreased in group 1. The changes occurred progressively in the population of responders, increased in magnitude during the treatment period, and were sustained. No clinical or biologic adverse effects were observed in the individuals, except for some local irritation at the highest concentration., Conclusion: IPP-201101 was found to be safe and well tolerated by subjects. Three SC doses of IPP-201101 at 200 microg significantly improved the clinical and biologic status of lupus patients.

The enigmatic fern genus Diellia, endemic to the Hawaiian archipelago, consists of five extant and one recently extinct species. Diellia is morphologically highly variable, and a unique combination of characters has led to several contrasting hypotheses regarding the relationship of Diellia to other ferns. A phylogenetic analysis of four chloroplast loci places Diellia within 'black-stemmed' rock spleenworts of the species-rich genus Asplenium, as previously suggested by W. H. Wagner. Using an external calibration point, we estimate the divergence of the Diellia lineage from its nearest relatives to have occurred at ca. 24.3 Myr ago matching an independent estimate for the renewal of Hawaiian terrestrial life (ca. 23 Myr ago). We therefore suggest that the ancestor of the Diellia lineage may have been among the first successful colonists of the newly emerging islands in the archipelago. Disparity between morphological and nucleotide sequence variation within Diellia is consistent with a recent rapid radiation. Our estimated time of the Diellia radiation (ca. 2 Myr ago) is younger than the oldest island of Kaua'i (ca. 5.1 Myr ago) but older than the younger major islands of Maui (ca. 1.3 Myr ago), Lana'i (ca. 1.3 Myr ago) and Hawaii (ca. 0.43 Myr ago).

The fern genus Dryopteris (Dryopteridaceae) is represented in the Hawaiian Islands by 18 endemic taxa and one non-endemic, native species. The goals of this study were to determine whether Dryopteris in Hawai'i is monophyletic and to infer the biogeographical origins of Hawaiian Dryopteris by determining the geographical distributions of their closest living relatives. We sequenced two chloroplast DNA fragments, rbcL and the trnL-F intergenic spacer (IGS), for 18 Hawaiian taxa, 45 non-Hawaiian taxa, and two outgroup species. For individual fragments, we estimated phylogenetic relationships using Bayesian inference and maximum parsimony. We performed a combined analysis of both cpDNA fragments employing Bayesian inference, maximum parsimony, and maximum likelihood. These analyses indicate that Hawaiian Dryopteris is not monophyletic, and that there were at least five separate colonizations of the Hawaiian Islands by different species of dryopteroid ferns, with most of the five groups having closest relatives in SE Asia. The results suggest that one colonizing ancestor, perhaps from SE Asia, gave rise to eight endemic taxa (the glabra group). Another colonizing ancestor, also possibly from SE Asia, gave rise to a group of five endemic taxa (the exindusiate group). Dryopteris fusco-atra and its two varieties, which are endemic to Hawai'i, most likely diversified from a SE Asian ancestor. The Hawaiian endemic Nothoperanema rubiginosum has its closest relatives in SE Asia, and while the remaining two species, D. wallichiana and D. subbipinnata, are sister species, their biogeographical origins could not be determined from these analyses due to the widespread distributions of D. wallichiana and its closest non-Hawaiian relative.

Acitretin (Soriatane, Roche Pharmaceuticals) is an aromatic retinoid, effective in the treatment of severe psoriasis. This study highlights data from two existing clinical trials to capture PASI 50 and PASI 75 responder rates which represent a common metric used in current psoriasis clinical trials. A review of pharmacokinetics, safety and a discussion of relapse rate establish acitretin as an efficacious, convenient, oral treatment for initial and maintenance therapy of severe psoriasis.

Recent studies of the phylogeny of several groups of native Hawaiian vascular plants have led to significant insights into the origin and evolution of important elements of the Hawaiian flora. No groups of Hawaiian pteridophytes have been subjected previously to rigorous phylogenetic analysis. We conducted a molecular phylogenetic analysis of the endemic Hawaiian fern genus Adenophorus employing DNA sequence variation from three cpDNA fragments: rbcL, atpbeta, and the trnL-trnF intergenic spacer (IGS). In the phylogenetic analyses we employed maximum parsimony and Bayesian inference. Bayesian phylogenetic inference often provided stronger support for hypothetical relationships than did nonparametric bootstrap analyses. Although phylogenetic analyses of individual DNA fragments resulted in different patterns of relationships among species and varying levels of support for various clades, a combined analysis of all three sets of sequences produced one, strongly supported phylogenetic hypothesis. The primary features of that hypothesis are: (1) Adenophorus is monophyletic; (2) subgenus Oligadenus is paraphyletic; (3) the enigmatic endemic Hawaiian species Grammitis tenella is strongly supported as the sister taxon to Adenophorus; (4) highly divided leaf blades are evolutionarily derived in the group and simple leaves are ancestral; and, (5) the biogeographical origin of the common ancestor of the Adenophorus-G. tenella clade remains unresolved, although a neotropical origin seems most likely., (Copyright 2003 Elsevier Science (USA))

Although stress is an extensively investigated phenomenon, the effects of specific stressors on the pharmacologic activity of routinely administered drugs are less well characterized. We designed the present study to investigate the effect of handling stress on catecholaminergic responsivity following an acute methylphenidate (MP, Ritalin) challenge in the medial prefrontal cortex (mPFC). Norepinephrine (NE) and dopamine (DA) levels were simultaneously measured in 15-min samples of PFC dialysate using HPLC coupled with electrochemical detection. Sprague-Dawley rats were handled for 15 min, which produced an increase from basal extracellular DA and NE levels. Handling stress attenuates the DA response when administered 2 h prior to IP MP, whereas handling stress enhances the DA response when administered simultaneously with IG MP. These findings suggest that persistent alterations in mesocorticolimbic DA-ergic activity are induced by a short exposure to restraint stress as evidenced by the altered response to MP challenge.

Protease inhibitors are a new class of drugs which has demonstrated activity for the treatment of HIV infection. The function of the HIV protease is to split a polyprotein to create smaller proteins which will be incorporated in the structure of the virus. The eight cleavage sites of the polyprotein constitute a template for the synthesis of potential inhibitors. Today, only inhibitors of the Phe-Pro cleavage have shown an antiproteinase activity specific for HIV. Clinical trials in HIV infection with saquinavir, indinavir, and ritonavir have demonstrated a decrease in viral load measured by plasma HIV-RNA PCR and an increase in CD4 lymphocyte counts. The use of protease inhibitors leads to a more or less rapid selection of mutant resistant viruses. However, these new drugs, either used alone or in combination, constitute a new therapeutic approach for the treatment of HIV disease.

A model is described for evaluating the activity of a retinoid based on its effect on the keratinization of the vaginal epithelium that occurs on estrus (day 4) of a 4-day cycle in female rats. This keratinization process is dependent on the endogenous estradiol (E2) secreted between the evening of diestrus 2 (day 2) and that of proestrus (day 3). Various doses of all-transretinoic acid (tRA) were injected at different time points during the estrous cycle and the vaginal keratinization was assessed by microscope examination of unstained native or Papanicolaou-stained smear preparations. Additionally, the preovulatory E2 secretion was measured and ovaries were histologically examined. A single injection of 10 mg/kg tRA either on diestrus 2 (evening) or on proestrus (early morning) was able to induce a complete inhibition of the vaginal keratinization in more than 80% of the cases. This can be considered as a direct effect on the vaginal epithelial differentiation since neither the E2 secretion nor the ovulatory process were affected. The inhibition of vaginal keratinization can be used as a rapid and convenient in vivo model for screening retinoid candidates with antikeratinizing activity.

Background: Retinoids were shown to be effective in the treatment of both oral and cutaneous forms of lichen planus., Objective: Confirm the beneficial effect of low doses of oral tretinoin in lichen planus., Methods: Eighteen patients with lichen planus were treated in an open study for up to 19 months. Efficacy and safety data were recorded., Results: Complete remission was observed in 13 (72%) and marked improvement in 4 (22%) out of 18 patients. Six patients showed moderate and 12 had no side effects., Conclusion: Tretinoin is a valuable drug when given at low doses to patients with lichen planus who failed to respond to other therapies.

Background: 9-cis-Retinoic acid (9-cis-RA) is as active as 13-cis-retinoic acid (13-cis-RA) in inhibiting the proliferation of cultured human sebocytes and in reducing the size of sebaceous glands of hamsters., Objective: Evaluate the anti-acne effect of 9-cis-RA compared to that of 13-cis-RA in a pilot study., Methods: Four young male patients with acne were treated in an open study consecutively with 9-cis-RA and 13-cis-RA given at similar doses., Results: No beneficial effects were observed with 9-cis-RA in any of the patients whereas all responded favorably to 13-cis-RA., Conclusion: For the two retinoids tested, the anti-acne effect correlates with the sebosuppressive effect in humans.

Background and Objective: It is generally accepted that the inhibition of sebum excretion has a predictive value for anti-acne activity. Whereas oral 13-cisretinoic acid (13-cis-RA) decreases sebum excretion, it has not been shown so far if oral all-trans-retinoic acid (tretinoin, tRA) does so. The aim of this exploratory study was to investigate the effect of oral tRA on the sebum excretion rate (SER) in young male subjects., Methods: 12 healthy volunteers with a baseline SER above 1.0 microgram/cm2/min were treated with 20 mg/day tRA for 4 weeks. The SER was measured at weeks 2 and 4. Adverse reactions were recorded., Results: The mean SER varied from 1.56 at baseline to 1.65 at week 2 and to 1.49 micrograms/cm2/min at week 4. Comparison with values obtained in the same subjects previously treated with either 13-cis-RA or 9-cis-retinoic acid indicated that tRA less sebosuppressive. Mucocutaneous reactions and headache were the most frequent side effects of oral tRA., Conclusion: The lack of effect on the SER suggests that oral tRA would probably be ineffective against acne. The fact that, of the three isomers tested, only 13-cis-RA (which does not bind to nuclear receptors) shows activity may suggest that sebosuppression is not nuclear receptor mediated. We discuss other hypotheses related to pharmacokinetics.

Metal fixation has been advocated to achieve immediate local stabilization during anterior cervical fusion surgery. Screw loosening, screw backout, and breakage of screws or plates remain clinical complications that warrant concern. This study examined the biomechanical characteristics of a prototype anterior cervical plating system with unique screw and plate geometries in comparison to a fixation system currently used clinically. Compared with a standard screw design, a taper screw design resulted in increased ultimate strength and fatigue life. The addition of a locking pin hole in the tapered screw made the screw's fatigue life comparable to the standard design. Pullout strength was comparable in all screw designs. The prototype fixation system had higher strength in pure compression and compression with bending than the comparative system, while also demonstrating improved fatigue characteristics. The tensile bending stiffness of the prototype was double that of the comparative system and within the anatomical range of cervical vertebrae, the bending moment was greater. Torsional yield strength was greater than the reported breaking strength of cervical disc in situ for both systems. The unique designs of the screw and plate geometry resulted in an anterior cervical plate fixation system that is stronger with decreased risk of fatigue failure than a currently used system. Clinical evaluation in patients requiring immediate stabilization is warranted.

Background and Objective: The marked efficacy of isotretinoin in the treatment of acne is undoubtedly due to its potential to inhibit sebaceous gland activity. The question arises if the anti-acne effect of new oral retinoids can be predicted by using the currently available experimental models., Methods: We reviewed the effects of various oral retinoids on sebum excretion in humans and their efficacy in acne. The human data were compared to the results obtained from in vitro and animal models., Results: Oral retinoids such as etretinate, acitretin and the so-called arotinoids were not able to inhibit the sebum production in humans and were ineffective against acne. In various animal models (i.e. sebum production in rats, flank organ size in hamsters, ear sebaceous gland size in hamster, most of these retinoids were shown to be effective. Furthermore, in addition to isotretinoin, some retinoids were able to suppress the proliferation of human sebocytes in vitro., Conclusions: The elucidation of the mechanism of action of isotretinoin on the sebocyte biology is critical for the search of more reliable models and for the discovery of new retinoids with anti-acne activity.

Several HPLC methods for quantification of acitretin and its 13-cis isomer in biological fluids have been described. Only limited data are available on determination of this drug in skin samples. Our objective was to improve the sensitivity and selectivity of existing methods to measure drug in small skin samples from humans treated with acitretin. With a new optimized mobile phase [methanol: acetonitrile (7:3, v/v), purified water with 1.5% (v/v) acetic acid, mixed in a 85:15 ratio (v/v)] and a new internal standard (arotinoid ethyl sulfone), a limit of quantification of 1 ng/g tissue was reached. Nine male volunteers were given an oral daily dose of 50 mg acitretin for up to 28 days. Blood and skin samples (punch and shave biopsies, suction blister skin, and fluid) were taken at various time points during and after treatment. Drug concentration and metabolism in plasma and skin samples appeared to be linked in that the trans-isomer concentration was always higher than the cis-isomer concentration during dosing and 3 h after the last dose. However, 7 and 14 days after the last dose in plasma and in all tissue samples (except the shave biopsy), the all-trans-acitretin concentration rapidly decreased and approached the detection limit. In the shave biopsy, the all-trans-acitretin concentration remained higher than the 13-cis-acitretin concentration. Furthermore, the elimination of two isomers from the shave biopsy was delayed.(ABSTRACT TRUNCATED AT 250 WORDS)

Background: Promising results have been reported from treatment with oral retinoids in patients with severe lichen sclerosus et atrophicus (LSA) of the vulva., Objective: The aim of our study was to determine the efficacy of acitretin (20 to 30 mg/day) for 16 weeks in LSA., Methods: Seventy-eight patients were enrolled into a multicenter, randomized, placebo-controlled, double-blind trial. The primary measure of efficacy was the "responder" rate based on the assessment of characteristic clinical features of LSA of the vulva (pruritus, burning, atrophy, hyperkeratosis, and secondary features such as erosions, ulcers, edema, or lichenification) and on the extent of the lesions., Results: From the 46 patients eligible for efficacy analysis, a significantly higher number of responders was observed in the acitretin-treatment group (14 of 22 patients) as compared with the placebo-treatment group (6 of 24 patients). Typical retinoid adverse reactions were observed in all patients receiving active drug., Conclusion: Acitretin is effective in treating women with severe LSA of the vulva.

Etretinate (Tigason, Tegison) and its active metabolite acitretin (Neotigason, Soriatane) are known teratogens. Pregnancy should be avoided during treatment and until 2 years after treatment discontinuation. The question is discussed whether a dose or a blood concentration of the drug below which there is no teratogenic risk can be determined. Animal experimental and human pharmacokinetic data are reviewed. An evaluation of the outcomes of pregnancies which occurred in mothers exposed to etretinate or acitretin was performed. A threshold dose in human therapy below which there is no risk of congenital malformation cannot be determined based on animal experimental data. With regard to pharmacokinetics, there are currently no data suggesting that blood levels of the drug below the detection limit of 2 ng/ml are associated with a teratogenic risk. The most useful information is given by reports in women who were exposed to either retinoid before or during pregnancy. The data indicate that the risk of spontaneous abortion or congenital malformation is high when the drug is administered during the first trimester of pregnancy. After treatment discontinuation, the risk is low since the number of abnormalities seems not to exceed those observed in a general population. There are currently no available data which suggest that the pregnancy warnings are inappropriate in terms of duration of contraception.

The aim of this study was to investigate the possible esterification of acitretin into etretinate by using hepatocytes in primary culture from the rat, monkey, dog and man. With rat and human hepatocytes, etretinate was detectable only when ethanol was co-administered with acitretin. With monkey and dog cells, traces of etretinate were found without ethanol addition, but the esterification of acitretin was highly enhanced by ethanol. The metabolic profile was not changed when cells were pre-incubated with ethanol. Therefore acitretin seems to act rather as a substrate than an enzymatic inducer.

Acitretin has recently been introduced for the systemic treatment of dermatologic diseases such as psoriasis and congenital disorders of keratinization. At present, only an oral form of this drug is available. However results from recent studies have shown that considerable drug concentrations can be delivered to the skin by topical administration of acitretin. Based on this data we addressed the question whether the topical administration of acitretin can produce in humans a drug concentration in the skin which exceeds the drug concentration that is found in the skin after multiple oral acitretin dosing and is reported to be clinical effective. Drug concentrations in the skin were investigated under conditions in which the maximum dose that can be administered in a therapeutic situation was applied. Additionally, three different skin sampling techniques, the punch biopsy, the shave biopsy and the suction blister technique were validated to quantitate acitretin in the skin. The drug concentrations in skin after systemic application in a steady state situation were comparable with the drug concentration reached after a single 24 hours topical application of a saturated acitretin/isopropylmyristate formulation. However, no unequivocal effects in psoriasis and disorders of keratinization were observed up to now by the topical administration of acitretin. The inverse drug concentration gradients which are present in the skin, depending on the route of administration, may explain differences in activity. The skin samples in our and other studies were homogenized or dissolved and thus much of the anatomical information is lost. The latter may be most important for the understanding of the local events.

Nearly two decades after the advent of synthetic retinoids for the treatment of many severe and incapacitating dermatologic conditions, the usefulness of these drugs is not universally accepted. The safety profile is well established. Other than teratogenicity, which can be avoided if the recommended precautions for use are followed, serious or unexpected adverse reactions rarely occur. This article concisely addresses some questions about etretinate and acitretin therapy that are most pertinent for the dermatologist.

In two decades, retinoids have nearly revolutionized some aspects of dermatologic practice. The dramatic response of severe acne to isotretinoin therapy is equally matched at times by the rapid response of pustular psoriasis treated with etretinate. Many other psoriatic patients, especially those who have failed the standard therapeutic regimens, have immensely benefited by the addition of retinoids to the therapeutic armamentaria. The use of etretinate or acitretin where available has repeatedly shown their utility, general safety, and cost effectiveness. Additionally, the advent of combination therapy with UV light has allowed better response using less retinoid and less light, eg, in retinoid-light combinations. With careful attention to the safety profile of retinoids, especially in the area of pregnancy prevention, a powerful therapy option is available for even the most recalcitrant patients. These responses would be sufficient reason for interest in retinoids but, when coupled with the exciting developments in molecular biology of retinoids, lead one to look with excitement on the dermatologic horizon for a new generation of significant breakthroughs.

The objective of this double-blind study was to compare the therapeutic effects of acitretin with those of etretinate in patients with Darier's disease. Twenty-six patients (10 males and 16 females) were included in the study. Patients were treated with 30 mg daily for the first 4 weeks and with an individually adjusted dose (10-50 mg/day) for the subsequent 12 weeks. Remission or marked improvement was obtained in 10 of the 13 acitretin-treated patients and in 8 of the 11 etretinate-treated patients who completed the 16-week treatment. The usual mucocutaneous adverse reactions of retinoids were observed in all but one patient. There were no significant differences between treatment groups with regard to the incidence of these reactions.

In a randomized, double-blind comparative study 60 patients with severe, widespread psoriasis were treated either with photochemotherapy (PUVA) alone or in combination with acitretin. Forty-eight patients completed the study; of these, 25 received placebo combined with PUVA and 23 received acitretin with PUVA. Marked or complete clearing of psoriasis occurred in 80% of the patients (20 of 25) without acitretin and in 96% of the patients (22 of 23) with adjunctive acitretin administration. The mean cumulative UVA dose given to patients in the acitretin-PUVA group was 42% less than that required for patients in the placebo-PUVA group. We conclude that acitretin substantially augments the efficacy of photochemotherapy in the treatment of severe psoriasis.

The purpose of this open, noncomparative study with acitretin (Ro 10-1670) was to evaluate the clinical response of patients with various nonpsoriatic disorders of keratinization and to establish for these patients the optimal dosage for both efficacy and tolerance. Thirty-three patients (21 adults and 12 children or adolescents) with ichthyoses, palmoplantar hyperkeratosis, or Darier's disease were treated for a period of 4 months. Most patients showed marked improvement or remission. The results obtained in congenital ichthyosiform erythroderma, lamellar ichthyosis, and Papillon-Lefèvre syndrome were judged as better than those usually reported with etretinate. The side effects observed in our patients were similar to those reported with etretinate, with the exception of scaling of palms and soles, which had an incidence and severity greater than expected with etretinate. The optimal acitretin dosage providing the best efficacy with minimal undesirable effects varied from patient to patient. The mean daily dose (+/- SD) was 27 +/- 11 mg in adults and 0.7 +/- 0.2 mg/kg in children or adolescents.

A carbon-fiber-reinforced polymer implant has been designed to aid interbody lumbar fusion. The cage-like implant has ridges or teeth to resist pullout or retropulsion, struts to support weight bearing, and a hollow center for packing of autologous bone graft. Because carbon is radiolucent, bony healing can be imaged by standard radiographic techniques. The device has been mechanically tested in cadaver spines and compared with posterior lumbar interbody fusion performed with donor bone. The carbon device required a pullout force of 353 N compared with 126 N for donor bone. In compression testing, posterior lumbar interbody fusion performed with the carbon device bore a load of 5,288 N before failure of the vertebral bone. Posterior lumbar interbody fusion performed with donor bone failed at 4,628 N, and unmodified motion segments failed at 6,043 N. The carbon fiber implant separates the mechanical and biologic functions of posterior lumbar interbody fusion.

Both etretinate and its principal metabolite, acitretin, are efficacious in the treatment of psoriasis. Because patients with severe psoriasis often require chronic therapy, this study was undertaken to determine the efficacy, tolerability, and safety of acitretin in patients on continuous treatment for 12 months. The initial daily dose of 50 mg was taken for 4 weeks. Thereafter the dose was increased or decreased by 10 mg at monthly intervals (10 to 70 mg) to produce the optimal response with minimal toxicity. Seventy percent of the patients who completed 12 months of treatment showed marked improvement. All patients experienced adverse reactions; dry lips, hair loss, skin peeling, pruritus, and nail disorders were the most frequent. Fourteen patients were withdrawn from the study because of one or more intolerable adverse reactions.

Sixty-five patients with lichen planus were included in a multicenter trial of acitretin. At the end of an 8-week placebo-controlled, double-blind phase, a significantly higher number of patients treated with 30 mg/day acitretin (64%) showed remission or marked improvement compared with placebo (13%). Furthermore, during the subsequent 8-week open phase, 83% of previously placebo-treated patients responded favorably to acitretin therapy. Typical retinoid adverse reactions were present in all patients on active drug. Laboratory studies did not show any clinically significant changes. This study shows that acitretin is an effective and acceptable therapy for severe cases of lichen planus.

Thirty-four patients with extensive psoriasis were treated in a double-blind parallel fashion with either acitretin plus bath PUVA (trimethylpsoralen bath + UVA) or etretinate plus bath PUVA. Each group consisted of 17 patients. The dose of retinoid was 40 mg/day during the 2-week monotherapy phase and subsequently 20 mg/day during the combination treatment. Bath PUVA was given three times a week starting with a UVA dose of 0.06 J/cm2. Remission (greater than 90% improvement) was achieved in all patients in 6-10 weeks. There were no significant differences in clinical response between the two groups; the mean +/- SD PASI score (psoriasis area and severity index) before treatment was 22.6 +/- 7.1 in the acitretin-PUVA group and 19.4 +/- 7.8 in the etretinate-PUVA group. The corresponding figures after treatment were 0.6 +/- 0.6 and 1.0 +/- 0.5, respectively. Side-effects related to retinoid treatment were frequent in both groups but they were usually mild and well-tolerated. There was only one case of diffuse alopecia after 8 weeks in the etretinate-PUVA group. Scaling of the palms and soles was seen in six patients in the acitretin-group but only in two patients in the etretinate-group. Triglycerides were elevated in about half of the patients in both groups. The present study shows that acitretin is as effective as etretinate in the combination with bath PUVA.

Six patients with persistent palmoplantar pustulosis were treated with acitretin, and the clinical response was compared with the effect on the intra-epidermal accumulation of polymorphonuclear PMN leukocytes. A prompt improvement of pustule formation and subsequently decreased scaling and erythema was seen in all patients. Following discontinuation of therapy, a relapse occurred within 2 weeks. With dosages of 45 or 55 mg/day, the clinical scores were only slightly better than with 25 or 35 mg/day. In patients using 25 mg acitretin a day, the leukotriene B4-induced intra-epidermal accumulation of polymorphonuclear leukocytes was not affected. However, a dosage of 35 mg/day resulted in a significant inhibition of PMN accumulation, dosages of 45 and 55 mg/day causing an even more pronounced inhibition of this process. Although the effect of different dosages of acitretin is not clearly expressed in the severity scores, the dose-dependent effect on PMN chemotaxis in vivo might be of relevance when combination therapies are considered, in order to achieve a complete clinical clearance.

Thirteen patients with Darier's disease with a mean extent of the lesions of 29.4 +/- 10% of the total skin area were treated with acitretin (the main metabolite of etretinate) for 16 weeks. The dose was 30 mg/day during the initial 8 weeks and was later adjusted individually to 10-30 mg/day in order to achieve optimal results. Three patients cleared completely, 7 patients showed marked improvement and 3 patients became slightly better during treatment. The mean extent of the lesions after the treatment was 7.3 +/- 8% of the skin area. Despite good clinical clearing, the improvement at the ultrastructural level was incomplete in the 3 patients studied by electron microscopy. Normal stratification did not develop and the size and number of desmosomes remained reduced. The main side effects during treatment were pruritus in 5 patients, diffuse alopecia in 2 patients and marked elevation in serum triglycerides in 4 patients. On the basis of this study, acitretin would seem to be a useful alternative to etretinate for the treatment of Darier's disease.

The aim of the study was to investigate the concentrations of Ro 10-1670 (acitretin) and its isomeric metabolite Ro 13-7652 (cis-acitretin) after multiple oral dosing of acitretin. We used a highly sensitive HPLC method for simultaneous determination of the 2 retinoids with a quantification limit of 2 ng/ml in plasma and 10 ng/g in total skin (epidermis and dermis). In hairless rats receiving orally 8 mg/kg acitretin once daily during 8 days, blood and skin samples were taken at different time points between 5 and 96 h after the last dose. After 96 h, appreciable concentrations of Ro 10-1670, but not Ro 13-7652 could be measured in the skin, whereas both isomers were below the quantification limit in plasma. In psoriatic patients treated with a once daily dose of 30 mg acitretin, blood samples and biopsies were taken after 1 month of treatment (i.e. under steady state conditions). 24 h after the last drug intake, skin concentrations of acitretin were approximately 10 times higher than those observed in plasma. Ro 10-1670 concentrations in the skin were approximately 3-5 times higher than for Ro 13-7652 and concentrations of both isomers were higher in lesional compared to uninvolved skin.

Four day cyclic female Rats were injected with dosages of FSH capable of causing superovulation and or superluteinization at the end of the cycle. A decrease in plasma LH and FSH was observed during the "critical period" on the afternoon of proestrus. The exogenous FSH was then supposed to increase the number of follicles sensitive to the ovulating and luteinizing action of LH.

Eighty patients with severe psoriasis were treated in a double-blind fashion with either an initial dose of 10 mg, 25 mg or 50 mg of etretin daily or with placebo. Follow-up examinations were carried out monthly and the efficacy of treatment was evaluated by using the PASI score. Adverse effects of the treatment were recorded monthly; liver enzymes, cholesterol and triglycerides were measured. After 2 months of treatment the maintenance dose was reduced in some of the patients either because of complete remission or adverse effects. After 2 months treatment, groups receiving 25 mg/day and 50 mg/day showed significantly lower PASI scores than the placebo group. The 10 mg/day group showed a response intermediate between the 25 mg and 50 mg groups and the placebo group. Thus, the optimal initial dose seems to be approximately 25 mg/day and the maintenance dose somewhat lower. Six months after the start of treatment there were no significant differences between the four groups; the last follow-up examination took place during the summer and some of the patients probably experienced spontaneous improvement. Although clinical adverse effects were frequent in all groups, severe side effects, namely hair loss and paronychia, occurred frequently only among patients treated with an initial dose of 50 mg of etretin daily. The effect of treatment on liver enzymes, cholesterol and triglycerides was minimal.