Using a culture model of glial tumorigenesis, we identified a novel gene that was up-regulated in malignant mouse astrocytes following the loss of p53. The gene represents the murine homologue of pescadillo, an uncharacterized gene that is essential for embryonic development in zebrafish. Pescadillo is a strongly conserved gene containing unique structural motifs such as a BRCA1 C-terminal domain, clusters of acidic amino acids and consensus motifs for post-translational modification by SUMO-1. Pescadillo displayed a distinct spatial and temporal pattern of gene expression during brain development, being detected in neural progenitor cells and postmitotic neurons. Although it is not expressed in differentiated astrocytes in vivo, the pescadillo protein is dramatically elevated in malignant human astrocytomas. Yeast strains harboring temperaturesensitive mutations in the pescadillo gene were arrested in either G 1 or G 2 when grown in nonpermissive conditions, demonstrating that pescadillo is an essential gene in yeast and is required for cell cycle progression. Consistent with the latter finding, DNA synthesis was only observed in mammalian cells expressing the pescadillo protein. These results suggest that pescadillo plays a crucial role in cell proliferation and may be necessary for oncogenic transformation and tumor progression.

A head-to-head comparison of ixekizumab vs. guselkumab in patients with moderate-to-severe plaque psoriasis: 12-week efficacy, safety and speed of response from a randomized, double-blinded trial* Summary Background Patients with psoriasis value rapid and complete skin clearance. No head-tohead studies have focused on early responses to interleukin (IL)-17 vs. IL-23 inhibitors. Objectives To compare early and complete skin clearance by the IL-17A inhibitor ixekizumab vs. the IL-23p19 inhibitor guselkumab. Methods IXORA-R, a 24-week, randomized, double-blinded study, enrolled adults with moderate-to-severe plaque psoriasis [static Physician's Global Assessment of Disease (sPGA) score of ≥ 3, Psoriasis Area and Severity Index (PASI) ≥ 12, and ≥ 10% body surface area]. Patients were randomized (1 : 1) to receive the approved dose of subcutaneous ixekizumab or guselkumab. Primary end point was 100% improvement in PASI (PASI 100) at week 12. Major secondary end points included other levels of improved PASI and sPGA at different time points. Comparisons were made using the Cochran-Mantel-Haenszel test with a multiple testing strategy. Nonresponder imputation was used for missing data. After the completion of the study, the final secondary end point (PASI 100 at 24 weeks) and safety data through week 24 will be reported. Results In total, 1027 patients were randomized. The primary end point PASI 100 at week 12 was met [215/520 ixekizumab (41%); 126/507 guselkumab (25%); P < 0Á001]. All major secondary end points measured up to week 12 were met, including PASI 50 at week 1 and PASI 75 at week 2. Serious adverse event frequency was 3% for each group; no new safety signals were identified. Conclusions Ixekizumab was superior to guselkumab for rapidly improving signs and symptoms in patients with moderate-to-severe plaque psoriasis by week 12. Adverse events were similar to previous ixekizumab and guselkumab studies. Compared with the IL-23 inhibitor guselkumab, ixekizumab can offer complete skin clearance more rapidly to patients with moderate-to-severe plaque psoriasis.

As syphilis becomes more common in many developed regions, it is important to recognize even atypical presentations of this clinical entity, especially among individuals who have unrecognized or early HIV infection.

PDL treatment of BCC represents a novel, quick, and relatively non-painful treatment that does not usually produce scar and may represent an alternative treatment for certain types of BCC in the appropriate clinical setting. This study confirms prior findings regarding the efficacy of PDL in the treatment of BCC, with longer follow-up period.

Epilepsy is a common neurological condition, affecting about 4% of individuals over their lifetime. Epilepsy can be idiopathic, secondary to an underlying genetic abnormality or unknown causes, or acquired. Known potential causes account for about one third of epilepsy. Control of epilepsy has primarily focused on suppressing seizure activity after epilepsy has developed. An intriguing possibility is to control acquired epilepsy by preventing epileptogenesis, the process by which the brain becomes epileptic. Many laboratory models simulate human epilepsy as well as provide a system for studying epileptogenesis. The kindling model involves repeated application of subconvulsive electrical stimulation to the brain, leading to spontaneous seizures. Other models include the cortical or systemic injection of various chemicals. These models suggest that many antiepileptic drugs, from phenobarbital and valproate (valproic acid) to levetiracetam and tiagabine, have antiepileptogenic potential. Some promising other possibilities include N-methyl-D-aspartate (NMDA) or alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) antagonists as well as the neurotrophins and their receptors. Phenobarbital, phenytoin, valproate, carbamazepine and, to a very limited extent, diazepam have been evaluated in clinical trials to test whether they actually prevent epileptogenesis in humans. Results have been very disappointing. Meta-analyses of 12 different drug-condition combinations show none with significantly lower unprovoked seizure rates among those receiving the active drug. In 4 of the 12, the observed rate was actually slightly higher among treated individuals. None of the newer drugs have been evaluated in antiepileptogenesis trials. Until some drugs demonstrate a clear antiepileptogenic effect in clinical trials, the best course to reduce the incidence of epilepsy is primary prevention of the risk-increasing events--for example, wearing helmets, using seat belts, or decreasing the risk of stroke by reducing smoking.

Objective: A 31-gene expression profile (GEP) test that has been clinically validated identifies melanoma patients with low (Class 1) or high (Class 2) risk of metastasis based on primary tumor biology.  This study aimed to prospectively evaluate the test impact on clinical management of melanoma patients.Methods:  Physicians at 16 dermatology, surgical or medical oncology centers examined patients to assess clinical features of the primary melanoma.  Recommendations for clinical follow-up and surveillance were collected.  Following consent of the patient and performance of the GEP test, recommendations for management were again collected, and pre- and post-test recommendations were assessed to determine changes in management resulting from the addition of GEP testing to traditional clinicopathologic risk factors.   Results:  Post-test management plans changed for 49% (122 of 247) of cases in the study when compared to pre-test plans. Thirty-six percent (66 of 181) of Class 1 cases had a management change, compared to 85% (56 of 66) of Class 2 cases.  GEP class was a significant factor for change in care during the study (p<0.001), with Class 1 accounting for 91% (39 of 43) of cases with decreased management intensity, and Class 2 accounting for 72% (49 of 68) of cases with increases.Conclusions: The reported study show that the 31-gene GEP test improves net health outcomes in the management of cutaneous melanoma.  Physicians used test results to guide risk-appropriate changes that match the biological risk of the tumor, including directing more frequent and intense surveillance to high-risk, Class 2 patients.

The optimum treatment of Type II odontoid fractures in the geriatric population remains controversial. Coexisting medical conditions encountered in the elderly patient often increase operative risk and make cervical immobilization difficult to tolerate. Previous studies have shown increased morbidity and mortality and decreased fusion rates for Type II odontoid fractures treated with cervical orthoses in the geriatric population, whereas low morbidity and mortality rates with operative management have recently been documented. To investigate the role of surgical and nonsurgical treatment, a retrospective analysis was performed of patients with Type II odontoid fractures who were at least 65 years old and were consecutively admitted to a single medical center from 1994 to 1998. Twenty patients met inclusion criteria. In 12 patients nonsurgical management with a cervical orthosis was attempted. The nonsurgical management failed early in six patients, with one associated death. Eleven patients were treated surgically with either anterior odontoid screw fixation or posterior C1–2 transarticular screw fixation and modified Gallie fusion. Postoperatively one patient required revision of the C1–2 transarticular screws, and there was one death. In conclusion Type II odontoid fractures in this elderly population were associated with early 10% morbidity and 20% mortality rates. Nonsurgical management of Type II odontoid fractures failed early in six (50%) of 12 patients, whereas surgical treatment failed early in one of 11 (9%) patients. Both the nonsurgical and surgical treatments resulted in approximately 10% morbidity and 10% mortality rates.

ImportanceLebrikizumab (LEB), a high-affinity monoclonal antibody targeting interleukin (IL)-13, demonstrated efficacy and safety in patients with moderate-to-severe atopic dermatitis (AD) during 16 weeks of monotherapy in a phase 2b trial, and two 52-week phase 3 trials.ObjectiveTo evaluate efficacy and safety of LEB combined with low- to mid-potency topical corticosteroids (TCS) in patients with moderate-to-severe AD.Design, Setting, and ParticipantsThe ADhere trial was a 16-week randomized, double-blinded, placebo (PBO)-controlled, multicenter, phase 3 clinical trial conducted from February 3, 2020, to September 16, 2021. The study was conducted at 54 outpatient sites across Germany, Poland, Canada, and the US and included adolescent (aged ≥12 to &amp;lt;18 years weighing ≥40 kg) and adult patients with moderate-to-severe AD. The treatment allocation ratio was 2:1 (LEB:PBO).InterventionsOverall, 211 patients were randomized to subcutaneous LEB (loading dose of 500 mg at baseline and week 2, followed by 250 mg every 2 weeks [Q2W] thereafter) or PBO Q2W in combination with TCS for 16 weeks.Main Outcomes and MeasuresEfficacy analyses at week 16 included proportions of patients achieving Investigator’s Global Assessment score of 0 or 1 (IGA [0,1]) with 2 or more points improvement from baseline, and 75% improvement in the Eczema Area and Severity Index (EASI-75). Key secondary end points included evaluation of itch, itch interference on sleep, and quality of life. Safety assessments included monitoring adverse events (AEs).ResultsThe mean (SD) age of patients was 37.2 (19.3) years, 103 (48.8%) patients were women, 31 (14.7%) patients were Asian, and 28 (13.3%) patients were Black/African American. At week 16, IGA (0,1) was achieved by 145 (41.2%) patients in the LEB+TCS group vs 66 (22.1%) receiving PBO+TCS (P = .01); corresponding proportions of patients achieving EASI-75 were 69.5% vs 42.2% (P &amp;lt; .001). The LEB+TCS group showed statistically significant improvements in all key secondary end points. Most treatment-emergent adverse events (TEAEs) were nonserious, mild or moderate in severity, and did not lead to study discontinuation. The TEAEs frequently reported in the LEB+TCS group included conjunctivitis (7 [4.8%]), headache (7 [4.8%]), hypertension (4 [2.8%]), injection site reactions (4 [2.8%]), and herpes infection (5 [3.4%]) vs 1.5% or less patient-reported frequencies in the PBO+TCS group. Similar frequencies of patient-reported serious AEs following LEB+TCS (n = 2, 1.4%) and PBO+TCS (n = 1, 1.5%).Conclusions and RelevanceIn this randomized phase 3 clinical trial, LEB+TCS was associated with improved outcomes in adolescents and adults with moderate-to-severe AD compared with TCS alone, and safety was consistent with previously reported AD trials.Trial RegistrationClinicalTrials.gov Identifier: NCT04250337