The Drosophila mitotic spindle orientation machinery requires activation, not just localization.

The orientation of the mitotic spindle at metaphase determines the placement of the daughter cells. Spindle orientation in animals typically relies on an evolutionarily conserved biological machine comprised of at least four proteins - called Pins, Gαi, Mud, and Dynein in flies - that exerts a pulling force on astral microtubules and reels the spindle into alignment. The canonical model for spindle orientation holds that the direction of pulling is determined by asymmetric placement of this machinery at the cell cortex. In most cell types, this placement is thought to be mediated by Pins, and a substantial body of literature is therefore devoted to identifying polarized cues that govern localized cortical enrichment of Pins. In this study we revisit the canonical model and find that it is incomplete. Spindle orientation in the Drosophila follicular epithelium and embryonic ectoderm requires not only Pins localization but also direct interaction between Pins and the multifunctional protein Discs large. This requirement can be over-ridden by interaction with another Pins interacting protein, Inscuteable.

Randomized, Placebo-Controlled Phase 1/2 Study to Determine the Appropriate ATX-101 Concentration for Reduction of Submental Fat.

BACKGROUND: ATX-101 is indicated for submental fat treatment. OBJECTIVE: Evaluate ATX-101 versus placebo for reducing submental fat. MATERIALS AND METHODS: Adults with unwanted submental fat across 6 global sites were randomized to ATX-101 (0.5%, 1.0%, or 2.0%) or placebo for ≤4 treatments every 28 days. Outcomes included safety (adverse events and pain visual analog scale) throughout the study and efficacy (submental fat rating, patient satisfaction, and submental fat improvements) at Week 16. RESULTS: Eighty-four of 85 enrolled patients received ≥1 ATX-101 treatment (0.5% [n = 20], 1.0% [n = 20], 2.0% [n = 22] or placebo [n = 22]). Most patients (n = 82) experienced adverse events, which were mostly mild/moderate, seemed to be dose-related, and led to no study discontinuations. The mean pain scores were highest in the ATX-101 1.0% and 2.0% groups. Week-16 change from baseline in the submental fat rating scale was significantly greater for ATX-101 0.5% and 1.0% versus placebo (p ≤ .05). At Week 16, 71%, 74%, 53%, and 40% of patients in the ATX-101 0.5%, 1.0%, 2.0%, and placebo groups, respectively, achieved a ≥1-grade reduction in submental fat from baseline. Satisfaction with appearance and patient-assessed global improvement ratings increased in all ATX-101 treatment groups versus placebo. CONCLUSION: All ATX-101 concentrations were safe and efficacious for moderate/severe submental fat reduction.

Periorbital Discolouration Diagnosis and Treatment: Evidence-Based Review.

Infraorbital dark circles are a significant esthetic concern with few publications however offering evidence-based recommendations for their classification and consequent management. A literature review has been undertaken to classify dark circles based on etiology: shadowing, vascular, idiopathic hyperpigmentation, post-inflammatory hyperpigmentation, constitutional and offer an analysis of current treatment modalities and their effectiveness in managing specific types of infraorbital circles. This review aims to provide a detailed account of dark circle etiology, assessment and management.

Volume restoration of hands with polycaprolactone by cannula delivery; a prospective single center consecutive case series evaluation.

Background: Dorsal hand volume loss results in the perception of aging appearance. Several volumizing fillers have been used for this correction.Objective: To report restoration of dorsal hand volume using cannula delivery of Polycaprolactone (PCL) microspheres and to assess efficacy, duration, and safety up to 3 years post treatment.Method: Fifteen patients with volume loss of their hands were evaluated by clinical examination, photography and a hand volume grading scale. PCL was injected by 25 G cannula after locating dorsal veins using a viewing laser to avoid intravascular injections. Patients' satisfaction and grade of severity were reevaluated at early (3-6 months) and late (12-18 months) timepoints following the procedure. A second treatment was offered if desired by the patient.Results: Eight participants required one treatment session to achieve satisfaction. Five had two treatments. Patients requiring a second treatment were reassessed after 12 months. All patients had improvements on the severity score by the end of the evaluation period. Side effects were minimal and transient. No patients developed bruising.Conclusion: PCL injections are reliable method for hand volumization. Results persisted for up to 3 years in some patients. Laser vein viewer and cannula delivery ensure uniform injections and avoid intravascular injuries.

Fractional radiofrequency in the treatment of skin aging: an evidence-based treatment protocol.

Fractional radiofrequency (FRF) has recently emerged for the treatment of scars, cellulite and skin rejuvenation. The aim of this paper was to investigate the evidence behind its use in skin aging and evaluate efficacy, safety, and standardization of protocols. The literature was systematically searched and finally 25 full-text articles were included. Two were randomized controlled trials, 3 were comparative studies, and 20 were case series. Most studies were underpowered with low methodological quality. The participants had skin phototype I-VI with variable baseline severity of signs. Fractional radiofrequency using microneedles or electrode pins was performed on the face, neck, and décolletage. There was heterogeneity in outcomes measurement, but the efficacy of FRF was confirmed in all relevant studies. Mainly, the improvement of rhytides and skin tightening were reported. Mild to moderate pain, transient erythema and edema were the commonest adverse events. Hyperpigmentation was also noted in some cases. There was no consistency in the protocols used and in the description of procedures. A clinical impact score was created to assess the studies and to aid the generation of an evidence-based protocol for minimally invasive radiofrequency procedures. However, there is a need for large scale, well-designed trials to better investigate the efficacy and safety of FRF and to produce clear guidelines.

Photodynamic Therapy: A Clinical Consensus Guide.

BACKGROUND: The American Society of Dermatologic Surgery (ASDS) periodically develops consensus documents for its members concerning various aspects of dermatologic surgery. Advances in photodynamic therapy (PDT) have been many and PDT use has been established in a variety of skin conditions. OBJECTIVE: The ASDS board of directors proposed a committee of experts in the field to develop consensus documents on different treatments. An expert panel reviewed the literature on PDT and discussed the findings. The consensus was reached with evidence-based recommendations on different clinical applications for PDT. PATIENTS AND METHODS: This consensus document includes discussions regarding PDT, including different photosensitizers and various light source activators, historical perspective, mechanism of action, various therapeutic indications and expected outcomes, pre- and post-care, and management of adverse outcomes. RESULTS: Photodynamic therapy is highly effective for pre-cancerous lesions, superficial nonmelanoma skin cancers, inflammatory acne vulgaris and other conditions. New protocols including laser mediated PDT significantly improve results for several indications. CONCLUSION: The ASDS consensus document on PDT will be helpful for educating members on safe and effective PDT for a variety of indications.

Botulinum toxin type B: pH change reduces injection pain, retains efficacy.

BACKGROUND: Injection of botulinum toxin Type B (BTX-B) is substantially more painful than injection of botulinum toxin Type A (BTX-A). OBJECTIVE: A method of reducing pain with BTX-B injection without reducing efficacy. This was evaluated in 2 BTX-A-resistant subjects and another BTX-B-naive subject. METHODS: Clinical evaluation and computer analysis of photographs were used to confirm efficacy to different dilutions of Type B toxin and confirm BTX-A resistance. A pilot study of 3 subjects involves BTX-B (usually pH 5.6) that was diluted with sodium bicarbonate to normalize the pH to 7.5 in the syringe immediately before injection. Pain assessment compared the different pH BTX-B solutions. RESULTS: Two patients with acquired resistance to 3 BTX-As in upper facial muscles responded to BTX-B. Injection pain of BTX-B changed to pH 7.5 was significantly reduced and retained efficacy over 10 weeks. CONCLUSION: Botulinum toxin Type A resistance is documented to 3 BTX-A brands in 2 patients. They had received low doses of Type A toxin, they responded to Type B toxin. Injection pain of the acidic solution of BTX-B neurotoxin was reduced and efficacy not compromised by changing pH of BTX-B solution to pH 7.5. This method improved patient tolerance to BTX-B injections.

Treatment of hyperhidrosis with Botox (onabotulinumtoxinA): Development, insights, and impact.

Hyperhidrosis (chronic excessive sweating) may substantially affect an individual's emotional and social well-being. Therapies available before onabotulinumtoxinA were generally topical, with limited effectiveness, application-site skin reactions, and frequent, time-consuming treatments. Intradermal injection of onabotulinumtoxinA to treat sweat glands arose as a novel therapeutic approach. To develop this treatment, appropriate dosing needed to be established, and training on administration was required. Further, no previous scale existed to measure the effects of hyperhidrosis on patients' lives, leading Allergan to develop and validate the 4-point Hyperhidrosis Disease Severity Scale (HDSS), which measures the disease's impact on daily activities. The onabotulinumtoxinA clinical development program for hyperhidrosis included 2 double-blind, placebo-controlled pivotal trials, immunogenicity studies, long-term studies of safety and efficacy, and quality of life assessments. In Europe and North America, the primary efficacy measures were, respectively, axillary sweat production measured gravimetrically and HDSS improvement. Compared with placebo, onabotulinumtoxinA treatment significantly reduced axillary sweat production and axillary hyperhidrosis severity, as measured by a 2-point or greater reduction on the HDSS. The effects of onabotulinumtoxinA occurred rapidly, within 1 week after injection, and lasted ≥6 months. Treatment with onabotulinumtoxinA was associated with significant quality of life improvements based on Short Form-12 physical and mental component scores. The Hyperhidrosis Impact Questionnaire also indicated greater treatment satisfaction, reduced negative impact on aspects of daily life, and improved emotional well-being with onabotulinumtoxinA versus placebo. The clinical development program and subsequent clinical experience showed that onabotulinumtoxinA treatment for hyperhidrosis was well tolerated with no new safety signals, and led to greater disease awareness.

Treatment of crow's feet lines and forehead lines with Botox (onabotulinumtoxinA): Development, insights, and impact.

Extrinsic and age-related intrinsic factors contribute to the development of facial lines, including lateral canthal lines (called crow's feet lines [CFL]) and horizontal forehead lines (FHL). OnabotulinumtoxinA is a highly effective treatment for facial lines that inhibits acetylcholine release at the neuromuscular junction. This temporary chemical denervation leads to localized muscle relaxation and subsequent wrinkle reduction. Early studies of onabotulinumtoxinA treatment for facial neuronal disorders such as dystonia documented improvements in FHL and CFL. After the neurotoxin was approved for treating frown lines (glabellar lines [GL]), individuals requested treatment for other rhytids, and physicians continued assessing use in new areas. Once onabotulinumtoxinA was in clinical trial development, its efficacy and safety for CFL and FHL were successively evaluated as required by the US Food and Drug Administration and by key global health authorities, including those in the European Union, Japan, and China. Allergan, collaborating with leading physicians, established clinical programs that included novel safety and efficacy measures to meet regulatory requirements. Global, phase 3, randomized, controlled studies of CFL and FHL met rigorous primary endpoints. Some countries mandated clinical trial data beyond US and European regulations, and Allergan conducted 11 studies in total, fulfilling diverse regulatory and study population data requirements. Adverse events associated with local spread, including brow and eyelid ptosis, diplopia, headache, and eyelid sensory disorder, were infrequent and well tolerated. Consequently, onabotulinumtoxinA treatment of upper facial lines is now established globally as a highly effective, minimally invasive treatment for patients to achieve a natural appearance and look younger.

Nonnucleoside reverse transcriptase inhibitor-resistant HIV is stimulated by efavirenz during early stages of infection.

Nonnucleoside reverse transcriptase inhibitors (NNRTIs) are potent and commonly prescribed antiviral agents used in combination therapy (CART) of human immunodeficiency virus type 1 (HIV-1) infection. The development of drug resistance is a major limitation of CART. Reverse transcriptase (RT) genotypes with the NNRTI resistance mutations K101E+G190S are highly resistant to efavirenz (EFV) and can develop during failure of EFV-containing regimens in patients. We have previously shown that virus with K101E+G190S mutations can replicate more efficiently in the presence of EFV than in its absence. In this study, we evaluated the underlying mechanism for drug-dependent stimulation, using a single-cycle cell culture assay in which EFV was added either during the infection or the virus production step. We determined that EFV stimulates K101E+G190S virus during early infection and does not affect late steps of virus replication, such as increasing the amount of active RT incorporated into virions. Additionally, we showed that another NNRTI, nevirapine (NVP), stimulated K101E+G190S virus replication during the early steps of infection similar to EFV, but that the newest NNRTI, etravirine (ETR), did not. We also showed that EFV stimulates K101E+Y188L and K101E+V106I virus, but not K101E+L100I, K101E+K103N, K101E+Y181C, or K101E+G190A virus, suggesting that the stimulation is mutation specific. Real-time PCR of reverse transcription intermediates showed that although the drug did not stimulate minus-strand transfer, it did stimulate minus-strand strong-stop DNA synthesis. Our results indicate that stimulation most likely occurs through a mechanism whereby NNRTIs stimulate priming or elongation of the tRNA.

Four methods of evaluation of facial erythema and pigment treated with intense pulsed light or cream.

AIM: To evaluate methods of evaluation of patients with mild to moderate facial pigmentation or erythema and compare clinical and photographic grading with instrumental evaluation. METHODS: Of the 24 female subjects treated, 12 were treated with intense pulsed light (IPL) and 12 were treated with daily cream program. Evaluations before and at 16 weeks consisted of: 1. Clinical examination and severity grading by a dermatologist without knowledge of treatment given. 2. Standardised photographs were evaluated by two other dermatologists without knowledge of treatment given. 3. A computer controlled photographic skin analysis systems was used to grade severity of erythema and pigmentation. 4. Subjects were asked to assess their response at the end of a 16-week period, that is, subject self-evaluation. RESULTS: On clinical evaluation of IPL subjects, 12 showed improvement. Of the cream subjects, 11 showed improvement. There was correlation between dermatologist facial examination and the instrumental method. Overall the different assessments showed a slightly greater trend for improvement with IPL treatments for erythema and pigmentation, but no statistical differences were found between the treatments using Student's t-test and Anova analysis of comparative improvement.

Three-dimensional digital surface imaging measurement of the volumizing effect of injectable poly-L-lactic acid for nasolabial folds.

INTRODUCTION: Injectable poly-l-lactic acid (PLLA) is a biocompatible and biodegradable polymer device indicated in Europe for correction of facial contour deficiencies, with a gradual onset of effect that is maintained for up to 25 months. METHODS: In this single-centre, open-label study, 20 adult subjects seeking treatment for facial contour deficiencies were treated with injectable PLLA every 4-6 weeks for ≤6 months or until optimal correction (0 or 1 on nasolabial photonumeric wrinkle assessment scale [0 = no wrinkles; 5 = very deep wrinkles, redundant fold]). 3-D digital surface imaging and standardized 2-D photography were used to assess mid-face and nasolabial volumetric correction and clinical improvement, respectively. RESULTS: Based on 3-D digital surface imaging, statistically significant increases in average mid-facial volume occurred with injectable PLLA after the first injection session and persisted through to the end of treatment. Investigator and subject ratings of 'much improved' or 'excellent' improvement were reported using 2-D photographs as a visual aid. Subjects reported high levels of satisfaction. No serious adverse events were reported. DISCUSSION: In this study, injectable PLLA was found to be safe and effective for mid-face and nasolabial fold volumetric correction.

Investigator global evaluations of efficacy of injectable poly-L-lactic acid versus human collagen in the correction of nasolabial fold wrinkles.

BACKGROUND: Injectable poly-L-lactic acid (PLLA) is indicated in the United States for use in immune-competent patients for correction of shallow-to-deep nasolabial fold contour deficiencies and other facial wrinkles in which a deep dermal grid pattern injection technique is appropriate. It is also indicated for restoration and/or correction of signs of lipoatrophy in patients with human immunodeficiency virus. OBJECTIVE: The authors examine the efficacy of injectable PLLA for correction of nasolabial fold wrinkles, based on Investigator Global Evaluations (IGE). METHODS: A randomized, multicenter, subject-blinded, parallel-group study compared injectable PLLA versus human collagen for correction of nasolabial fold wrinkles for 13 months after up to four treatments (intent-to-treat population, 233). Injectable PLLA-treated subjects were followed up for an additional 12 months (total, 25 months) after the final treatment session. Efficacy was also assessed through secondary IGE for improvement, which is the subject of this report. RESULTS: IGE reports of improvement were significantly greater in subjects who received injectable PLLA versus those who received human collagen (p < .001). Overall improvement with injectable PLLA was 100% three weeks after the final treatment, remaining above 85% through month 25. Overall IGE of improvement with human collagen declined from 94.0% at week three to 6.0% at month 13. Both treatment groups had similar safety profiles. CONCLUSIONS: IGE of improvement were significantly greater with injectable PLLA treatment than with human collagen treatment at all time points following the last treatment. Injectable PLLA treatment continued to show a beneficial effect for up to 25 months.

The use of simulation in medical student education on the topic of breaking bad news: A systematic review.

BACKGROUND: Simulated patients (SPs) are widely used, but the most effective way of utilising them in undergraduate breaking bad news (BBN) medical education is unknown. OBJECTIVES: To conduct a systematic review into SP's use in developing BBN skills in medical students. METHODS: 14 databases searched with the terms "Medical education", "Patient simulation", "Bad news". Data was systematically extracted, and thematic analysis undertaken. RESULTS: Of 2117 articles screened, 29 publications met the inclusion criteria. These demonstrated a variety of SP models, including actors as patients (65.5%), peers (7.0%), and cancer survivors (3.5%). with delivery at varying times in the curricula. SPs are uniformly reported as having positive impact, but there is a lack of high-quality evidence comparing the use of differing forms of training. There was some evidence that virtual SPs were as useful as in-person SPs. CONCLUSIONS: SPs allow students to practise vital BBN communication skills without risking detriment to patient care. Despite the heterogeneity of ways in which SPs have been used, the benefits of different approaches and when and how these should be delivered remains unclear. PRACTICE IMPLICATIONS: Further educational development and research is needed about the use of SPs to support undergraduate BBN communication skills development.

Acyclovir-Resistant Cutaneous Herpes Simplex Virus in DOCK8 Deficiency.

Patients with dedicator of cytokinesis 8 (DOCK8) deficiency are susceptible to development of severe viral cutaneous infections, including herpes simplex virus (HSV). We report a 32-month-old girl with homozygous DOCK8 deficiency who developed a posterior auricular cutaneous lesion that was culture positive for HSV despite acyclovir prophylaxis. Resolution of this lesion was only observed after addition of foscarnet to the treatment regimen. Prophylactic acyclovir may be insufficient for suppression of cutaneous HSV in patients with DOCK8 deficiency, and a high index of suspicion for viral resistance is necessary for prompt initiation of appropriate antiviral treatment in these patients.

Assessment of Natural Sunlight Protection Provided by 10 High-SPF Broad-Spectrum Sunscreens and Sun-Protective Fabrics.

In 1978, the FDA Advisory Panel proposed both indoor and natural sunlight SPF testing methods but reverted to indoor testing only in 1993. Today's sunscreen sun protection and broad-spectrum claims are based on mandated clinical tests using solar simulators and in vitro spectrophotometers. This research evaluated the protection of 10 high-SPF (30-110), broad-spectrum sunscreen products, as well as 6 sun-protective fabrics against natural sunlight in Arequipa, Peru. Each of the 17 subjects was exposed to natural sunlight for 1 h and 59 min under clear skies, with temperatures and humidity similar to those in an indoor clinical laboratory. Test sites were photographed 16-24 h later. Four dermatologists evaluated the photographs for erythema and persistent pigment darkening (PPD). Perceptible sun-induced skin injury (sunburn and/or pigmentation) was detected at 97% of the sunscreen-protected scores. The most sun-sensitive subjects obtained the least erythema protection. The higher the SPF was, the higher the erythema protection, but the intensity of PPD was also higher. The 2 sunscreens using only FDA-approved sunscreen filters rated 30 SPF and 45+ SPF performed poorly: Eighty-one percent of the 136 scores were graded 1 minimal erythema dose or higher erythema, achieving, at a maximum, SPF of 5-7 in natural sunlight. Sun-protective fabrics tested provided excellent sun protection. The erythema and PPD observed through the sunscreens in less than 2 h are incongruous with the broad-spectrum, high-SPF sunscreen claims. Reapplying these sunscreens and staying in the sun longer, as stated on the product labels, would have subjected the subjects to even more UV exposure. High-SPF, broad-spectrum sunscreen claims based on indoor solar simulator testing do not agree with the natural sunlight protection test results.

Cannabis, alcohol and other drug findings in fatally injured drivers in Ontario.

OBJECTIVE: The purpose of this study was to determine the prevalence of cannabis, alcohol and other drug use in drivers of motor vehicles who died in crashes in the Canadian province of Ontario from January 2016 through December 2018 along with the characteristics of these drivers and some of the circumstances of the crash in which they were involved. METHODS: Toxicological tests were performed on blood samples obtained from 921 driver fatalities for whom postmortem blood samples were submitted to the Center of Forensic Sciences for analysis. The results were coded into a database along with basic demographic and crash characteristics and examined for prominent characteristics and patterns. RESULTS: Overall, among the 921 cases examined, 495 (53.7%) tested positive for alcohol, cannabis (tetrahydrocannabinol or THC), or another psychoactive drug. The number of cases that tested positive for THC (251) exceeded the number of cases that tested positive for alcohol (241) as well as the number that tested positive for a drug other than THC (235). In 38% of positive cases, more than one substance was detected. Alcohol and THC were most commonly detected among males; females most frequently tested positive for a drug other than THC, notably medications with depressant effects. Alcohol-involved driver fatalities were most common on weekends and most likely involved single vehicle crashes. Driver fatalities that tested positive for THC or another drug were more evenly distributed throughout the week and were more likely to have been in multi-vehicle crashes. CONCLUSIONS: The present study highlights the use of cannabis and other drugs by drivers. The patterns of crashes and the characteristics of drivers involved indicate that the characteristics of driver fatalities involving cannabis and/or other drug use differ from those of alcohol and require new, innovative approaches targeting high-risk times, groups and behaviors. Continued monitoring of the toxicological findings from blood samples obtained from drivers killed in motor vehicle crashes will be a key element in efforts to reduce the impact of drug use by drivers on road safety.

Homeostatic control of nuclear-encoded mitochondrial gene expression by the histone variant H2A.Z is essential for neuronal survival.

Histone variants are crucial regulators of chromatin structure and gene transcription, yet their functions within the brain remain largely unexplored. Here, we show that the H2A histone variant H2A.Z is essential for neuronal survival. Mice lacking H2A.Z in GABAergic neurons or Purkinje cells (PCs) present with a progressive cerebellar ataxia accompanied by widespread degeneration of PCs. Ablation of H2A.Z in other neuronal subtypes also triggers cell death. H2A.Z binds to the promoters of key nuclear-encoded mitochondrial genes to regulate their expression and promote organelle function. Bolstering mitochondrial activity genetically or by organelle transplant enhances the survival of H2A.Z-ablated neurons. Changes in bioenergetic status alter H2A.Z occupancy at the promoters of nuclear-encoded mitochondrial genes, an adaptive response essential for cell survival. Our results highlight that H2A.Z fulfills a key, conserved role in neuronal survival by acting as a transcriptional rheostat to regulate the expression of genes critical to mitochondrial function.

A randomized study of the efficacy and safety of injectable poly-L-lactic acid versus human-based collagen implant in the treatment of nasolabial fold wrinkles.

BACKGROUND: Injectable poly-L-lactic acid (PLLA) is a synthetic, biodegradable, biocompatible polymer device. OBJECTIVE: We sought to compare the efficacy and safety of injectable PLLA with human-derived collagen in treating nasolabial fold wrinkles. METHODS: In this randomized, evaluator-blinded, parallel-group, multicenter study, subjects received injectable PLLA (n = 116) or collagen (n = 117) injections (1-4 visits, 3-week intervals). Wrinkle Assessment Scale scores were calculated at screening; posttreatment week 3; months 3, 6, 9, and 13 (injectable PLLA or collagen groups); and months 19 and 25 (injectable PLLA group). Safety data were obtained from subject interviews and case report forms. RESULTS: Injectable PLLA significantly improved mean Wrinkle Assessment Scale scores (all time points, P < .001). Improvements (up to 25 months after last treatment) were significantly greater (P < .001) than with collagen for posttreatment months 3 to 13. LIMITATIONS: Mostly white women and subjects with Fitzpatrick skin types II and III were included. CONCLUSION: Injectable PLLA provides well-tolerated, effective, and long-lasting (up to 25 months) nasolabial fold wrinkle correction.