Neonatal respiratory care practice among level III and IV NICUs in New England.

OBJECTIVES: To assess respiratory care guidelines and explore variations in management of very low birth weight (VLBW) infants within a collaborative care framework. Additionally, to gather clinical leaders' perspectives on guidelines and preferences for ventilation modalities. STUDY DESIGN: Leaders from each NICU participated in a practice survey regarding the prevalence of unit clinical guidelines, and management, at many stages of care. RESULTS: Units have an average of 4.3 (±2.1) guidelines, of 9 topics queried. Guideline prevalence was not associated with practice or outcomes. An FiO2 requirement of 0.3-0.4 and a CPAP of 6-7 cmH2O, are the most common thresholds for surfactant administration, which is most often done after intubation, and followed by weaning from ventilatory support. Volume targeted ventilation is commonly used. Extubation criteria vary widely. CONCLUSIONS: Results identify trends and areas of variation and suggest that the presence of guidelines alone is not predictive of outcome.

Frequency of phototherapy for treating psoriasis: a systematic review.

INTRODUCTION: Narrow band ultraviolet B (NB-UVB) and psoralen-ultraviolet A (PUVA) remain inexpensive and effective anti-psoriatic therapies adopted worldwide with different frequency protocols. We aimed to systematically assess the evidence on the effects of different frequency protocols of phototherapy in treating psoriasis. EVIDENCE ACQUISITION: We used the following terms, namely "photochemotherapy," "phototherapy," "psoriasis," "UVB," "UVA" and "ultraviolet therapy," to search the Cochrane Controlled Register of Trials, MEDLINE and Embase databases on August 1, 2019. We organized results using a PRISMA diagram and analyzed bias risks with RoB-2 tool. EVIDENCE SYNTHESIS: We included five randomized controlled trials (RCTs) on oral PUVA and three RCTs on NB-UVB. The five studies on PUVA included a total of 1452 patients with plaque psoriasis and did not find any significant difference in efficacy comparing two- vs. three- vs. four times weekly protocols. The three studies on NB-UVB included a total of 248 patients with plaque psoriasis. No differences in efficacy were reported in comparing different frequencies in delivering NB-UVB, namely twice vs. thrice weekly, twice vs. four times weekly, and thrice- vs. five times weekly protocols. Although protocols with higher treatments frequency per week achieved clearance faster than lower frequency ones, but they did not differ in terms of efficacy. CONCLUSIONS: PUVA and NB-UVB remain effective anti-psoriatic treatments; however further studies are needed to elucidate which protocol may be more effective in different skin phototypes.

Safety Profile of Thread Lifts on the Face and Neck: An Evidence-Based Systematic Review.

BACKGROUND: "Thread lifting" has quickly gained popularity as a minimally invasive treatment for facial rejuvenation. However, the effectiveness is questionable, and the safety and adverse effects are often not discussed. OBJECTIVE: To identify and discuss the adverse effects associated with various types of threads. MATERIALS AND METHODS: Studies describing the use of thread lifts were identified using a PubMed search. Inclusion criteria included studies in which barbed and nonbarbed threads were used for the face and neck. RESULTS: Fifty-nine articles consisting of 14,222 patients (14,134 barbed, 81 nonbarbed, and 7 combined cases) were included. The most common side effects overall were facial asymmetry (n = 6,143), edema/tumefaction (n = 453), and ecchymosis (n = 407). Serious adverse effects were rare and consisted of paresthesias, alopecia, and injuries to vessels/glands. Most adverse effects were transient and self-resolving, with the exception of contour irregularities, injuries to vessels/glands, infections, and inflammatory reactions. CONCLUSION: Most side effects associated with threads were self-resolving, whereas more serious cases subsided with treatment. Future studies are critical to further determine whether thread lifting provides long-lasting, safe, and satisfying results.

Safety Profile for Microneedling: A Systematic Review.

BACKGROUND: Microneedling is a minimally invasive procedure that stimulates collagen and elastin proliferation. It is used in the treatment of various skin pathologies, that is, scarring, photodamage, and hair loss; however, its safety profile has yet to be comprehensively reviewed. OBJECTIVE: This review will discuss the reported side effects of microneedling in the current literature and delineate factors that increase the risk of complications. MATERIALS AND METHODS: A literature search in August 2019 was conducted using the PubMed database to identify studies reporting adverse events (AEs) after microneedling therapy. RESULTS: Eighty-five articles were included in this systematic review. The most common reported AEs are transient procedural events that are expected postprocedure lasting up to 7 days, such as transient erythema/edema and pain, postinflammatory hyperpigmentation (PIH), dry skin/exfoliation, lymphadenopathy, and irritant contact dermatitis. Persistent serious adverse effects included PIH, tram-track scarring, and granulomatous reactions. Factors that increase the risk of events are active infections, darker skin, and metal allergies. CONCLUSION: Microneedling is a relatively safe therapy. Most reported AEs are minimal, resolving quickly and spontaneously. Caution should be taken in patients with active infection, darker skin types, metal allergies, and when used in conjunction with products not approved for intradermal use.

The global, regional, and national burden of atopic dermatitis in 195 countries and territories: An ecological study from the Global Burden of Disease Study 2017.

INTRODUCTION: Numerous population-based studies have focused on the global prevalence of atopic dermatitis (AD), but there are few studies on the global trends of the burden associated with AD. METHODS: We analyzed the global AD trends in 2017 in 195 countries worldwide using the Global Burden of Disease (GBD) Study database, including prevalence rates, age and sex patterns, and AD burden, using disability-adjusted life years (DALYs). Age-standardized DALYs were also compared to the sociodemographic index values of all the countries in 2017. RESULTS: The age-specific DALYs in 2017 showed a right-skewed distribution, with the highest DALYs between 1 and 5 years of age. Females had a higher burden of AD throughout all age groups and geographic regions. The GBD super region with the greatest burden of DALYs caused by AD was high income (178.63 DALYs per 100,000 males, 231.8 for females), and the country with the highest DALYs was Sweden (326.91). The GBD super region with the lowest age-standardized DALY burden caused by AD was south Asia (84.51 DALYs per 100,000 males, 100.54 for females). CONCLUSION: There is a large GBD caused by AD. The observed burden is the greatest in resource-rich countries, females, and young children.

The global, regional, and national burden of fungal skin diseases in 195 countries and territories: A cross-sectional analysis from the Global Burden of Disease Study 2017.

INTRODUCTION: Fungal skin diseases are highly prevalent worldwide, but few existing studies focus on the burden of dermatomycoses. METHODS: An analysis of fungal skin disease trends in 2017 in 195 countries worldwide was conducted using the Global Burden of Disease Study database, including prevalence rates, age and sex patterns, and fungal burden, using disability-adjusted life years (DALYs). Age-standardized DALYs were also compared to the sociodemographic index values of all the countries in 2017. RESULTS: The age-specific fungal skin disease DALYs in 2017 showed a right-skewed distribution, with a peak between 1 and 5 years of age. The world region with the greatest burden of fungal skin disease was sub-Saharan Africa (DALY rate 89.3 per 100,000 males, 78.42 for females), and the individual country with the greatest DALY rate was Mali (122). The Global Burden of Disease super region with the lowest fungal skin disease burden had high incomes (DALY rate 33.12 per 100,000 males, 30.16 for females), which includes southern Latin America, western Europe, high-income North America, Australasia, and high-income southern Pacific. CONCLUSION: Skin mycoses place a substantial burden on patients worldwide. This burden is the greatest in resource-poor countries, tropical regions, and children between 1 and 5 years of age. DALYs can potentially serve as a purposeful measure for directing health policy resources to improve the global impact of fungal skin disease.

Burden of skin disease and associated socioeconomic status in Asia: A cross-sectional analysis from the Global Burden of Disease Study 1990-2017.

INTRODUCTION: Skin diseases have a significant global impact on quality of life, mental health, and loss of income. The burden of dermatologic conditions and its relationship with socioeconomic status in Asia is currently not well understood. METHODS: We selected Global Burden of Disease Study datasets to analyze disability-adjusted life years (DALYs) in 50 Asian countries, including Central Asia, northern Asia, eastern Asia, western Asia, southeastern Asia, and southern Asia, between 1990 and 2017. We compared DALYs to the socioeconomic status using the sociodemographic index and gross domestic product per capita of a country. Statistical analysis was performed using Pearson's correlation. RESULTS: Some countries had higher or lower than expected age-standardized DALY rates of skin diseases. Asian countries, especially high-income countries, had a high burden of inflammatory dermatoses, including acne, alopecia areata, atopic dermatitis, contact dermatitis, decubitus ulcers, psoriasis, pruritus, and seborrheic dermatitis. The burden of infectious dermatoses was greater in low-income Asian countries. The burden of skin cancer in Asia was relatively low. CONCLUSION: There is a high burden of skin disease, especially inflammatory conditions, in Asian countries, but the burden of individual dermatoses in Asia varies by country and socioeconomic status. DALYs can potentially serve as a purposeful measure for directing resources to improve the burden of skin disease in Asia.

Validated Outcome Measures and Postsurgical Scar Assessment Instruments in Auricular Surgery: A Systematic Review.

BACKGROUND: The utilization of an assessment instrument that successfully analyzes validated outcome measures for auricular surgery is important for advancing evidence-based medicine. OBJECTIVE: To systematically review postsurgical scar assessment instruments and outcome measures after auricular surgery to assess if any individual or combination of 2 assessment instruments encompass all relevant, validated auricular outcome measures. METHODS: Two systematic reviews were conducted using the PubMed/MEDLINE and Ovid databases: one for postauricular surgical outcome measures and another for postsurgical scar assessment instruments. Auricular outcome measure articles were selected for inclusion if they included at least one auricular-specific validated outcome measure, and assessment tool articles were included if they referenced one or more specific tool(s) specifically designed to assess postsurgical scars. Assessment tools were evaluated based on which outcome measures each covered. RESULTS: There was no single postsurgical scar assessment instrument or combination of 2 instruments that covered all outcome measures within the 5 different categories (psychosocial well-being, functional, objective appearance, subjective appearance, and clinical-related outcomes) after auricular surgery. None of the instruments measured functional outcomes, such as the ability to wear glasses and hearing outcomes. CONCLUSION: There is currently no existing postsurgical scar assessment instrument that covers all outcome measures after auricular surgery.

Validated Outcome Measures and Postsurgical Scar Assessment Instruments in Eyelid Surgery: A Systematic Review.

BACKGROUND: Determining which postsurgical scar assessment instruments, if any, cover important eyelid outcome measures can either attest to the strength of one or more instruments or reveal the need for a more comprehensive scale. OBJECTIVE: To systematically review validated outcome measures after eyelid surgery and postsurgical scar assessment tools to see whether any individual or combination of 2 assessment tools encompass all relevant, validated eyelid outcome measures. METHODS: Systematic reviews of validated eyelid outcome measures and postsurgical scar assessment tools were conducted using PubMed/MEDLINE and Ovid. Outcome measure papers that met inclusion criteria were sorted into 8 categories: Patient Subjective, Visual Function, Mechanical Function, Daily Activities, Adverse Effects, Aesthetic Quantitative: Clinical Measurements, Aesthetic Qualitative: Global, and Aesthetic Qualitative: Specific. Outcome measure papers were categorized into tiers of evidence support, and assessment tools were evaluated based on which outcome measures each covered. RESULTS: No one or combination of 2 assessment tools covered all selected eyelid outcome measures. Although measures related to the subjective patient experience were included in several of the assessment scales, none covered measures of visual function or eyelid-specific clinical measurements. CONCLUSION: There is currently no existing postsurgical scar assessment instrument that covers all important eyelid-specific outcome measures.

Ibrexafungerp, a Novel Oral Triterpenoid Antifungal in Development: Overview of Antifungal Activity Against Candida glabrata.

Systemic infections caused by Candida species are an important cause of morbidity and mortality among immunocompromised and non-immunocompromised patients. In particular, Candida glabrata is an emerging species within the Candida family that causes infections ranging from superficial to life-threatening systemic disease. Echinocandins and azoles are typically the first-line therapies used to treat infections caused by C. glabrata, however, there is an increasing prevalence of resistance to these antifungal agents in patients. Thus, a need exists for novel therapies that demonstrate high efficacy against C. glabrata. Ibrexafungerp is a first-in-class glucan synthase inhibitor with oral availability developed to address this increasing antifungal resistance. Ibrexafungerp demonstrates broad in vitro activity against wild-type, azole-resistant, and echinocandin-resistant C. glabrata species. Furthermore, ibrexafungerp has shown efficacy in low pH environments, which suggests its potential effectiveness in treating vulvovaginal candidiasis. Additional preclinical and clinical studies are needed to further examine the mechanism(s) of ibrexafungerp, including acting as a promising new agent for treating C. glabrata infections.

Invasive fungal disease and the immunocompromised host including allogeneic hematopoietic cell transplant recipients: Improved understanding and new strategic approach with sargramostim.

In hosts with damaged or impaired immune systems such as those undergoing hematopoietic cell transplant (HCT) or intensive chemotherapy, breakthrough fungal infections can be fatal. Risk factors for breakthrough infections include severe neutropenia, use of corticosteroids, extended use of broad-spectrum antibiotics, and intensive care unit admission. An individual's cumulative state of immunosuppression directly contributes to the likelihood of experiencing increased infection risk. Incidence of invasive fungal infection (IFI) after HCT may be up to 5-8%. Early intervention may improve IFI outcomes, although many infections are resistant to standard therapies (voriconazole, caspofungin, micafungin, amphotericin B, posaconazole or itraconazole, as single agents or in combination). We review herein several contributing factors that may contribute to the net state of immunosuppression in recipients of HCT. We also review a new approach for IFI utilizing adjunctive therapy with sargramostim, a yeast-derived recombinant human granulocyte-macrophage colony-stimulating factor (rhu GM-CSF).

Pure and Mixed Desmoplastic Melanomas: A Retrospective Clinicopathologic Comparison of 33 Cases.

BACKGROUND: Pure and mixed desmoplastic melanomas (DMs) may have different natural histories and behaviors. METHODS: We conducted a retrospective review of patients diagnosed with DM at our institution between January 1997 and April 2019. A total of 33 unique DMs were identified and subsequently analyzed based on the histologic type (pure vs. mixed). RESULTS: The majority (57.6%) of our cases were classified as pure histology. Patients with pure DMs were more likely to be men (P = 0.035) and be older than 65 years (P = 0.019) compared with patients with mixed DMs. Patients with mixed DM were more likely to have mitoses present (P = 0.001) compared with patients with pure DM. There were no differences in ulceration, perineural invasion, vascular invasion, or survival between patients with pure and mixed histologic subtypes. In addition, no differences in sentinel lymph node biopsy, radiation, or chemotherapy were noted between the 2 histologic subtypes. Immunohistochemistry showed that 27.3% of the pure DMs stained with Melan-A and HMB45 were positive for these immunomarkers. CONCLUSIONS: Pure and mixed variants of DM were found to have similar clinicopathologic characteristics. Patients with the mixed histologic subtype were more likely to have mitoses, but no difference in the therapeutic management or patient survival was seen between the 2 subtypes.

An Initiative to Reduce Preterm Infants Pre-discharge Growth Failure Through Time-specific Feeding Volume Increase.

Very low birth weight infants often demonstrate poor postnatal longitudinal growth, which negatively impacts survival rates and long-term health outcomes. Improving extrauterine growth restriction (EUGR) among extremely premature infants has become a significant focus of quality improvement initiatives. Prior efforts in the University of Massachusetts Memorial Medical Center neonatal intensive care unit were unsuccessful in improving the EUGR rate at discharge. METHODS: The primary aim of this initiative was to improve EUGR at discharge [defined as weight less than 10th percentile for postmenstrual age (PMA)] for infants born ≤32 0/7 weeks from a baseline of 25% to 20% by June 2019. We excluded all small for gestational age infants due to the limitation in the EUGR definition. A multidisciplinary team implemented evidence-based nutritional guideline changes using the Institute of Healthcare Improvement methods. The most notable change was the time-specific feeding volume advancement that increased the goal feeding volume between 31 0/7 and 34 0/7 weeks PMA from 150-160 to 170-180 milliliters per kilogram per day. The team monitored nutritional intake, weight, necrotizing enterocolitis (NEC), bronchopulmonary dysplasia (BPD), and length of stay (LOS). RESULTS: The EUGR rate improved from 25% to 12% after initiation of increased time-specific, enteral feeding guidelines at 31-34 weeks PMA. NEC rate, BPD rate, and LOS remained unchanged throughout the initiative. CONCLUSIONS: By implementing a time-specific volume increase guideline from 31 0/7 to 34 0/7 weeks PMA, the EUGR rate improved from baseline of 25% to 12% without increasing NEC rate, BPD rate, and LOS.

A Second-Generation Fungerp Analog, SCY-247, Shows Potent In Vitro Activity against Candida auris and Other Clinically Relevant Fungal Isolates.

Due to the increase of antifungal drug resistance and difficulties associated with drug administration, new antifungal agents for invasive fungal infections are needed. SCY-247 is a second-generation fungerp antifungal compound that interferes with the synthesis of the fungal cell wall polymer ß-(1,3)-d-glucan. We conducted an extensive antifungal screen of SCY-247 against yeast and mold strains compared with the parent compound ibrexafungerp (IBX; formerly SCY-078) to evaluate the in vitro antifungal properties of SCY-247. SCY-247 demonstrated similar activity to IBX against all of the organisms tested. Moreover, SCY-247 showed a higher percentage of fungicidal activity against the panel of yeast and mold isolates than IBX. Notably, SCY-247 showed considerable antifungal properties against numerous strains of Candida auris Additionally, SCY-247 retained its antifungal activity when evaluated in the presence of synthetic urine, indicating that SCY-247 maintains activity and structural stability under environments with decreased pH levels. Finally, a time-kill study showed SCY-247 has potent anti-Candida, -Aspergillus, and -Scedosporium activity. In summary, SCY-247 has potent antifungal activity against various fungal species, indicating that further studies on this fungerp analog are warranted.

A Second-Generation Fungerp Analog, SCY-247, Shows Potent In Vivo Activity in a Murine Model of Hematogenously Disseminated Candida albicans.

Echinocandins are a first-line therapy for Candida infections through their ability to inhibit the synthesis of polymer ß-(1,3)-d-glucan. However, there has been an emergence of multidrug-resistant fungal species necessitating the development of novel antifungal agents to combat invasive fungal infections. SCY-247, a second-generation glucan synthase inhibitor of the triterpenoid class (fungerps), is currently being developed as a potential therapy option. We determined the pharmacokinetics (PKs) of SCY-247 following oral (gavage) administration in mice and evaluated the efficacy of SCY-247 in a murine model of hematogenously disseminated candidiasis caused by Candida albicans Plasma concentrations of SCY-247 were measurable through the last collected time point in all dose groups. Mean concentrations of SCY-247 increased with dose levels, with concentrations of SCY-247 higher after multiple doses than after a single dose. Treatment with SCY-247 resulted in decreased fungal burden and improvement in survival rates against C. albicans disseminated infection. Treatment with 10 mg/kg of body weight of SCY-247 showed a significant reduction in CFU compared with the untreated control (3-log decrease on average) (P = 0.008). Similarly, 40 mg/kg SCY-247 demonstrated a statistically significant reduction in kidney CFU compared with untreated mice (average log CFU ± SD of 2.38 ± 2.58 versus 6.26 ± 0.51; P = 0.001). Mice treated with SCY-247 at 40 mg/kg exhibited a 100% survival rate at the end of the study, contrasted with 62.5% (5 of 8) survival rate in untreated mice. The results of this investigation indicate that SCY-247 is a promising novel anti-fungal agent with activity against Candida infections.

Macrophage Response to Simulated Solar Radiation in the Development of Human Malignant Melanoma.

Background: IFN-γ is widely debated regarding its purported anti- or pro-tumorigenic properties. We initiated a pilot study of primary malignant melanoma patients to investigate whether macrophage-derived IFN-γ is produced in humans as proposed in murine melanomagenesis models. Methods: Biopsy specimens of fresh-frozen primary melanoma tissue were used to quantify co-localization of IFN-γ, macrophages, lymphocytes, and downstream IFN-γ signatures. Additionally, we analyzed simulated solar radiation (SSR) exposed skin in patients with a history of melanoma versus healthy controls to compare the relative magnitude of macrophage infiltration. Results: Our data identified a subset of tumor infiltrating CD68+ macrophages that co-localized with IFN-γ (Pearson's Correlation = 0.33 ± 0.11) in patients with primary melanoma (Stage 0-III). Additionally, a population of infiltrating CD3+ lymphocytes strongly co-localized with IFN-γ (Pearson's Correlation = 0.57 ± 0.11). Malignant melanoma cells were double positive for downstream IFN-γ response elements, MIG/CXCL9, and phosphorylated STAT-1 (P-STAT-1). Cellular signaling pathways were also observed when we exposed the skin of melanoma patients to SSR. Despite robust CXCL9 expression in the epidermis of SSR-exposed skin of melanoma patients, we observed decreased macrophage infiltration into melanoma patient skin. Conclusion: Peritumoral macrophages in melanoma patient skin produce IFN-γ and melanocytes appear to exhibit in vivo responsiveness to IFN-γ, such as P-STAT-1 and upregulated CXCL9 expression. However, despite producing CXCL9 in response to SSR, the normal skin of melanoma patients demonstrates a weak leukocyte infiltration. Immune-modulatory studies for the prevention or treatment of human malignant melanoma may need to address complex tissue and melanocyte signaling and crosstalk.

Oral isotretinoin for the treatment of dermatologic conditions other than acne: a systematic review and discussion of future directions.

While isotretinoin has been the gold-standard of therapy for severe acne since its approval in 1982, its anti-inflammatory properties makes it a potentially applicable and versatile therapy for a wide variety of dermatologic conditions yet to be explored. This systematic review comprehensively recounts the success of oral isotretinoin in non-acne cutaneous diseases and provide insight into future directions of isotretinoin utility. A systematic literature review was performed using PubMed. Search terms included "isotretinoin" OR "accutane" AND "skin" OR "dermatology" OR "hair" OR "nails" OR "rosacea" OR "psoriasis" OR "pityriasis rubra pilaris" OR "condyloma acuminata" OR "granuloma annulare" OR "darier's disease" OR "non-melanoma skin cancer" OR "frontal fibrosing alopecia" OR "cutaneous lupus erythematosus" OR "hidradenitis suppurativa" OR "photodamaged skin" OR "skin aging" OR "wart" OR "flat warts" OR "plane warts" OR "lichen planus" OR "dissecting cellulitis" OR "folliculitis decalvans" OR "sebaceous hyperplasia" OR "cutaneous t-cell lymphoma" OR "mycosis fungoides." A total of 169 studies discuss the use of oral isotretinoin for 16 non-acne dermatologic conditions, the most common being non-melanoma skin cancers (0.2-8.2 mg/kg/day), cutaneous T-cell lymphomas (0.5-2 mg/kg/day), and rosacea (0.22-1 mg/kg/day). Inflammatory conditions such as rosacea, granuloma annulare, and hidradenitis suppurativa benefit from lower oral isotretinoin dosage of 0.3-1 mg/kg/day, whereas, hyperkeratotic diseases such as psoriasis and pityriasis rubra pilaris, consistently respond better to higher dosages of up to 2-4 mg/kg/day for lesion clearance. Recurrence of disease following discontinuation of isotretinoin have been reported for rosacea, psoriasis, granuloma annulare, Darier's disease, dissecting cellulitis, and non-melanoma skin cancers. Disease exacerbation was reported in some patients with hidradenitis suppurativa. Off-label isotretinoin is an effective treatment choice for dermatological conditions beyond acne. Further prospective, randomized human trials are needed to clarify when and how to prescribe off-label isotretinoin for maximum efficacy and safety.

Adverse Events Associated With Cryolipolysis: A Systematic Review of the Literature.

BACKGROUND: Cryolipolysis is a popular procedure for people seeking noninvasive body contouring. As with any novel therapy, it is critical for providers to familiarize themselves with related adverse events (AEs), to provide appropriate information to patients before treatment. OBJECTIVE: To describe reported complications and AEs associated with cryolipolysis. MATERIALS AND METHODS: A systematic review was completed using the PubMed database and following search terms: "cryolipolysis" or "lipocryolysis" or "CoolSculpting." Only randomized clinical trials, prospective cohort studies, retrospective studies, case series, and case reports describing AEs related to cryolipolysis as well as studies written in English were included for review. RESULTS: Fifty-three articles were included in this review. The most common AEs associated with cryolipolysis were treatment site erythema, numbness/paresthesia, bruising, and edema. More serious complications of cryolipolysis include severe/persistent pain, dysesthesia, skin hyperpigmentation, motor neuropathy, and paradoxical adipose hyperplasia. CONCLUSION: Cryolipolysis is a safe option for patients seeking noninvasive body contouring. Most reported AEs are minimal and resolve quickly. It is important that physicians are aware of serious, irreversible AEs and are prepared to counsel patients appropriately before treatment.