Capturing the catalytic intermediates of parkin ubiquitination.

Parkin is an E3 ubiquitin ligase implicated in early-onset forms of Parkinson's disease. It catalyzes a transthiolation reaction by accepting ubiquitin (Ub) from an E2 conjugating enzyme, forming a short-lived thioester intermediate, and transfers Ub to mitochondrial membrane substrates to signal mitophagy. A major impediment to the development of Parkinsonism therapeutics is the lack of structural and mechanistic detail for the essential, short-lived transthiolation intermediate. It is not known how Ub is recognized by the catalytic Rcat domain in parkin that enables Ub transfer from an E2~Ub conjugate to the catalytic site and the structure of the transthiolation complex is undetermined. Here, we capture the catalytic intermediate for the Rcat domain of parkin in complex with ubiquitin (Rcat-Ub) and determine its structure using NMR-based chemical shift perturbation experiments. We show that a previously unidentified α-helical region near the Rcat domain is unmasked as a recognition motif for Ub and guides the C-terminus of Ub toward the parkin catalytic site. Further, we apply a combination of guided AlphaFold modeling, chemical cross-linking, and single turnover assays to establish and validate a model of full-length parkin in complex with UbcH7, its donor Ub, and phosphoubiquitin, trapped in the process of transthiolation. Identification of this catalytic intermediate and orientation of Ub with respect to the Rcat domain provides important structural insights into Ub transfer by this E3 ligase and explains how the previously enigmatic Parkinson's pathogenic mutation T415N alters parkin activity.

Parkin and mitochondrial signalling.

Aging, toxic chemicals and changes to the cellular environment are sources of oxidative damage to mitochondria which contribute to neurodegenerative conditions including Parkinson's disease. To counteract this, cells have developed signalling mechanisms to identify and remove select proteins and unhealthy mitochondria to maintain homeostasis. Two important proteins that work in concert to control mitochondrial damage are the protein kinase PINK1 and the E3 ligase parkin. In response to oxidative stress, PINK1 phosphorylates ubiquitin present on proteins at the mitochondrial surface. This signals the translocation of parkin, accelerates further phosphorylation, and stimulates ubiquitination of outer mitochondrial membrane proteins such as Miro1/2 and Mfn1/2. The ubiquitination of these proteins is the key step needed to target them for degradation via the 26S proteasomal machinery or eliminate the entire organelle through mitophagy. This review highlights the signalling mechanisms used by PINK1 and parkin and presents several outstanding questions yet to be resolved.

Clinical Coders' Perspectives on Pressure Injury Coding in Acute Care Services in Victoria, Australia.

Pressure injuries (PIs) substantively impact quality of care during hospital stays, although only when they are severe or acquired as a result of the hospital stay are they reported as quality indicators. Globally, researchers have repeatedly highlighted the need to invest more in quality improvement, risk assessment, prevention, early detection, and care for PI to avoid the higher costs associated with treatment of PI. Coders' perspectives on quality assurance of the clinical coded PI data have never been investigated. This study aimed to explore challenges that hospital coders face in accurately coding and reporting PI data and subsequently, explore reasons why data sources may vary in their reporting of PI data. This article is based upon data collected as part of a multi-phase collaborative project to build capacity for optimizing PI prevention across Monash Partners health services. We have conducted 16 semi-structured phone interviews with clinical coders recruited from four participating health services located in Melbourne, Australia. One of the main findings was that hospital coders often lacked vital information in clinicians' records needed to code PI and report quality indicators accurately and highlighted the need for quality improvement processes for PI clinical documentation. Nursing documentation improvement is a vital component of the complex capacity building programs on PI prevention in acute care services and is relied on by coders. Coders reported the benefit of inter-professional collaborative workshops, where nurses and coders shared their perspectives. Collaborative workshops had the potential to improve coders' knowledge of PI classification and clinicians' understanding of what information should be included when documenting PI in the medical notes. Our findings identified three methods of quality assurance were important to coders to ensure accuracy of PI reporting: (1) training prior to initiation of coding activity and (2) continued education, and (3) audit and feedback communication about how to handle specific complex cases and complex documentation. From a behavioral perspective, most of the coders reported confidence in their own abilities and were open to changes in coding standards. Transitioning from paper-based to electronic records highlighted the need to improve training of both clinicians and coders.

A Text-Based Intervention to Promote Literacy: An RCT.

BACKGROUND AND OBJECTIVES: Children entering kindergarten ready to learn are more likely to thrive. Inequitable access to high-quality, early educational settings creates early educational disparities. TipsByText, a text-message-based program for caregivers of young children, improves literacy of children in preschool, but efficacy for families without access to early childhood education was unknown. METHODS: We conducted a randomized controlled trial with caregivers of 3- and 4-year-olds in 2 public pediatric clinics. Intervention caregivers received TipsByText 3 times a week for 7 months. At pre- and postintervention, we measured child literacy using the Phonological Awareness Literacy Screening Tool (PALS-PreK) and caregiver involvement using the Parent Child Interactivity Scale (PCI). We estimated effects on PALS-PreK and PCI using multivariable linear regression. RESULTS: We enrolled 644 families, excluding 263 because of preschool participation. Compared with excluded children, those included in the study had parents with lower income and educational attainment and who were more likely to be Spanish speaking. Three-quarters of enrollees completed pre- and postintervention assessments. Postintervention PALS-PreK scores revealed an unadjusted treatment effect of 0.260 (P = .040); adjusting for preintervention score, child age, and caregiver language, treatment effect was 0.209 (P = .016), equating to ∼3 months of literacy gains. Effects were greater for firstborn children (0.282 vs 0.178), children in 2-parent families (0.262 vs 0.063), and 4-year-olds (0.436 vs 0.107). The overall effect on PCI was not significant (1.221, P = .124). CONCLUSIONS: The health sector has unique access to difficult-to-reach young children. With this clinic-based texting intervention, we reached underresourced families and increased child literacy levels.

Rapid Review of SARS-CoV-1 and SARS-CoV-2 Viability, Susceptibility to Treatment, and the Disinfection and Reuse of PPE, Particularly Filtering Facepiece Respirators.

In the COVID-19 pandemic caused by SARS-CoV-2, hospitals are often stretched beyond capacity. There are widespread reports of dwindling supplies of personal protective equipment (PPE), particularly N95-type filtering facepiece respirators (FFRs), which are paramount to protect frontline medical/nursing staff, and to minimize further spread of the virus. We carried out a rapid review to summarize the existing literature on the viability of SARS-CoV-2, the efficacy of key potential disinfection procedures against the virus (specifically ultraviolet light and heat), and the impact of these procedures on FFR performance, material integrity, and/or fit. In light of the recent discovery of SARS-CoV-2 and limited associated research, our review also focused on the closely related SARS-CoV-1. We propose a possible whole-of-PPE disinfection solution for potential reuse that could be rapidly instituted in many health care settings, without significant investments in equipment.

Reevaluation of the global warming impacts of algae-derived biofuels to account for possible contributions of nitrous oxide.

The environmental impacts of algae biofuels have been evaluated by life-cycle assessment (LCA); however, these analyses have overlooked nitrous oxide (N2O), a potent greenhouse gas. A literature analysis was performed to estimate algal N2O emissions and assess the impacts of growth conditions on flux magnitudes. Nitrogen source and dissolved oxygen concentration were identified as possible key contributors; therefore, their individual and combined impacts were evaluated using bench-scale experiments. It was observed that maximum N2O emissions (77.5µg/galgae/day) occur under anoxic conditions with nitrite. Conversely, minimum emissions (6.25µg/galgae/day) occur under oxic conditions with nitrate. Aggregated N2O flux estimates were then incorporated into a LCA framework for algae biodiesel. Accounting for "low" N2O emissions mediated no significant increase (<1%) compared to existing GWP estimates; however, "high" N2O emissions mediate an increase of roughly 25%, potentially jeopardizing the anticipated economic and environmental performances of algae biofuels.

Costello syndrome with severe nodulocystic acne: unexpected significant improvement of acanthosis nigricans after oral isotretinoin treatment.

We report the case of 17-year-old female diagnosed with Costello syndrome. Genetic testing provided a proof with G12S mutation in the HRAS gene since 3 years of age with a presentation of severe nodulocystic acne on her face. After 2 months of oral isotretinoin treatment, improvement in her acne was observed. Interestingly, an unexpected significant improvement of acanthosis nigricans on her neck and dorsum of her hands was found as well. We present this case as a successful treatment option by using oral isotretinoin for the treatment of acanthosis nigricans in Costello syndrome patients.

Easter egg hunt dermatitis: systemic allergic contact dermatitis associated with chocolate ingestion.

Pediatric systemic allergic contact dermatitis to nickel has previously been reported in association with cocoa. We present four clinical cases of hypersensitivity temporally associated with chocolate consumption at Easter. Clinicians should be aware of the potential for foods high in nickel to provoke patients with known nickel sensitivity and systemic dermatitis.

Hemorrhagic acneiform lesions in a teenager as the initial presentation of granulomatosis with polyangiitis.

A 19-year-old girl presented with hemorrhagic acneiform lesions on the face for several months that was unresponsive to conventional acne treatment. A biopsy revealed a noninfectious suppurative granulomatous dermatitis with hemorrhage, possibly representing a ruptured folliculitis. A second biopsy revealed chronic granulomatous dermal inflammation and hemorrhage with foreign body giant cells non-infectious by stains. No vasculitis was noted in either biopsy. Later in her course she developed a severe sinusitis and eventually presented with severe fevers, rapid weight loss, sinusitis, and cough. Further workup produced the diagnosis of granulomatosis with polyangiitis (Wegener's granulomatosis). She rapidly improved with intravenous steroids and rituximab. To date, acneiform lesions have only been reported in young adult patients and may represent a clinical manifestation of granulomatosis with polyangiitis unique to this age group, as illustrated in our patient.

Facial angiofibromas in a mosaic pattern tuberous sclerosis: A case report.

Tuberous sclerosis is a rare genetic disorder presenting clinically with multiple hamartomas in different organs including the skin. The cutaneous manifestations include facial angiofibromas, hypopigmented macules (ash leaves), connective tissue nevi (shagreen patches), and periungual fibromas (Koenen tumors). We present a case of facial angiofibromas in a mosaic pattern tuberous sclerosis in an 11-year-old boy.

Allergic contact dermatitis to Pampers Drymax.

We present four cases of children less than 2 years of age, seen in four different practices, with a similar, unique, and specific presentation of diaper dermatitis, all while using Pampers Baby Dry with Drymax technology. To date, no reported cases exist of allergic contact dermatitis to Pampers Dryweave in medical literature.

S100-negative indeterminate cell histiocytosis in an African American child responsive to narrowband ultraviolet B.

Indeterminate cell histiocytosis is a rare cutaneous disease characterized by the presence of dendritic cells that lack Birbeck granules and immunophenotypically shares features of both Langerhans cells and macrophages. We describe a case of a 4-year-old African American boy affected by a disseminated, exclusively mucocutaneous form of indeterminate cell histiocytosis. The eruption was successfully treated with narrowband ultraviolet B. The peculiar negativity of the Langerhans cell marker S100 is also discussed.

Propranolol vs corticosteroids for infantile hemangiomas: a multicenter retrospective analysis.

OBJECTIVE: To determine whether propranolol therapy is safe and effective and superior to oral corticosteroids for treating infantile hemangiomas (IHs). DESIGN: Multicenter retrospective chart review. SETTING: University of Miami and Miami Children's Hospital, Miami, Florida. Patients  The study included 110 patients with IHs. MAIN OUTCOME MEASURES: The percentage of clearance was quantified by documented serial global photography and clinical examinations (length, height, and width) to segregate patients into 2 groups: patients who had clearance of 75% or more and patients who had less than 75% clearance. RESULTS: The mean duration of treatment was 7.9 months for propranolol and 5.2 months for oral corticosteroids. Fifty-six of 68 patients (82%) who were receiving propranolol achieved clearance of 75% or more compared with 12 of 42 patients (29%) who were receiving oral corticosteroids (P < .01). Adverse effects were minimal in the propranolol group: 1 patient had hypoglycemia and 2 patients had a nonspecifice skin eruption that was not associated with propranolol therapy. All 42 patients in the corticosteroid group had 1 or more adverse effects (P < .01). Relapse after discontinuation of propranolol therapy occurred in 2 of the 68 patients; however, both patients responded to propranolol therapy on reinitiation of treatment. Surgical referrals after treatment were required in 8 patients (12%) in the propranolol group and 12 patients (29%) in the oral corticosteroid group (P < .01). CONCLUSIONS: Propranolol therapy was more clinically effective and more cost-effective than oral corticosteroids in treating IHs. It also resulted in fewer surgical interventions and demonstrated better tolerance, with minimal adverse effects, compared with oral corticosteroids. Therefore, propranolol should be considered a first-line agent given its safety and efficacy in the treatment of IHs.

Early localized morphea mimicking an acquired port-wine stain.

Port-wine stains (PWS) and morphea are distinct conditions that are easily recognized and diagnosed in pediatric patients. Rarely, early localized morphea may mimic an acquired PWS. We present 4 such cases, in two of which the initial clinical impression of acquired PWS was thought to be confirmed by histopathology. A diagnosis of morphea was made approximately 6 months to 3 years after the onset of the acquired PWS. Clinicians should be aware that an apparent acquired PWS may be an early manifestation of localized morphea and continue to monitor these lesions.

Halo nevi in Turner syndrome.

Turner syndrome is a genetic disorder characterized by an abnormal or missing X-chromosome. Rarely reported cutaneous manifestations in Turner syndrome include hemangiomas, angiokeratomas, hirsutism, and halo nevi. A recent study demonstrated an increased prevalence of halo nevi in Turner syndrome when compared to vitiligo. We present a case of halo nevi with multiple melanocytic nevi in an 11-year-old patient with Turner syndrome on growth hormone.

Heat treatment increases the incidence of alopecia areata in the C3H/HeJ mouse model.

Alopecia areata (AA) is a common autoimmune disease characterized by non-scarring hair loss. Previous studies have demonstrated an association between AA and physiological/psychological stress. In this study, we investigated the effects of heat treatment, a physiological stress, on AA development in C3H/HeJ mice. Whereas this strain of mice are predisposed to AA at low incidence by 18 months of age, we observed a significant increase in the incidence of hair loss in heat-treated 8-month-old C3H/HeJ mice compared with sham-treated mice. Histological analysis detected mononuclear cell infiltration in anagen hair follicles, a characteristic of AA, in heat-treated mouse skin. As expected, increased expression of induced HSPA1A/B (formerly called HSP70i) was detected in skin samples from heat-treated mice. Importantly, increased HSPA1A/B expression was also detected in skin samples from C3H/HeJ mice that developed AA spontaneously. Our results suggest that induction of HSPA1A/B may precipitate the development of AA in C3H/HeJ mice. For future studies, the C3H/HeJ mice with heat treatment may prove a useful model to investigate stress response in AA.

Excision and grafting of palmoplantar keratoderma.

Palmoplantar keratodermas may present to the clinician with an extremely broad series of clinical findings. Management has also taken on a wide variety of medical and surgical modalities. The literature seems to provide evidence that optimum management consists of surgical excision with skin grafting. It is believed that this will eliminate all of the underlying tissue and associated skin appendages, which are believed to be the source of this abnormal skin entity. We present a case of a patient in which tangential excision with delayed split-thickness skin grafting was performed after initial application of an acellular dermal matrix (Integra). Unfortunately, there was nearly immediate recurrence of this disease, and we, therefore, suggest a more aggressive approach to the initial excision.

Treatment of facial molluscum contagiosum with trichloroacetic acid.

Molluscum contagiosum (MC) virus is a common cutaneous infection in the pediatric population, most commonly affecting school-aged children. Spontaneous clearing of lesions usually occurs over time; however, treatment is often sought due to cosmetic significance, pruritus, or concerns of transmission and autoinoculation. Chemical destruction with cantharidin, which is derived from blister beetle extract, is very safe and highly effective, making it the treatment of choice in the pediatric population. However, treatment of facial lesions or those in the diaper area are not recommended with this agent. Trichloroacetic acid is a safe and effective agent frequently utilized in dermatologic practice, most commonly in the treatment of verrucae. We have successfully used topical trichloroacetic acid to treat facial molluscum contagiousum and present the following technique for proper application.