Work hours, weekend working, nonstandard work schedules and sleep quantity and quality: findings from the UK household longitudinal study.

BACKGROUND: Atypical temporal work patterns such as working longer than the standard 35-40 h/ week, weekend working, and nonstandard work schedules (i.e. outside of the typical 9-5, including but not restricted to shiftwork) are increasingly prevalent in the UK. Aside from occupation-specific studies, little is known about the effects of these atypical temporal work patterns on sleep among workers in the UK, even though poor sleep has been linked to adverse health problems, lower workplace productivity, and economic costs. METHOD: We used regression models to investigate associations between three types of atypical temporal work patterns (long and short weekly work hours, weekend working, and nonstandard schedules) and sleep duration and disturbance using data from over 25,000 employed men and women from 2012-2014 and/or 2015-2017 in the UK Household Longitudinal Study, adjusting for potential confounders and psychosocial work factors. RESULTS: We found that relative to a standard 35-40 h/week, working 55 h/week or more was related to short sleep (less than 7 h/night) and sleep disturbance. Working most/all weekends compared to non-weekends was associated with short sleep, long sleep (more than 8 h/night), and sleep disturbance, as was working nonstandard schedules relative to standard schedules (fixed day-time schedules). Further analyses suggested some gender differences. CONCLUSIONS: These results should prompt employers and policymakers to recognise the need for rest and recovery, consider how the timing and scheduling of work might be improved to better support workers' health and productivity, and consider appropriate compensation for anyone required to work atypical temporal work patterns.

Nivolumab-induced localized genital bullous pemphigoid in a 60-year-old male.

A 60-year-old man with metastatic renal cell carcinoma presented with a 6-month history of a pruritic, exquisitely painful genital eruption appearing 3 months after initiation of nivolumab. Examination demonstrated a poorly defined, lichenified scrotal plaque studded with erosions, yellow crust, and tense vesicles. There was no other lesion on the body or mucosae. Histopathology revealed a subepidermal blister with a mixed lymphocytic, neutrophilic, and eosinophilic infiltrate. Direct immunofluorescence of perilesional skin demonstrated subclinical blister and linear/fibrillary patchy IgG and IgA along the dermoepidermal junction. Bullous pemphigoid (BP) serologies revealed normal IgG BP230 antibodies and minimally elevated IgG BP180 antibodies. Indirect immunofluorescence revealed positive IgG at the basement membrane ("epidermal pattern") in human split skin and monkey esophagus substrates; no IgA antibodies were detected. The patient was diagnosed with nivolumab-induced localized genital BP (LGBP). BP is a reported adverse effect of immune checkpoint inhibitors including nivolumab; however, cases are typically generalized. LGBP is a rare BP variant typically presenting in children and females; there are few reports of LGBP in adult males. We report a novel case of nivolumab-induced LGBP with unique histopathologic and clinical challenges. LGBP should be considered in patients on immune checkpoint inhibitor therapy with bullous genital eruptions.

In vivo cutaneous antinuclear antibody positivity in palisaded neutrophilic and granulomatous dermatitis.

Palisaded neutrophilic and granulomatous dermatitis (PNGD) is commonly associated with underlying systemic inflammatory and neoplastic diseases, infections, and drug reactions. In vivo cutaneous antinuclear antibodies (ANA) have been described in skin biopsies from patients with known autoimmune disorders, but not previously reported in the setting of PNGD. We present two patients with systemic lupus erythematosus (SLE) and histopathologically confirmed PNGD. Direct immunofluorescence (DIF) studies revealed in vivo cutaneous ANA positivity in both patients. DIF findings in the skin mirrored serum autoantibody results. ANA positivity in skin specimens is reported as highly predictive of systemic connective tissue diseases (SCTD), although specific testing is not currently recommended as part of the laboratory work-up or diagnostic criteria for these disorders. In this case report, positive ANA results in skin biopsies of PNGD reflect the serological findings and clinical evidence of SLE in both patients. In vivo cutaneous ANA positivity is an interesting and supportive finding in PNGD in the setting of SCTD.

Dupilumab in the Treatment of Dyshidrosis: A Report of Two Cases.

Dupilumab (Dupixent, Regeneron Pharmaceuticals and Sanofi Genzyme) is a novel biologic medication recently approved by the FDA for the treatment of moderate-to-severe atopic dermatitis in adults who have not achieved adequate control with topical medications. Dyshidrotic eczema is a distinct entity, often considered on the spectrum of atopic dermatitis, that primarily effects the palms and soles; it is often associated with considerable morbidity yet is frequently challenging to treat. We report two cases of recalcitrant dyshidrotic eczema treated successfully with dupilumab at standard dosing. Further studies to establish the efficacy of dupilumab in the treatment of dyshidrosis are warranted.

J Drugs Dermatol. 2018;17(3):355-356.

Malignancies with a tendency to metastasize to the eyelid or ocular structures.

Metastatic tumors to the eye and eyelid are generally seen in patients with disseminated metastases in the setting of advanced disease. Occasionally, they can present as the first sign of occult malignancy. The choroid is the most common site of intraocular metastases secondary to its dense vascular supply. Similar to the eye, metastatic tumors to the eyelid can present with a variety of clinical findings and are most often seen in patients with a known history of cancer. The most common skin malignancy that can spread to ocular structures is cutaneous melanoma, whereas the most common noncutaneous malignancy is breast cancer followed by lung cancer. In pediatric patients, metastatic disease to the eye is rare and can be seen in neuroblastoma and Ewing sarcoma. The overall prognosis of metastatic lesions involving the eye and eyelid is typically poor, with a mean survival of months. Ophthalmologists play an important role in the diagnosis of metastatic disease of the eye and eyelid; therefore, it is imperative for patients to undergo a complete ophthalmic examination and systemic workup if they have new-onset vision changes and a known history of cancer. Early diagnosis and management with systemic and local therapies can maximize quality of life and preserve vision.

Deletion of macrophage migration inhibitory factor worsens stroke outcome in female mice.

Sex is an important factor in the response to ischemic insults in both the laboratory and the clinic. Inflammation and cell death are points where sex-specific pathways diverge in stroke, and serum estrogen level status affect the response to inflammation. The cytokine macrophage migration inhibitory factor (MIF) is detrimental in experimental stroke models in male animals. However MIF is known to have sex-specific actions on inflammation and wound healing. The role of MIF in the ischemic female brain has not been evaluated. A transient middle cerebral artery occlusion (MCAO/90min) model was used to induce stroke in male, intact female, and ovariectomized female wildtype (WT) and MIF knockout (KO) mice. Infarct size was quantified 72h after stroke. Protein and cytokine levels were assessed post stroke. Female MIF KO mice had significantly larger strokes compared to WT females (mean hemispheric infarct±SEM: 63%±2% versus 29%±3%; n=8; p<0.05). Ovariectomized female MIF KO mice also had larger infarcts than ovariectomized WT littermates (70%±3% versus 47%±4%; n=11; p<0.05). In males, however, infarct size was equivalent between MIF KO and WT mice (63%±2% versus 67%±3%; n=9; p=0.25). There were no significant differences in cytokine levels at 6h post-infarct between mice of either genotype in brain. MIF KO females displayed more microglial activation (ionized calcium binding adaptor molecule 1 (Iba1) immunofluorescence) after stroke than did WT mice or MIF KO males. The larger infarcts in MIF KO females were associated with an early increase in mitochondrial localization of Jun activation domain-binding protein 1 (JAB1). Loss of MIF exacerbated injury in the female brain after experimental stroke, which was independent of changes in pro-inflammatory cytokine levels. This response is sex-specific, and is in part independent of physiological serum levels of estrogen.

Neonatal testosterone exposure protects adult male rats from stroke.

BACKGROUND: Men have a higher stroke incidence compared to women until advanced age. The contribution of hormones to these sex differences has been extensively debated. In experimental stroke, estradiol is neuroprotective, whereas androgens are detrimental. However, prior studies have only examined the effects of acute treatment paradigms; therefore, the timing and mechanism by which ischemic sexual dimorphism arises are unknown. METHODS: The effects of exogenous neonatal androgen exposure on subsequent injury induced by middle cerebral artery occlusion in adulthood in male rats were examined. Rats were administered vehicle (oil), testosterone propionate (TP) or the non-aromatizable androgen dihydrotestosterone (DHT) for 5 days after birth. At 3 months of age, a focal stroke was induced. RESULTS: Testosterone-treated rats (but not DHT-treated animals) had decreased infarct volumes (20 vs. 33%, p < 0.05) as well as increased estradiol levels (39.4 vs. 18.6 pg/ml, p < 0.0001) compared to oil-treated animals. TP-injected males had increased testicular aromatase (P450arom) levels (3.6 vs. 0.2 ng/ml, p < 0.0001) compared to oil-treated males. The level of X-linked inhibitor of apoptosis, the primary endogenous inhibitor of caspase-induced apoptosis, was increased in TP-treated rats compared with the oil-treated males. CONCLUSIONS: Neonatal exposure to exogenous testosterone upregulates testicular aromatase expression in male rats and leads to adult neuroprotection secondary to changes in serum estradiol levels and cell death proteins. This study suggests that early exposure to gonadal hormones can have dramatic effects on the response to adult cerebrovascular injury.

Atypical Wells syndrome successfully treated with dupilumab.

Wells syndrome, also referred to as eosinophilic cellulitis, is a rare and often sporadic inflammatory skin condition whose aetiology remains uncertain. Clinically, this condition presents as a collection of erythematous, oedematous, and tender skin lesions most often affecting the extremities and trunk that can mimic cellulitis. Histologically, Wells syndrome is characterised by inflammatory changes and eosinophilic infiltration of the dermis with the absence of underlying infection, thereby distinguishing it from cellulitis. Due to the rarity of this syndrome and its ambiguous presentation, there remains to be a definitive strategy for treatment. Recent case reports have documented varying success and recurrence with the use of oral and topical corticosteroids, antifungals, antibiotics, immunosuppressants and antihistamines. Here, we report a unique case of progressively worsening neutrophilic-rich Wells syndrome on the vertex of the scalp that was successfully treated with a combination of dupilumab and oral corticosteroids.

Dermatofibrosarcoma Protuberans of the Face.

Dermatofibrosarcoma protuberans (DFSP) is a locally aggressive tumor with high rate of local recurrence but low metastatic potential. Its high-grade fibrosarcomatous variant and occurrence on the head and neck are rare findings associated with increased morbidity and mortality. The most significant prognostic feature of DFSP is obtaining tumor free surgical margins. As such, accurate recognition and proper management of this uncommon and locally aggressive malignancy is especially crucial in head and neck surgery.

NF-κB contributes to the detrimental effects of social isolation after experimental stroke.

Social isolation (SI) is increasingly recognized as a risk factor for stroke. Individuals with lack of social support systems have an increased incidence of stroke, poorer recovery, and greater functional decline after injury compared to individuals with social support. Attesting to the importance of social factors in stroke outcome is that these same effects can be reproducibly demonstrated in animals; social interaction improves behavioral deficits and reduces damage after experimental stroke, whereas SI enhances injury. The mechanism by which SI exacerbates injury is unclear. We investigated the role of nuclear factor-kappaB (NF-κB) signaling in male mice that were pair housed (PH) with an ovariectomized female prior to random assignment into continued PH or SI for 7 days prior to middle cerebral artery occlusion. The effects of SI on infarct volume and functional recovery were assessed at 72 h post-stroke. Nuclear NF-κB levels and activity were assessed by Western blot and transcriptional assays. SI significantly exacerbated infarct size in both male and female mice compared to PH mice. SI mice had delayed functional recovery compared to PH mice. An elevation of systemic IL-6 levels, increased nuclear NF-κB transcriptional activity, and enhanced nuclear translocation of NF-κB was seen in SI stroke animals. Interference with NF-κB signaling using either a pharmacological inhibitor or genetically engineered NF-κB p50 knockout mice abolished the detrimental effects of SI on both infarct size and functional recovery. This suggests that NF-κB mediates the detrimental effects of SI.

EMMPRIN/CD147 plays a detrimental role in clinical and experimental ischemic stroke.

BACKGROUND: Ischemic stroke is a devastating disease, often resulting in death or permanent neurological deficits. EMMPRIN/CD147 is a plasma membrane protein that induces the production of matrix metalloproteinases (MMPs), which contribute to secondary damage after stroke by disrupting the blood brain barrier (BBB) and facilitating peripheral leukocyte infiltration into the brain. RESULTS: CD147 surface expression increased significantly after stroke on infiltrating leukocytes, astrocytes and endothelial cells, but not on resident microglia. Inhibition of CD147 reduced MMP levels, decreased ischemic damage, and improved functional, cognitive and histological outcomes after experimental ischemic stroke in both young and aged mice. In stroke patients, high levels of serum CD147 24 hours after stroke predicted poor functional outcome at 12 months. Brain CD147 levels were correlated with MMP-9 and secondary hemorrhage in post-mortem samples from stroke patients. CONCLUSIONS: Acute inhibition of CD147 decreases levels of MMP-9, limits tissue loss, and improves long-term cognitive outcomes following experimental stroke in aged mice. High serum CD147 correlates with poor outcomes in stroke patients. This study identifies CD147 as a novel, clinically relevant target in ischemic stroke.

Long work hours, weekend working and depressive symptoms in men and women: findings from a UK population-based study.

BACKGROUND: Globalised and 24/7 business operations have fuelled demands for people to work long hours and weekends. Research on the mental health effects of these intensive temporal work patterns is sparse, contradictory or has not considered gender differences. Our objective was to examine the relationship between these work patterns and depressive symptoms in a large nationally representative sample of working men and women in the UK. METHOD: The current study analysed data from Understanding Society, the UK Household Longitudinal Study, of 11 215 men and 12 188 women in employment or self-employment at the time of the study. Ordinary least squares regression models, adjusted for potential confounders and psychosocial work factors, were used to estimate depressive symptoms across categories of work hours and weekend work patterns. RESULTS: Relative to a standard 35-40 hours/week, working 55 hours/week or more related to more depressive symptoms among women (ß=0.75, 95% CI 0.12 to 1.39), but not for men (ß=0.24, 95% CI -0.10 to 0.58). Compared with not working weekends, working most or all weekends related to more depressive symptoms for both men (ß=0.34, 95% CI 0.08 to 0.61) and women (ß=0.50, 95% CI 0.20 to 0.79); however, working some weekends only related to more depressive symptoms for men (ß=0.33, 95% CI 0.11 to 0.55), not women (ß=0.17, 95% CI -0.09 to 0.42). CONCLUSION: Increased depressive symptoms were independently linked to working extra-long hours for women, whereas increased depressive symptoms were associated with working weekends for both genders, suggesting these work patterns may contribute to worse mental health.

The good, the bad, and the ugly of medication coverage: Is altering a diagnosis to ensure medication coverage ethical?

Recently, a patient presented to the dermatology clinic suffering from disabling, recurrent palmoplantar vesicles and pustules. Biopsy demonstrated nondiagnostic histologic findings without unequivocal evidence for psoriasis. The localized rash was recalcitrant to a host of standard therapies. An anti-tumor necrosis factor biologic was considered, and experience suggested that this expensive medication would only be approved for coverage if a diagnosis was submitted for a Food and Drug Administration-approved indication as psoriasis. All health-care providers face similar dilemmas in caring for their own patients. To whom is the physician's primary responsibility when what is best for the patient may not align with the realities of our health-care system? Should a physician alter or exaggerate a medical diagnosis to obtain insurance coverage for a needed medication? What are the ethical implications of this action? If the physician's fiduciary duty to the patient had no limits, there would be multiple potential consequences including compromise of the health-care provider's integrity and relationships with patients, other providers, and third-party payers as well as the risk to an individual patient's health and creation of injustices within the health-care system.