Yellow Nail Syndrome

HISTORY: A 62-year-old Caucasian female presented for finger and toenail yellowing with associated poor nail growth and intermittent nail shedding over the past 10 years. She also has a history of recurrent pulmonary effusions and lower extremity lymphedema that was diagnosed at approximately the same time. EXAMINATION: There was yellow discoloration of all fingernails and toenails with prominent distal onycholysis without subungual debris. Lunula and cuticles were absent. Fingernails were more affected than toenails. Some nails had slightly thickened and overly curved nail plates without other dystrophic changes. The bilateral lower legs (left worse than right) demonstrated lymphedema. COURSE AND THERAPY: Nail PAS and fungal culture were negative. Prior to presentation, patient received courses of oral terbinafine and fluconazole without improvement. She was placed on vitamin E 1000 units daily and pulse fluconazole for 3 months. Due to minimal improvement, fluconazole was stopped; however, vitamin E was continued. She also performs dilute vinegar soaks to reduce potential superinfection in the setting of onycholysis. Recently, she underwent pulmonary wedge resection and right partial pleurectomy. With regards to her lymphedema, she has been using home pneumatic compression pumps with transient relief. DISCUSSION: Yellow nail syndrome (YNS) is a rare idiopathic disorder characterized by the triad of yellow nails, lymphedema, and respiratory tract problems, however this classic triad occurs only in about one-third of patients. The diagnosis only requires the presence of the typical nail changes. Lymphedema and respiratory tract involvement may develop before, during, or after the nail dystrophy. YNS affects men and women equally, and typically presents in the fourth to sixth decade of life. All nails may be affected, and nails are usually slow growing or appear to have stopped growing. Nails become thicker and turn a pale yellow or green-yellow color with slightly darker edges. Nails can remain smooth, develop cross-ridging, or prominent curvature transversely and longitudinally. There is a loss of cuticles, and the lunula is no longer visible. Onycholysis may affect one or more nails and may extend proximally to the distal matrix, causing nail shedding. The cause of yellow nail syndrome is relatively unknown with most cases occurring sporadically. Possible etiologies include microangiopathy with protein leakage or dysfunctional lymphatic drainage. Lymphedema occurs in about 80% of patients and most frequently affects legs. Respiratory tract involvement usually manifests as pleural effusions, affecting 36% of patients. Patients can also provide a history of recurrent attacks of bronchitis, chronic sinusitis, and pneumonia. Improvement in respiratory disease has been linked to improvement in the appearance and growth of nails. Vitamin E, recommended at 1200 IU daily, has been reported to improve the appearance of nails. Additionally, pulse therapy with itraconazole or fluconazole has been reported to stimulate nail growth and may be given in combination with vitamin E.https://scholarlycommons.henryford.com/merf2019caserpt/1012/thumbnail.jp

A man with diffuse hyperkeratotic papules and plaques

HISTORY: A 47-year-old African American man with no relevant past medical history presented to Dermatology with a rash that began 2-3 years prior with a sudden onset on the arms and knees and has since spread diffusely. He endorses oral involvement. Denies any history of hepatitis C, syphilis, or HIV. No family history of similar condition. EXAMINATION: Diffusely on the body were many hyperkeratotic scaly papules coalescing into plaques with underlying violaceous macules and patches on the arms, legs, buttocks, and hips. Many papules and plaques were in a linear distribution, suggesting possibility of koebnerization. The mouth had hyperkeratotic papules along the oral commissures, cobblestoning of the palate, and reticulated white streaks on the upper and lower mucosal lip and the left buccal mucosa. HISTOPATHOLOGY: Pathology revealed marked verrucous epidermal hyperplasia with overlying parakeratosis and neutrophils in the stratum corneum. A lichenoid infiltrate at dermal-epidermal junction and necrotic keratinocytes were also seen. Negative HPV staining. DIFFERENTIAL DIAGNOSIS: Hypertrophic lichen planus (HLP) vs keratosis lichenoides chronica (KLC) vs less likely extensive verruca. LABORATORY: CBC and CMP within normal limits. Hepatitis C, syphilis, and HIV negative. DIAGNOSIS: The KLC and HLP present similarly histologically with hyperkeratosis and lichenoid infiltrate with interface change. Given clinical similarity, both are high in the differential in this case. KLC was favored due chronicity of individual lesions and due to the confluent parakeratosis and corneal neutrophils seen on pathology which are uncharacteristic of HLP. COURSE AND THERAPY: At time of presentation, he was on a regimen of acitretin 50 mg daily, betamethasone dipropionate ointment to the body, and tacrolimus 0.1% ointment to the face without significant improvement. Patient was continued on topical steroids and acitretin, and was also started on CellCept 500mg BID, later increased to 1000mg BID. DISCUSSION: HLP and KLC can present similarly with erythematous to violaceous hyperkeratotic papules and plaques. These are usually present on the lower extremities but may present more diffusely, including on the trunk and face. KLC is a rarer condition with a chronic course. Lesions can be pruritic and are typically in a reticular or linear pattern as seen in our patient. Oral and nail involvement, as in our patient, have been reported in about 20-30% of patients. KLC also may present with facial eruption similar to seborrheic dermatitis or rosacea. KLC may present at any age and has a slight male predominance. The etiology of this condition is unknown and given its similarity to other keratotic skin diseases as well as its rarity, it has not been well-studied. Although difficult to treat, oral retinoids such as acitretin and phototherapy have had some documented efficacy in treating KLC.HLP is a variant of lichen planus (LP) with a similar presentation of hyperkeratotic papules and plaques and usually a more chronic course. Lesions often are pruritic and koebnerization may play a role, causing more linear formations. Oral involvement, particularly Wickham striae, or nail changes may also be observed. Given longstanding inflammation, hypertrophic LP may develop malignant transformation to squamous cell carcinomas or keratoacanthomas. Treatments for HLP include topical or intralesional corticosteroids, methotrexate, metronidazole, cyclosporine, dapsone, azathioprine, and phototherapy. Acitretin and mycophenolate mofetil (CellCept) have shown efficacy in resistant HLP.https://scholarlycommons.henryford.com/merf2020caserpt/1002/thumbnail.jp

Radiation and soil temperature interactions on the growth and physiology of eastern white pine (Pinus strobus L.) seedlings

A greenhouse experiment was set up during one growing season to test the hypothesis that soil temperature controls a significant part of the light response of eastern white pine (Pinus strobus L.) seedlings that is observed in the field. The experimental design was a three by three factorial split-plot design, with three levels of light availability: 10%, 40% and 80% of full light; and three levels of soil temperature: 16 °C, 21 °C, and 26 °C in the soil at midday. The results show significant interactions between light and soil temperature factors on several variables (gas exchange, root growth, leaf-mass ratio and leaf–mass per unit area), but not on shoot dry mass. These interactions indicate that, in the field, a significant proportion of the light response of young eastern white pine could result from changes in soil temperature, especially under conditions of limiting water availability. Our results suggest that soil temperature must be taken explicitly into account as a driving variable when relating the growth of young eastern white pine to photosynthetic radiation

Senescence and Inflammatory Markers for Predicting Clinical Progression in Parkinson's Disease: The ICICLE-PD Study.

BACKGROUND: Cognitive decline is a frequent complication of Parkinson's disease (PD) and the identification of predictive biomarkers for it would help in its management. OBJECTIVE: Our aim was to analyse whether senescence markers (telomere length, p16 and p21) or their change over time could help to better predict cognitive and motor progression of newly diagnosed PD patients. We also compared these senescence markers to previously analysed markers of inflammation for the same purpose. METHODS: This study examined the association of blood-derived markers of cell senescence and inflammation with motor and cognitive function over time in an incident PD cohort (the ICICLE-PD study). Participants (154 newly diagnosed PD patients and 99 controls) underwent physical and cognitive assessments over 36 months of follow up. Mean leukocyte telomere length and the expression of senescence markers p21 and p16 were measured at two time points (baseline and 18 months). Additionally, we selected five inflammatory markers from existing baseline data. RESULTS: We found that PD patients had shorter telomeres at baseline and 18 months compared to age-matched healthy controls which also correlated to dementia at 36 months. Baseline p16 levels were associated with faster rates of motor and cognitive decline over 36 months in PD cases, while a simple inflammatory summary score at baseline best predicted cognitive score over this same time period in PD patients. CONCLUSION: Our study suggests that both inflammatory and senescence markers (p16) are valuable predictors of clinical progression in PD patients.This study was supported by a Newcastle upon Tyne Hospital Trust (Brain Research Unit PD0612) grant to GS. ICICLE-PD is funded by Parkinson’s UK (grant no J-0802, G-1301) and supported by the National Institute for Health Research (NIHR) Newcastle Biomedical Research Centre in Ageing and Chronic Disease and the Biomedical Research Unit in Lewy Body Dementia based at Newcastle upon Tyne Hospitals NHS Foundation Trust and Newcastle University (CM-R) and the National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre (146281). This work was also supported by grants from the Academy of Medical Sciences, UK, the Rosetrees Trust, and the Stevenage Biosciences Catalyst. CHWG is supported by a RCUK/UKRI Research Innovation Fellowship awarded by the Medical Research Council (MR/R007446/1). RAB is an NIHR Senior Investigator (NF-SI-0616-10011) and is supported by the WT/MRC Stem Cell Institute (203151/Z/16/Z

Ibrutinib Plus Venetoclax in Relapsed/Refractory Chronic Lymphocytic Leukemia: The CLARITY Study.

PURPOSE:The treatment of chronic lymphocytic leukemia (CLL) has been revolutionized by targeted therapies that either inhibit proliferation (ibrutinib) or reactivate apoptosis (venetoclax). Both significantly improve survival in CLL and replace chemoimmunotherapy for many patients. However, individually, they rarely lead to eradication of measurable residual disease (MRD) and usually are taken indefinitely or until progression. We present the CLARITY trial that combined ibrutinib with venetoclax to eradicate detectable CLL with the intention of stopping therapy. PATIENTS AND METHODS:CLARITY is a phase II trial that combined ibrutinib with venetoclax in patients with relapsed or refractory CLL. The primary end point was eradication of MRD after 12 months of combined therapy. Key secondary end points were response by International Workshop on CLL criteria, safety, and progression-free and overall survival. RESULTS:In 53 patients after 12 months of ibrutinib plus venetoclax, MRD negativity (fewer than one CLL cell in 10,000 leukocytes) was achieved in the blood of 28 (53%) and the marrow of 19 (36%). Forty-seven patients (89%) responded, and 27 (51%) achieved a complete remission. After a median follow-up of 21.1 months, one patient progressed, and all patients were alive. A single case of biochemical tumor lysis syndrome was observed. Other adverse effects were mild and/or manageable and most commonly were neutropenia or GI events. CONCLUSION:The combination of ibrutinib plus venetoclax was well tolerated in patients with relapsed or refractory CLL. There was a high rate of MRD eradication that led to the cessation of therapy in some patients. The progression-free and overall survival rates are encouraging for relapsed and refractory CLL

A Population-Based Study of Childhood Cancer Survivors’ Body Mass Index

Background. Population-based studies are needed to estimate the prevalence of underweight or overweight/obese childhood cancer survivors. Procedure. Adult survivors (diagnosed ≤20 years) were identified from the linked Utah Cancer Registry and Utah Population Database. We included survivors currently aged ≥20 years and ≥5 years from diagnosis (N=1060), and a comparison cohort selected on birth year and sex (N=5410). BMI was calculated from driver license data available from 2000 to 2010. Multivariable generalized linear regression models were used to calculate prevalence relative risks (RR) and 95% confidence intervals (95% CI) of BMI outcomes for survivors and the comparison cohort. Results. Average time since diagnosis was 18.5 years (SD=7.8), and mean age at BMI for both groups was 30.5 (survivors SD=7.7, comparison SD=8.0). Considering all diagnoses, survivors were not at higher risk for being underweight or overweight/obese than the comparison. Male central nervous system tumor survivors were overweight (RR=1.12, 95% CI 1.01–1.23) more often than the comparison. Female survivors, who were diagnosed at age 10 and under, had a 10% higher risk of being obese than survivors diagnosed at ages 16–20 (P<0.05). Conclusion. While certain groups of childhood cancer survivors are at risk for being overweight/obese, in general they do not differ from population estimates

Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans

Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in 25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16 regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of correlated variation was observed at 39 regions; 35 of which are now described by a novel more significantly associated lead SNP, while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in Europeans that had been previously reported only in East-Asian GWAS. Based on statistical evidence and linkage disequilibrium (LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region. Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the refined data for existing association signals, we estimate that these loci now explain ∼38.9% of the familial relative risk of PrCa, an 8.9% improvement over the previously reported GWAS tag SNPs. This suggests that a significant fraction of the heritability of PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent signals within the same regio

Progressive exercise compared with best practice advice, with or without corticosteroid injection, for the treatment of patients with rotator cuff disorders (GRASP): a multicentre, pragmatic, 2 × 2 factorial, randomised controlled trial

Background Corticosteroid injections and physiotherapy exercise programmes are commonly used to treat rotator cuff disorders but the treatments' effectiveness is uncertain. We aimed to compare the clinical effectiveness and cost-effectiveness of a progressive exercise programme with a single session of best practice physiotherapy advice, with or without corticosteroid injection, in adults with a rotator cuff disorder. Methods In this pragmatic, multicentre, superiority, randomised controlled trial (2 × 2 factorial), we recruited patients from 20 UK National Health Service trusts. We included patients aged 18 years or older with a rotator cuff disorder (new episode within the past 6 months). Patients were excluded if they had a history of significant shoulder trauma (eg, dislocation, fracture, or full-thickness tear requiring surgery), neurological disease affecting the shoulder, other shoulder conditions (eg, inflammatory arthritis, frozen shoulder, or glenohumeral joint instability), received corticosteroid injection or physiotherapy for shoulder pain in the past 6 months, or were being considered for surgery. Patients were randomly assigned (centralised computer-generated system, 1:1:1:1) to progressive exercise (≤6 sessions), best practice advice (one session), corticosteroid injection then progressive exercise, or corticosteroid injection then best practice advice. The primary outcome was the Shoulder Pain and Disability Index (SPADI) score over 12 months, analysed on an intention-to-treat basis (statistical significance set at 1%). The trial was registered with the International Standard Randomised Controlled Trial Register, ISRCTN16539266, and EuDRACT, 2016-002991-28. Findings Between March 10, 2017, and May 2, 2019, we screened 2287 patients. 708 patients were randomly assigned to progressive exercise (n=174), best practice advice (n=174), corticosteroid injection then progressive exercise (n=182), or corticosteroid injection then best practice advice (n=178). Over 12 months, SPADI data were available for 166 (95%) patients in the progressive exercise group, 164 (94%) in the best practice advice group, 177 (97%) in the corticosteroid injection then progressive exercise group, and 175 (98%) in the corticosteroid injection then best practice advice group. We found no evidence of a difference in SPADI score between progressive exercise and best practice advice when analysed over 12 months (adjusted mean difference −0·66 [99% CI −4·52 to 3·20]). We also found no evidence of a difference between corticosteroid injection compared with no injection when analysed over 12 months (−1·11 [–4·47 to 2·26]). No serious adverse events were reported. Interpretation Progressive exercise was not superior to a best practice advice session with a physiotherapist in improving shoulder pain and function. Subacromial corticosteroid injection provided no long-term benefit in patients with rotator cuff disorders

State of the climate in 2018

In 2018, the dominant greenhouse gases released into Earth’s atmosphere—carbon dioxide, methane, and nitrous oxide—continued their increase. The annual global average carbon dioxide concentration at Earth’s surface was 407.4 ± 0.1 ppm, the highest in the modern instrumental record and in ice core records dating back 800 000 years. Combined, greenhouse gases and several halogenated gases contribute just over 3 W m−2 to radiative forcing and represent a nearly 43% increase since 1990. Carbon dioxide is responsible for about 65% of this radiative forcing. With a weak La Niña in early 2018 transitioning to a weak El Niño by the year’s end, the global surface (land and ocean) temperature was the fourth highest on record, with only 2015 through 2017 being warmer. Several European countries reported record high annual temperatures. There were also more high, and fewer low, temperature extremes than in nearly all of the 68-year extremes record. Madagascar recorded a record daily temperature of 40.5°C in Morondava in March, while South Korea set its record high of 41.0°C in August in Hongcheon. Nawabshah, Pakistan, recorded its highest temperature of 50.2°C, which may be a new daily world record for April. Globally, the annual lower troposphere temperature was third to seventh highest, depending on the dataset analyzed. The lower stratospheric temperature was approximately fifth lowest. The 2018 Arctic land surface temperature was 1.2°C above the 1981–2010 average, tying for third highest in the 118-year record, following 2016 and 2017. June’s Arctic snow cover extent was almost half of what it was 35 years ago. Across Greenland, however, regional summer temperatures were generally below or near average. Additionally, a satellite survey of 47 glaciers in Greenland indicated a net increase in area for the first time since records began in 1999. Increasing permafrost temperatures were reported at most observation sites in the Arctic, with the overall increase of 0.1°–0.2°C between 2017 and 2018 being comparable to the highest rate of warming ever observed in the region. On 17 March, Arctic sea ice extent marked the second smallest annual maximum in the 38-year record, larger than only 2017. The minimum extent in 2018 was reached on 19 September and again on 23 September, tying 2008 and 2010 for the sixth lowest extent on record. The 23 September date tied 1997 as the latest sea ice minimum date on record. First-year ice now dominates the ice cover, comprising 77% of the March 2018 ice pack compared to 55% during the 1980s. Because thinner, younger ice is more vulnerable to melting out in summer, this shift in sea ice age has contributed to the decreasing trend in minimum ice extent. Regionally, Bering Sea ice extent was at record lows for almost the entire 2017/18 ice season. For the Antarctic continent as a whole, 2018 was warmer than average. On the highest points of the Antarctic Plateau, the automatic weather station Relay (74°S) broke or tied six monthly temperature records throughout the year, with August breaking its record by nearly 8°C. However, cool conditions in the western Bellingshausen Sea and Amundsen Sea sector contributed to a low melt season overall for 2017/18. High SSTs contributed to low summer sea ice extent in the Ross and Weddell Seas in 2018, underpinning the second lowest Antarctic summer minimum sea ice extent on record. Despite conducive conditions for its formation, the ozone hole at its maximum extent in September was near the 2000–18 mean, likely due to an ongoing slow decline in stratospheric chlorine monoxide concentration. Across the oceans, globally averaged SST decreased slightly since the record El Niño year of 2016 but was still far above the climatological mean. On average, SST is increasing at a rate of 0.10° ± 0.01°C decade−1 since 1950. The warming appeared largest in the tropical Indian Ocean and smallest in the North Pacific. The deeper ocean continues to warm year after year. For the seventh consecutive year, global annual mean sea level became the highest in the 26-year record, rising to 81 mm above the 1993 average. As anticipated in a warming climate, the hydrological cycle over the ocean is accelerating: dry regions are becoming drier and wet regions rainier. Closer to the equator, 95 named tropical storms were observed during 2018, well above the 1981–2010 average of 82. Eleven tropical cyclones reached Saffir–Simpson scale Category 5 intensity. North Atlantic Major Hurricane Michael’s landfall intensity of 140 kt was the fourth strongest for any continental U.S. hurricane landfall in the 168-year record. Michael caused more than 30 fatalities and $25 billion (U.S. dollars) in damages. In the western North Pacific, Super Typhoon Mangkhut led to 160 fatalities and$6 billion (U.S. dollars) in damages across the Philippines, Hong Kong, Macau, mainland China, Guam, and the Northern Mariana Islands. Tropical Storm Son-Tinh was responsible for 170 fatalities in Vietnam and Laos. Nearly all the islands of Micronesia experienced at least moderate impacts from various tropical cyclones. Across land, many areas around the globe received copious precipitation, notable at different time scales. Rodrigues and Réunion Island near southern Africa each reported their third wettest year on record. In Hawaii, 1262 mm precipitation at Waipā Gardens (Kauai) on 14–15 April set a new U.S. record for 24-h precipitation. In Brazil, the city of Belo Horizonte received nearly 75 mm of rain in just 20 minutes, nearly half its monthly average. Globally, fire activity during 2018 was the lowest since the start of the record in 1997, with a combined burned area of about 500 million hectares. This reinforced the long-term downward trend in fire emissions driven by changes in land use in frequently burning savannas. However, wildfires burned 3.5 million hectares across the United States, well above the 2000–10 average of 2.7 million hectares. Combined, U.S. wildfire damages for the 2017 and 2018 wildfire seasons exceeded $40 billion (U.S. dollars)