PRAME expression in melanoma is negatively regulated by TET2-mediated DNA hydroxymethylation.

Preferentially Expressed Antigen in Melanoma (PRAME) and Ten-Eleven Translocation (TET) dioxygenase-mediated 5-hydroxymethylcytosine (5hmC) are emerging melanoma biomarkers. We observed an inverse correlation between PRAME expression and 5hmC levels in benign nevi, melanoma in situ, primary invasive melanoma, and metastatic melanomas via immunohistochemistry and multiplex immunofluorescence: nevi exhibited high 5hmC and low PRAME, whereas melanomas showed the opposite pattern. Single-cell multiplex imaging of melanoma precursors revealed that diminished 5hmC coincides with PRAME upregulation in premalignant cells. Analysis of TCGA and GTEx databases confirmed a negative relationship between TET2 and PRAME mRNA expression in melanoma. Additionally, 5hmC levels were reduced at the PRAME 5' promoter in melanoma compared to nevi, suggesting a role for 5hmC in PRAME transcription. Restoring 5hmC levels via TET2 overexpression notably reduced PRAME expression in melanoma cell lines. These findings establish a function of TET2-mediated DNA hydroxymethylation in regulating PRAME expression and demonstrate epigenetic reprogramming as pivotal in melanoma tumorigenesis. Teaser: Melanoma biomarker PRAME expression is negatively regulated epigenetically by TET2-mediated DNA hydroxymethylation.

Educational and occupational aspirations of adolescent and young adult cancer survivors: a qualitative analysis.

PURPOSE: Adolescent and young adult cancer survivors (AYACS) are patients diagnosed with cancer between 15 and 39 years of age. AYACS are often derailed from planned educational and occupational endeavors due to disruption from cancer treatment and its consequences. The study objective was to examine how a personal cancer diagnosis impacted AYACS' experiences related to these endeavors. METHODS: Semi-structured interviews were conducted as part of a larger study assessing psychosocial challenges among a younger AYACS subset aged 15-25 years old at the time of cancer diagnosis. Interviews were coded based on responses and were used to develop themes related to educational and occupational endeavors. RESULTS: Data were collected from 35 participants. Five themes emerged: (1) Pauses in educational attainment had a detrimental effect on educational goals for some participants, but further solidified and sculpted educational plans for others; (2) Although participants experienced challenges accomplishing educational goals, supportive school environments helped surmount these challenges; (3) Participants reflected on rethinking career aspirations, though some desired to pursue the same occupation planned before cancer diagnosis; (4) Participants experienced challenges, including physical and cognitive limitations, upon returning to work; and (5) Participants valued autonomy and normalcy through work and appreciated supportive and flexible work environments. CONCLUSIONS: AYACS prioritize professional achievement, yet encounter challenges in achieving professional goals. Our findings create a foundation for developing and testing prospective interventions to promote continuance of school and work during cancer treatment when feasible, and proactive reintegration strategies for those who paused professional goals due to cancer treatment.

Variant Transcript of ROR1 ENST00000545203 Does Not Encode ROR1 Protein.

Drs. John and Ford reported in biomedicines that a variant transcript encoding receptor tyrosine kinase-like orphan receptor 1 (ROR1), namely ENST00000545203 or variant 3 (ROR1V3), was a predominant ROR1 transcript of neoplastic or normal cells in the Bioinformatic database, including GTEx and the 33 datasets from TCGA. Unlike the full-length ROR1 transcript, Drs. John and Ford deduced that ROR1V3 encoded a cytoplasmic ROR1 protein lacking an apparent signal peptide necessary for transport to the cell surface, which they presumed made it unlikely to function as a surface receptor for Wingless/Integrated (Wnt) factors. Moreover, they speculated that studies evaluating ROR1 via immunohistochemistry using any one of several anti-ROR1 mAbs actually may have detected cytoplasmic protein encoded by ROR1V3 and that anti-cancer therapies targeting surface ROR1 thus would be ineffective against "cytoplasmic ROR1-positive" cancers that express predominately ROR1V3. We generated lentivirus vectors driving the expression of full-length ROR1 or the ROR1v3 upstream of an internal ribosome entry site (IRES) of the gene encoding a red fluorescent reporter protein. Although we find that cells that express ROR1 have surface and cytoplasmic ROR1 protein, cells that express ROR1v3 neither have surface nor cytoplasmic ROR1, which is consistent with our finding that ROR1v3 lacks an in-frame initiation codon for ribosomal translation into protein. We conclude that the detection of ROR1 protein in various cancers cannot be ascribed to the expression of ROR1v3.

Treatment Failure After Repair of Displaced Femoral Neck Fractures in Patients Compared by "Decade of Life": An Analysis of 565 Cases in Adults Less Than 60 years of Age.

OBJECTIVES: To study the results of displaced femoral neck fractures (FNFs) in adults less than 60 years of age by comparing patients, injury, treatment, and the characteristics of treatment failure specifically according to patients' age at injury, that is, by their "decade of life" [ie, "under 30" (29 years and younger), "the 30s" (30-39 years), "the 40s" (40-49 years), and "the 50s" (50-59 years)]. DESIGN: Multicenter retrospective comparative cohort series. SETTING: Twenty-six North American Level 1 Trauma Centers. PATIENT SELECTION CRITERIA: Skeletally mature patients aged 18-59 years with operative repair of displaced FNFs. OUTCOME MEASURES AND COMPARISONS: Main outcome measures were treatment failures (fixation failure and/or nonunion, osteonecrosis, malunion, and the need for subsequent major reconstructive surgery (arthroplasty or proximal femoral osteotomy). These were compared across decades of adult life through middle age (<30 years, 30-39 years, 40-49 years, and 50-59 years). RESULTS: Overall, treatment failure was observed in 264 of 565 (47%) of all hips. The mean age was 42.2 years, 35.8% of patients were women, and the mean Pauwels angle was 53.8 degrees. Complications and the need for major secondary surgeries increased with each increasing decade of life assessed: 36% of failure occurred in patients <30 years of age, 40% in their 30s, 48% in their 40s, and 57% in their 50s (P < 0.001). Rates of osteonecrosis increased with decades of life (under 30s and 30s vs. 40s vs. 50s developed osteonecrosis in 10%, 10%, 20%, and 27% of hips, P < 0.001), while fixation failure and/or nonunion only increased by decade of life to a level of trend (P = 0.06). Reparative methods varied widely between decade-long age groups, including reduction type (open vs. closed, P < 0.001), reduction quality (P = 0.030), and construct type (cannulated screws vs. fixed angle devices, P = 0.024), while some variables evaluated did not change with age group. CONCLUSIONS: Displaced FNFs in young and middle-aged adults are a challenging clinical problem with a high rate of treatment failure. Major complications and the need for complex reconstructive surgery increased greatly by decade of life with the patients in their sixth decade experiencing osteonecrosis at the highest rate seen among patients in the decades studied. Interestingly, treatments provided to patients in their 50s were notably different than those provided to younger patient groups. LEVEL OF EVIDENCE: Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.

Optimal Fixation Strategies for Displaced Femoral Neck Fractures in Patients 18-59 Years of Age: An Analysis of 565 Cases Treated at 26 Level 1 Trauma Centers.

OBJECTIVES: The objective of this study was to determine the difference in failure rates of surgical repair for displaced femoral neck fractures in patients younger than 60 years of age according to fixation strategy. DESIGN: This is a retrospective, comparative cohort study. SETTING: Twenty-six Level 1 North American trauma centers. PATIENT SELECTION CRITERIA: Patients younger than 60 years of age with a displaced femoral neck fracture (OTA 31-B2, B3) undergoing surgical repair from 2005 to 2017. OUTCOME MEASURES AND COMPARISONS: Patient demographics, injury characteristics, repair methods used, and treatment failure (nonunion/failed fixation, avascular necrosis, and need for secondary surgery) were compared according to fixation strategy. RESULTS: Five hundred and sixty-five patients met inclusion criteria and were studied. The mean age was 42 years, 36% were female, and the average Pauwels' angle of fractures was 55 degrees. There were 305 patients treated with multiple cannulated screws (MCS) and 260 treated with a fixed-angle (FA) construct. Treatment failures were 46% overall, but was more likely to occur in MCS constructs versus FA devices (55% vs. 36%, P < 0.001). When FA constructs were substratified, the use of a sliding hip screw with addition of a medial femoral neck buttress plate (FNBP) and "antirotation" (AR) screw demonstrated better results than either FNBP or AR screw alone or neither with the lowest overall construct failure rate of 11% (P < 0.036). CONCLUSIONS: Historically used fixation constructs for femoral neck fractures (eg, multiple cannulated screws and sliding hip screw) in young and middle-aged adults performed poorly compared with more recently proposed constructs, including those using a medial femoral neck buttress plate and an antirotation screw. Fixed-angle constructs outperformed multiple cannulated screws overall, and augmentation of fixed-angle constructs with a medial femoral neck buttress plate and antirotation screw improved the likelihood of successful treatment. Surgeons should prioritize fixation decisions when repairing displaced femoral neck fractures in patients. LEVEL OF EVIDENCE: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.

Primary human papillomavirus testing versus CO-testing: clinical outcomes in populations with different disease prevalence.

Implementation of primary human papillomavirus (HPV) testing has been slow in the US perhaps due to concerns of decreased sensitivity compared with concurrent HPV and cytology testing (cotesting). We used the National Breast and Cervical Cancer Early Detection Program (NBCCEDP) and the Kaiser Permanente of Northern California (KPNC) cohort to quantify potential trade-offs with primary HPV compared with cotesting in four US populations with differing precancer/cancer prevalence. In all settings, cotesting required more lab tests and more colposcopies compared to primary HPV testing. Additional cervical intraepithelial neoplasia grade 3 or cancer (CIN3+) immediately detected from cotesting vs primary HPV decreased with decreasing population-average CIN3+ prevalence, from 71 per 100,000 screened among never/rarely screened individuals in the NBCCEDP (prevalence = 1,212 per 100,000) to 4 per 100,000 screened among individuals with prior HPV-negative results in KPNC (prevalence = 86 per 100,000). These data suggest that cotesting confer an unfavorable benefit-to-harm ratio over primary HPV testing.

Potential COVID-19 remedies from repurposed drugs and herbal small RNAs.

To date, SARS-CoV-2 has caused millions of deaths, but the choice of treatment is limited. We previously established a platform for identifying Food and Drug Administration (FDA)-approved repurposed drugs for avian influenza A virus infections that could be used for coronavirus disease 2019 (COVID-19) treatment. In this study, we analyzed blood samples from two cohorts of 63 COVID-19 patients, including 19 patients with severe disease. Among the 39 FDA-approved drugs we identified for COVID-19 therapy in both cohorts, 23 drugs were confirmed by literature mining data, including 14 drugs already under COVID-19 clinical trials and 9 drugs reported for COVID-19 treatments, suggesting the remaining 16 FDA-approved drugs may be candidates for COVID-19 therapy. Additionally, we previously reported that herbal small RNAs (sRNAs) could be effective components in traditional Chinese medicine (TCM) for treating COVID-19. Based on the abundance of sRNAs, we screened the 245 TCMs in the Bencao (herbal) sRNA Atlas that we had previously established, and we found that the top 12 TCMs for COVID-19 treatment was consistent across both cohorts. We validated the efficiency of the top 30 sRNAs from each of the top 3 TCMs for COVID-19 treatment in poly(I:C)-stimulated human non-small cell lung cancer cells (A549 cells). In conclusion, our study recommends potential COVID-19 remedies using FDA-approved repurposed drugs and herbal sRNAs from TCMs.

Molecular basis for receptor recognition and broad host tropism for merbecovirus MjHKU4r-CoV-1.

A novel pangolin-origin MERS-like coronavirus (CoV), MjHKU4r-CoV-1, was recently identified. It is closely related to bat HKU4-CoV, and is infectious in human organs and transgenic mice. MjHKU4r-CoV-1 uses the dipeptidyl peptidase 4 (DPP4 or CD26) receptor for virus entry and has a broad host tropism. However, the molecular mechanism of its receptor binding and determinants of host range are not yet clear. Herein, we determine the structure of the MjHKU4r-CoV-1 spike (S) protein receptor-binding domain (RBD) complexed with human CD26 (hCD26) to reveal the basis for its receptor binding. Measuring binding capacity toward multiple animal receptors for MjHKU4r-CoV-1, mutagenesis analyses, and homology modeling highlight that residue sites 291, 292, 294, 295, 336, and 344 of CD26 are the crucial host range determinants for MjHKU4r-CoV-1. These results broaden our understanding of this potentially high-risk virus and will help us prepare for possible outbreaks in the future.

Uncommon P1 Anchor-featured Viral T Cell Epitope Preference within HLA-A*2601 and HLA-A*0101 Individuals.

The individual HLA-related susceptibility to emerging viral diseases such as COVID-19 underscores the importance of understanding how HLA polymorphism influences peptide presentation and T cell recognition. Similar to HLA-A*0101, which is one of the earliest identified HLA alleles among the human population, HLA-A*2601 possesses a similar characteristic for the binding peptide and acts as a prevalent allomorph in HLA-I. In this study, we found that, compared with HLA-A*0101, HLA-A*2601 individuals exhibit distinctive features for the T cell responses to SARS-CoV-2 and influenza virus after infection and/or vaccination. The heterogeneous T cell responses can be attributed to the distinct preference of HLA-A*2601 and HLA-A*0101 to T cell epitope motifs with negative-charged residues at the P1 and P3 positions, respectively. Furthermore, we determined the crystal structures of the HLA-A*2601 complexed to four peptides derived from SARS-CoV-2 and human papillomavirus, with one structure of HLA-A*0101 for comparison. The shallow pocket C of HLA-A*2601 results in the promiscuous presentation of peptides with "switchable" bulged conformations because of the secondary anchor in the median portion. Notably, the hydrogen bond network formed between the negative-charged P1 anchors and the HLA-A*2601-specific residues lead to a "closed" conformation and solid placement for the P1 secondary anchor accommodation in pocket A. This insight sheds light on the intricate relationship between HLA I allelic allomorphs, peptide binding, and the immune response and provides valuable implications for understanding disease susceptibility and potential vaccine design.

Leptochelins A-C, Cytotoxic Metallophores Produced by Geographically Dispersed Leptothoe Strains of Marine Cyanobacteria.

Metals are important cofactors in the metabolic processes of cyanobacteria, including photosynthesis, cellular respiration, DNA replication, and the biosynthesis of primary and secondary metabolites. In adaptation to the marine environment, cyanobacteria use metallophores to acquire trace metals when necessary as well as to reduce potential toxicity from excessive metal concentrations. Leptochelins A-C were identified as structurally novel metallophores from three geographically dispersed cyanobacteria of the genus Leptothoe. Determination of the complex structures of these metabolites presented numerous challenges, but they were ultimately solved using integrated data from NMR, mass spectrometry and deductions from the biosynthetic gene cluster. The leptochelins are comprised of halogenated linear NRPS-PKS hybrid products with multiple heterocycles that have potential for hexadentate and tetradentate coordination with metal ions. The genomes of the three leptochelin producers were sequenced, and retrobiosynthetic analysis revealed one candidate biosynthetic gene cluster (BGC) consistent with the structure of leptochelin. The putative BGC is highly homologous in all three Leptothoe strains, and all possess genetic signatures associated with metallophores. Postcolumn infusion of metals using an LC-MS metabolomics workflow performed with leptochelins A and B revealed promiscuous binding of iron, copper, cobalt, and zinc, with greatest preference for copper. Iron depletion and copper toxicity experiments support the hypothesis that leptochelin metallophores may play key ecological roles in iron acquisition and in copper detoxification. In addition, the leptochelins possess significant cytotoxicity against several cancer cell lines.

Management of a Traumatic Collapse of the First Carpometacarpal Joint After Trapeziectomy With Suture Suspensionplasty: A Case Report.

Arthritis of the first carpometacarpal (CMC) joint is a common pathology hand surgeons encounter. Treatment begins with conservative measures, but when they fail, surgery is a viable option for providing relief to patients. The most widely used surgical technique is CMC arthroplasty with ligament reconstruction and tendon interposition (LRTI). However, more novel techniques such as trapeziectomy with suspensionplasty are gaining popularity. When surgical measures fail, it is important to identify the mechanism of failure and proper treatment options. There are multiple options for revision surgery at the surgeon's disposal, with no consensus on a superior technique. This case illustrates a patient with painful subsidence secondary to a traumatic collapse of the first CMC joint eight months status post suspensionplasty with trapeziectomy. After conservative measures failed to provide relief, it was decided that a surgical revision was appropriate. The surgeon chose to move forward with suture button suspensionplasty, as it has multiple advantages over LRTI. In the short-term follow-up after revision, the patient experienced improvements in pain and range of motion, along with radiographic evidence of proper alignment of the first metacarpal without subsidence. Regarding the treatment of a case such as this, the authors believe this case should serve as a reference that may be used by future physicians when deciding which surgical technique to employ for the revision of a traumatically collapsed first CMC joint after trapeziectomy with CMC joint suspensionplasty.

Cervical Cancer Screening Among Female Medicaid Beneficiaries With and Without Schizophrenia.

BACKGROUND AND HYPOTHESIS: In the United States, women with schizophrenia face challenges in receiving gynecologic care, but little is known about how cervical cancer screening rates vary across time or states in a publicly insured population. We hypothesized that women Medicaid beneficiaries with schizophrenia would be less likely to receive cervical cancer screening across the United States compared with a control population, and that women with schizophrenia and other markers of vulnerability would be least likely to receive screening. STUDY DESIGN: This retrospective cohort study used US Medicaid administrative data from across 44 states between 2002 and 2012 and examined differences in cervical cancer screening test rates among 283 950 female Medicaid beneficiaries with schizophrenia and a frequency-matched control group without serious mental illness, matched on age and race/ethnicity. Among women with schizophrenia, multivariable logistic regression estimated the odds of receiving cervical cancer screening using individual sociodemographics, comorbid conditions, and health care service utilization. STUDY RESULTS: Compared to the control group, women with schizophrenia were less likely to receive cervical cancer screening (OR = 0.76; 95% CI 0.75-0.77). Among women with schizophrenia, nonwhite populations, younger women, urban dwellers, those with substance use disorders, anxiety, and depression and those connected to primary care were more likely to complete screening. CONCLUSIONS: Cervical cancer screening rates among US women Medicaid beneficiaries with schizophrenia were suboptimal. To address cervical cancer care disparities for this population, interventions are needed to prioritize women with schizophrenia who are less engaged with the health care system or who reside in rural areas.

The mGlu5 receptor negative allosteric modulator mavoglurant reduces escalated cocaine self-administration in male and female rats.

RATIONALE: Cocaine use disorder (CUD) is a brain disorder for which there is no Food and Drug Administration-approved pharmacological treatment. Evidence suggests that glutamate and metabotropic glutamate receptor subtype 5 (mGlu5) play critical roles in synaptic plasticity, neuronal development, and psychiatric disorders. OBJECTIVE: In the present study, we tested the hypothesis that the mGlu5 receptor is functionally involved in intravenous cocaine self-administration and assessed the effects of sex and cocaine exposure history. METHODS: We used a preclinical model of CUD in rats that were allowed long access (LgA; 6 h/day) or short access (ShA; 1 h/day) to intravenous cocaine (750 µg/kg/infusion [0.1 ml]) self-administration. Rats received acute intraperitoneal or oral administration of the mGlu5 receptor negative allosteric modulator mavoglurant (1, 3, and 10 mg/kg) or vehicle. RESULTS: Both intraperitoneal and oral mavoglurant administration dose-dependently reduced intravenous cocaine self-administration in the first hour and in the entire 6 h session in rats in the LgA group, with no effect on locomotion. In the ShA group, mavoglurant decreased locomotion but had no effects on cocaine self-administration. We did not observe significant sex × treatment interactions. CONCLUSIONS: These findings suggest that the mGlu5 receptor is involved in escalated cocaine self-administration. These findings support the development of clinical trials of mavoglurant to evaluate its potential therapeutic benefits for CUD.

Indulging Curiosity: Preliminary Evidence of an Anxiolytic-like Effect of Castor Oil and Ricinoleic Acid.

In the process of validating the elevated zero maze, a common test of anxiety-like behavior, in our laboratory, we demonstrated an anxiolytic-like effect of castor oil and its primary component, ricinoleic acid. We tested the effects of vehicle and chlordiazepoxide in male mice in the elevated zero maze following a 30-min pretreatment time. Chlordiazepoxide is a United States Food and Drug Administration-approved drug that was previously shown to exert anxiolytic-like effects in both the elevated zero maze and elevated plus maze. Chlordiazepoxide was administered at doses of 5 or 10 mg/kg. We used 5% polyoxyl 35 castor oil (Kolliphor® EL) and saline as treatment vehicles and found that the effect of chlordiazepoxide on open zone occupancy and open zone entries was blunted when 5% Kolliphor was used as the vehicle. These tests demonstrated that chlordiazepoxide increased open zone occupancy and entries in the elevated zero maze more effectively when saline was used as the treatment vehicle and that Kolliphor dampened the anxiolytic-like effect of chlordiazepoxide when it was used as the treatment vehicle. Notably, 5% Kolliphor alone slightly increased baseline open zone occupancy and entries. Given that Kolliphor is a derivative of castor oil, we next tested the effect of 5% castor oil and 5% ricinoleic acid, which is a major component of castor oil. We found that both castor oil and ricinoleic acid increased open zone occupancy but not entries compared with saline. Altogether, our findings demonstrate that Kolliphor, castor oil, and ricinoleic acid may exert anxiolytic-like effects in male mice in the elevated zero maze. This potential anxiolytic-like effect of castor oil is consistent with its well-established beneficial effects, including anti-inflammatory, antioxidant, antifungal, and pain-relieving properties.

The impact of adjusting for hysterectomy prevalence on cervical cancer incidence rates and trends among women aged 30 years or older-United States, 2001-2019.

Hysterectomy protects against cervical cancer when the cervix is removed. However, measures of cervical cancer incidence often fail to exclude women with a hysterectomy from the population-at-risk denominator, underestimating and distorting disease burden. In this study, we estimated hysterectomy prevalence from the Behavioral Risk Factor Surveillance System surveys to remove the women who were not at risk of cervical cancer from the denominator and combined these estimates with the US Cancer Statistics data. From these data, we calculated age-specific and age-standardized incidence rates for women aged >30 years from 2001-2019, adjusted for hysterectomy prevalence. We calculated the difference between unadjusted and adjusted incidence rates and examined trends by histology, age, race and ethnicity, and geographic region using joinpoint regression. The hysterectomy-adjusted cervical cancer incidence rate from 2001-2019 was 16.7 per 100 000 women-34.6% higher than the unadjusted rate. After adjustment, incidence rates were higher by approximately 55% among Black women, 56% among those living in the East South Central division, and 90% among women aged 70-79 and ≥80 years. These findings underscore the importance of adjusting for hysterectomy prevalence to avoid underestimating cervical cancer incidence rates and masking disparities by age, race, and geographic region. This article is part of a Special Collection on Gynecological Cancers.

Tubal Sterilization and Cervical Cancer Underscreening in the United States.

Background: Tubal sterilization is more commonly utilized by racial/ethnic minority groups and has been implicated in underscreening for cervical cancer. The objective is to determine if prior tubal sterilization is a risk factor for cervical cancer underscreening. Methods: National Survey of Family Growth dataset from 2015 to 2019 used for analysis; data were weighted to represent the 72 million women in the U.S. population aged 22-49. Chi-square tests, Fisher exact tests, and logistic regression were used for analysis. The primary predictor variable was tubal sterilization which was categorized into no previous sterilization, sterilization completed <5 years ago, and sterilization completed ≥5 years ago. The outcome variable was underscreened versus not underscreened. Other predictor variables included age, household income as a percent of federal poverty level, previous live birth, primary care provider, and insurance status. Results: Prevalence of tubal sterilization completed 5 or more years ago was 12.5% and varied by most measured characteristics in univariate analyses. Approximately 8% of women were underscreened for cervical cancer. In multivariable analyses, women with a tubal sterilization 5 or more years ago had 2.64 times the odds (95% confidence interval = 1.75-4.00) of being underscreened for cervical cancer compared with women who did not have a tubal sterilization. Conclusions: Approximately 4.3 million women ages 22-49 in the United States are potentially underscreened for cervical cancer and women with previous tubal ligation ≥5 years ago are more likely to be underscreened. These results may inform the need for culturally sensitive public health messages informing people who have had these procedures about the need for continued screening.

Clinicopathologic correlation of dermatologic diseases in patients with darker pigmentation.

OBJECTIVES: Cutaneous diseases that disproportionately affect patients with darker pigmentation and their histologic features are historically understudied and undertreated. This review article aims to highlight the key clinical features, histopathology, and diagnostic pearls of several cutaneous diseases that commonly present in patients with darker pigmentation. METHODS: A literature search was conducted, and a list of cutaneous diseases that frequently affect patients with darker pigmentation was compiled. A group of experts expounded upon those that were most common or misdiagnosed according to scientific evidence and clinical practice. RESULTS: The diseases were divided into hypopigmented disorders, hyperpigmented disorders, scarring disorders, and alopecic disorders. Within each category, the etiology, clinical features, histopathology, and key histologic differential diagnoses are described and discussed. CONCLUSIONS: As many clinicians are taught that there are no effective treatment options or that these diseases are considered "cosmetic" in nature, patients often do not get a thorough medical workup or skin biopsy. This article aims to decrease the knowledge gap and serve as a resource for anyone involved in the care of patients with these cutaneous conditions.

Lymphadenopathy and lymph node rejection following facial vascularized composite allotransplantation.

BACKGROUND: Apart from the skin, little is known about the immunological processes in deeper tissues, which are typically not accessible to biopsy and inspection, of vascularized composite allografts (VCAs). Face transplant patients develop prominent adenopathy shortly after transplantation that resolves over time. The mechanisms underlying this process are not understood. MATERIALS AND METHODS: A retrospective cohort study was conducted on 9 patients who underwent 10 facial VCAs at the Brigham and Women's Hospital, Boston, MA, between April 2009 and July 2019. Clinical, radiological, and histological data related to lymphadenopathy of the head and neck were reviewed. RESULTS: Patients who received donor-derived lymph nodes (LNs) developed bilateral lymphadenopathy of the submental or submandibular superficial LNs. Median time of presentation was POD18 (range POD6-POM3). Notably, bilateral adenopathy of the neck was not observed in later stages of follow-up (mean follow-up, 115 months). Histology of 3 LNs showed increased histiocytes and apoptosis, with the features reminiscent of necrotizing histiocytic lymphadenitis, and B and T lymphocytes (mostly CD8 + T) admixed with CD163 + histiocytes and dendritic cells. Molecular chimerism analysis in one case showed the coexistence of donor (81%) and recipient (19%) derived lymphocytes. Granzyme B (GZMB) expression confirmed the presence of increased cytotoxic T cells in this LN sample. CONCLUSION: Our data suggested the involvement of an immunological process within the donor-derived LNs after facial allotransplantation between the recipient and donor cells. GZMB expression suggested LN rejection that can occurred independently of skin rejection. This finding supports the need to better define the role of donor-derived immune cells in the context of allograft rejection.

Combining neuroimaging and brain stimulation to test alternative causal pathways for nicotine addiction in schizophrenia.

The smoking rate is high in patients with schizophrenia. Brain stimulation targeting conventional brain circuits associated with nicotine addiction has also yielded mixed results. We aimed to identify alternative circuitries associated with nicotine addiction in both the general population and schizophrenia, and then test whether modulation of such circuitries may alter nicotine addiction behaviors in schizophrenia. In Study I of 40 schizophrenia smokers and 51 non-psychiatric smokers, cross-sectional neuroimaging analysis identified resting state functional connectivity (rsFC) between the dorsomedial prefrontal cortex (dmPFC) and multiple extended amygdala regions to be most robustly associated with nicotine addiction severity in healthy controls and schizophrenia patients (p = 0.006 to 0.07). In Study II with another 30 patient smokers, a proof-of-concept, patient- and rater-blind, randomized, sham-controlled rTMS design was used to test whether targeting the newly identified dmPFC location may causally enhance the rsFC and reduce nicotine addiction in schizophrenia. Although significant interactions were not observed, exploratory analyses showed that this dmPFC-extended amygdala rsFC was enhanced by 4-week active 10Hz rTMS (p = 0.05) compared to baseline; the severity of nicotine addiction showed trends of reduction after 3 and 4 weeks (p ≤ 0.05) of active rTMS compared to sham; Increased rsFC by active rTMS predicted reduction of cigarettes/day (R = -0.56, p = 0.025 uncorrected) and morning smoking severity (R = -0.59, p = 0.016 uncorrected). These results suggest that the dmPFC-extended amygdala circuit may be linked to nicotine addiction in schizophrenia and healthy individuals, and future efforts targeting its underlying pathophysiological mechanisms may yield more effective treatment for nicotine addiction.