Intrauterine exposure to SARS-CoV-2 infection and early newborn brain development.

Epidemiologic studies suggest that prenatal exposures to certain viruses may influence early neurodevelopment, predisposing offspring to neuropsychiatric conditions later in life. The long-term effects of maternal COVID-19 infection in pregnancy on early brain development, however, remain largely unknown. We prospectively enrolled infants in an observational cohort study for a single-site study in the Washington, DC Metropolitan Area from June 2020 to November 2021 and compared these infants to pre-pandemic controls (studied March 2014-February 2020). The primary outcomes are measures of cortical morphometry (tissue-specific volumes), along with global and regional measures of local gyrification index, and sulcal depth. We studied 210 infants (55 infants of COVID-19 unexposed mothers, 47 infants of COVID-19-positive mothers, and 108 pre-pandemic healthy controls). We found increased cortical gray matter volume (182.45 ± 4.81 vs. 167.29 ± 2.92) and accelerated sulcal depth of the frontal lobe (5.01 ± 0.19 vs. 4.40 ± 0.13) in infants of COVID-19-positive mothers compared to controls. We found additional differences in infants of COVID-19 unexposed mothers, suggesting both maternal viral exposures, as well as non-viral stressors associated with the pandemic, may influence early development and warrant ongoing follow-up.

Molecular aspects of Interleukin-36 cytokine activation and regulation.

Interleukin-36 (IL-36) cytokines are structurally similar to other Interleukin-1 superfamily members and are essential to convey inflammatory responses at epithelial barriers including the skin, lung, and gut. Due to their potent effects on immune cells, IL-36 cytokine activation is regulated on multiple levels, from expression and activation to receptor binding. Different IL-36 isoforms convey specific responses as a consequence of particular danger- or pathogen-associated molecular patterns. IL-36 expression and activation are regulated by exogenous pathogens, including fungi, viruses and bacteria but also by endogenous factors such as antimicrobial peptides or cytokines. Processing of IL-36 into potent bioactive forms is necessary for host protection but can elevate tissue damage. Indeed, exacerbated IL-36 signalling and hyperactivation are linked to the pathogenesis of diseases such as plaque and pustular psoriasis, emphasising the importance of understanding the molecular aspects regulating IL-36 activation. Here, we summarise facets of the electrochemical properties, regulation of extracellular cleavage by various proteases and receptor signalling of the pro-inflammatory and anti-inflammatory IL-36 family members. Additionally, this intriguing cytokine subfamily displays many characteristics that are unique from prototypical members of the IL-1 family and these key distinctions are outlined here.

International validation of meaningfulness of postural sway and gait to assess myeloneuropathy in adults with adrenoleukodystrophy.

BACKGROUND: The most common manifestation of X-linked adrenoleukodystrophy (ALD) is a slowly progressive myeloneuropathy, which leads to imbalance and gait disturbances. The variable progression of the disease complicates evaluation of its progression rate. Wearable sensors allow for easy and frequent balance and gait collection. This study reports baseline data from a longitudinal study on the quantitative assessment of balance and gait with wearable sensors and their clinical relevance. METHODS: Data were collected from adult patients in two institutions. Postural body sway and gait parameters were measured using accelerometers. Disease severity was measured by the Expanded Disability Severity Scale (EDSS). Falling frequency and quality of life (QOL) were collected in men. The relationship between sway and gait variables and EDSS score, participants' use of a walking aid, and falling frequency was evaluated. RESULTS: One hundred twenty individuals with ALD were included. Sway variables significantly differentiate participants' assistive device use. Sway and gait variables were correlated to the EDSS in both sexes. Both gait speed and sway were correlated with falling frequency in men from one institution. Select QOL subscores were correlated with the EDSS in males from one institution. Accelerometry generated comparable results across sites. DISCUSSION: This study confirms the clinical correlation between spinal cord disease and imbalance and gait in ALD. For the first time, this study shows clinically meaningful relationships for sway and gait with use of an assistive device, falling frequency and QOL. Wearable accelerometers are a valid means to measure sway and gait in ALD. These measures are promising outcomes for clinical trial designs to assess myeloneuropathy in ALD and to monitor disease progression in individuals.

NCCN Guidelines® Insights: Distress Management, Version 2.2023.

These NCCN Guidelines for Distress Management discuss the identification and treatment of psychosocial problems in patients with cancer. All patients experience some level of distress associated with a cancer diagnosis and the effects of the disease and its treatment regardless of the stage of disease. Clinically significant levels of distress occur in a subset of patients, and identification and treatment of distress are of utmost importance. The NCCN Distress Management Panel meets at least annually to review comments from reviewers within their institutions, examine relevant new data from publications and abstracts, and reevaluate and update their recommendations. These NCCN Guidelines Insights describe updates to the NCCN Distress Thermometer (DT) and Problem List, and to the treatment algorithms for patients with trauma- and stressor-related disorders.

Dissociation between abnormal motor synergies and impaired reaching dexterity after stroke.

Most patients with stroke experience motor deficits, usually referred to collectively as hemiparesis. Although hemiparesis is one of the most common and clinically recognizable motor abnormalities, it remains undercharacterized in terms of its behavioral subcomponents and their interactions. Hemiparesis comprises both negative and positive motor signs. Negative signs consist of weakness and loss of motor control (dexterity), whereas positive signs consist of spasticity, abnormal resting posture, and intrusive movement synergies (abnormal muscle co-activations during voluntary movement). How positive and negative signs interact, and whether a common mechanism generates them, remains poorly understood. Here, we used a planar, arm-supported reaching task to assess poststroke arm dexterity loss, which we compared with the Fugl-Meyer stroke scale; a measure primarily reflecting abnormal synergies. We examined 53 patients with hemiparesis after a first-time ischemic stroke. Reaching kinematics were markedly more impaired in patients with subacute (<3 mo) compared to chronic (>6 mo) stroke even for similar Fugl-Meyer scores. This suggests a dissociation between abnormal synergies (reflected in the Fugl-Meyer scale) and loss of dexterity, which in turn suggests different underlying mechanisms. Moreover, dynamometry suggested that Fugl-Meyer scores capture weakness as well as abnormal synergies, in line with these two deficits sharing a neural substrate. These findings have two important implications: First, clinical studies that test for efficacy of rehabilitation interventions should specify which component of hemiparesis they are targeting and how they propose to measure it. Metrics used widely for this purpose may not always be chosen appropriately. For example, as we show here, the Fugl-Meyer score may capture some hemiparesis components (abnormal synergies and weakness) but not others (loss of dexterity). Second, there may be an opportunity to design rehabilitation interventions to address specific subcomponents of hemiparesis.NEW & NOTEWORTHY Motor impairment is common after stroke and comprises reduced dexterity, weakness, and abnormal muscle synergies. Here we report that, when matched on an established synergy and weakness scale (Fugl-Meyer), patients with subacute stroke have worse reaching dexterity than chronic ones. This result suggests that the components of hemiparesis are dissociable and have separable mechanisms and, thus, may require distinct assessments and treatments.

Impact of Locoregional Treatment on Survival in Young Patients with Early-Stage Breast Cancer undergoing Upfront Surgery.

BACKGROUND: Randomized, controlled trials comparing breast-conserving therapy (BCT) with mastectomy have demonstrated equivalent overall survival (OS), but recent observational studies have shown improved OS in patients undergoing BCT. These studies provide limited data on young patients who are traditionally offered mastectomy due to perceived higher disease risk. This study examines the OS in a contemporary series of young women with breast cancer undergoing upfront BCT compared with mastectomy. METHODS: Women ≤40 years old with primary invasive T1-T2, N0-N1 breast cancer were identified from the National Cancer Database between 2006 and 2016. Patient cohorts were based according to locoregional treatment: BCT, mastectomy alone (Mx), and mastectomy with radiotherapy (Mx/RT). Kaplan-Meier method followed by Cox proportional-hazards regression with inverse probability of treatment weighting (IPTW) were performed to account for treatment selection bias effects in OS. RESULTS: A total of 15,611 patients met the study criteria; 9,509 patients (60.9%) had BCT, 4,020 (25.8%) had Mx/RT, and 2,082 (13.3%) had Mx alone. The median follow-up was 4.6 years (interquartile range [IQR] 3.0-6.4). After IPTW-adjustment, the 5-year OS was similar for BCT (95%), Mx (95%), and Mx/RT (94%), and there was no significant difference in OS in Mx (hazard ratio [HR] = 1.16, 95% confidence interval [CI] 0.90-1.51) and Mx/RT (HR = 1.08, 95% CI 0.88-1.34) compared with BCT. Mx/RT was associated with decreased survival in patients with pT2N0 (HR = 1.78, 95% CI 1.12-2.84). CONCLUSIONS: Among young patients with early-stage breast cancer, overall survival was equivalent regardless of surgical approach. Breast-conserving therapy remains a safe option in young women despite the clinical tendency to offer upfront mastectomy in young patients.

Predicting Regional Lymph Node Recurrence in the Modern Age of Tumor-Positive Sentinel Node Melanoma: The Role of the First Postoperative Ultrasound.

BACKGROUND: The Multicenter Selective Lymphadenectomy Trial II (MSLT-II) led to a change in the management of tumor-positive sentinel lymph nodes (SLNs) from completion node dissection (CLND) to nodal observation. This study aimed to evaluate prognostic factors for predicting sentinel node basin recurrence (SNBR) using data from MSLT-II trial participants. METHODS: In MSLT-II, 1076 patients were treated with observation. Patients were included in the current study if they had undergone a post-sentinel node basin ultrasound (PSNB-US) within 4 months after surgery. The study excluded patients with positive SLN by reverse transcription-polymerase chain reaction (RT-PCR) or incomplete SLN pathologic data. Primary tumor, patient, PSNB-US, and SLN characteristics were evaluated. Multivariable regression analyses were performed to determine independent prognostic factors associated with SNBR. RESULTS: The study enrolled 737 patients: 193 (26.2%) patients with SNBR and 73 (9.9%) patients with first abnormal US. The patients with an abnormal first US were more likely to experience SNBR (23.8 vs. 5.0%). In the multivariable analyses, increased risk of SNBR was associated with male gender (adjusted hazard ratio [aHR], 1.38; 95% confidence interval [CI], 1.00-1.9; p = 0.049), increasing Breslow thickness (aHR, 1.10; 95% CI, 1.01-1.2; p = 0.038), presence of ulceration (aHR, 1.93; 95% CI, 1.42-2.6; p < 0.001), sentinel node tumor burden greater than 1 mm (aHR, 1.91; 95% CI, 1.10-3.3; p = 0.022), lymphovascular invasion (aHR, 1.53; 95% CI, 1.00-2.3; p = 0.048), and presence of abnormal PSNB-US (aHR, 4.29; 95% CI, 3.02-6.1; p < 0.001). CONCLUSIONS: The first postoperative US together with clinical and pathologic factors may play an important role in predicting SNBR.

Macrococcus armenti sp. nov., a novel bacterium isolated from the skin and nasal cavities of healthy pigs and calves.

Gram-positive coccoid bacteria were isolated from the nasal cavities of pigs and calves as well as from axillar and inguinal skin regions of pigs. Phylogenetic analysis of seven strains based on complete genome, 16S rRNA, hsp60, dnaJ, rpoB and sodA gene sequences and MALDI-TOF MS profiles revealed that they belonged to the genus Macrococcus with the closest relatedness to Macrococcus canis, Macrococcus caseolyticus subsp. caseolyticus and Macrococcus caseolyticus subsp. hominis. DNA relatedness of the type strain JEK37T with the type strains of M. canis, M. caseolyticus subsp. caseolyticus and M. caseolyticus subsp. hominis was 23.4, 23.1 and 23.0 % by digital DNA-DNA hybridization and 80.39, 80.45 and 80.87 % by average nucleotide identity (ANI) calculations, confirming that they do not belong to the same species. The DNA G+C content of JEK37T was 35.65 mol%. The novel strains can be differentiated from M. canis KM 45013T by the ability to fermentate d-ribose and by the absence of DNAase production and haemolysis, from M. caseolyticus subsp. caseolyticus CCUG 15606T by the ability to fermentate sucrose and from both species by the inability to grow in 9 and 12% NaCl. They differ from M. caseolyiticus subsp. hominis by the presence of α-glucosidase. The most common fatty acids of JEK37T were C14 : 0, C18 : 1 ω9c and C18 : 0. Known polar lipids consisted of diphosphatidylglycerol, phosphatidylglycerol, aminolipid, aminoglycolipid, aminophospholipid, glycolipid and phospholipid. Cell-wall peptidoglycan of JEK37T was of type A3α l-Lys-Gly2-L-Ser-Gly (similar to A11.3) and the respiratory quinolone was menaquinone 6. Based on their genotypic and chemotaxonomic characteristics, these strains represent a novel species of the genus Macrococcus, for which we propose the name Macrococcus armenti sp. nov. The type strain is JEK37T (=DSM 112712T=CCOS 1982T).

Sensorimotor outcomes in adrenomyeloneuropathy show significant disease progression.

Current outcomes used to evaluate adrenomyeloneuropathy are limited by rater bias, not sensitive to preclinical changes, and require years to decades to detect disease progression. Quantitative outcomes are needed that detect meaningful change in a short time period over a broad range of disability. The study aim was to track sensorimotor outcomes in adults with adrenomyeloneuropathy and evaluate differences in progression between men and women. This prospective observational cohort study analyzes data collected annually in the Phase III study of adults with adrenomyeloneuropathy. Outcomes include postural sway in four static standing conditions, great-toe vibration, hip strength, walking velocity, timed up-and-go, and 6-minute walk distance. Linear mixed model analysis was used to detect change in the outcomes in 2 years, correcting for age, sex, disability, symptom duration, and treatment across the cohort. Modeling was repeated for each sex to evaluate differences. Power computations were carried out by sex and for the full dataset. Sixty-one men and 87 women participated. Average age, 46 ± 12 years; Expanded Disability Status Scale, 3 (1-6.5); symptom duration, 10.8 ± 9.4 years. The cohort showed significant worsening in all standing conditions (P < .001), sensation (P = .0223) and strength (P = .001); but more stability in walking with only velocity (P < .0337) significantly declining. For each sex, postural sway declines significantly in all conditions (P < .01) except for eyes closed feet together for women. Strength declines significantly by sex for hip flexion (P < .03). Sex-specific significant decline is seen in walking (velocity P = .0276; distance P = .0072) for men only. Quantitative measures of postural sway, sensation strength, and walking are effective measures of adrenomyeloneuropathy progression in 2 years.

Cerebellar Contributions to Motor and Cognitive Control in Multiple Sclerosis✰✰✰.

OBJECTIVE: To evaluate relationships between specific cerebellar regions and common clinical measures of motor and cognitive function in persons with multiple sclerosis (PwMS). DESIGN: Cross-sectional. SETTING: Laboratory. PARTICIPANTS: Twenty-nine PwMS and 28 age- and sex-matched controls without multiple sclerosis (MS) (N=57). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Both diffusion and lobule magnetic resonance imaging analyses and common clinical measures of motor and cognitive function were used to examine structure-function relationships in the cerebellum. RESULTS: PwMS demonstrate significantly worse motor and cognitive function than controls, including weaker strength, slower walking, and poorer performance on the Symbol Digit Modalities Test, but demonstrate no differences in cerebellar volume. However, PwMS demonstrate significantly worse diffusivity (mean diffusivity: P=.0003; axial diffusivity: P=.0015; radial diffusivity: P=.0005; fractional anisotropy: P=.016) of the superior cerebellar peduncle, the primary output of the cerebellum. Increased volume of the motor lobules (I-V, VIII) was significantly related to better motor (P<.022) and cognitive (P=.046) performance, and increased volume of the cognitive lobules (VI-VII) was also related to better motor (P<.032) and cognitive (P=.008) performance, supporting the role of the cerebellum in both motor and cognitive functioning. CONCLUSIONS: These data highlight the contributions of the cerebellum to both motor and cognitive function in PwMS. Using novel neuroimaging techniques to examine structure-function relationships in PwMS improves our understanding of individualized differences in this heterogeneous group and may provide an avenue for targeted, individualized rehabilitation aimed at improving cerebellar dysfunction in MS.

Prognostic indicators for undifferentiated carcinoma with/without osteoclast-like giant cells of the pancreas.

BACKGROUND: Undifferentiated carcinoma of the pancreas (UPC) is a rare malignancy. There are no standardized guidelines for treatment. Current management has been extrapolated from smaller reviews. METHODS: 858 patients with UPC were identified in the 2004-2017 NCDB. Kaplan-Meier method followed by Cox proportional-hazards regression examined independent prognostic factors associated with overall survival (OS). Logistic regression analyses were performed to determine independent predictors of surgical intervention and the status of surgical resection by histologic subtype. RESULTS: Patients with osteoclast-like giant cells (OCLGC) had a longer median OS compared to those without (aHR 0.52: 95% CI 0.41-0.67). Of the non-OCLGC subtypes, pleomorphic large cell demonstrated the shortest median OS (2.4 months). Surgical resection was associated with improved survival in all histologies except for pleomorphic cell carcinoma. R0 resection and negative lymph nodes were independently associated with an improved OS. CONCLUSION: This is the largest database review published to date on UCP. OCLGC histology is associated with an improved survival compared to those without OCLGC. Of the non-OCLGC subtypes, pleomorphic large cell is associated with the shortest overall survival. Surgical resection is associated with a significant survival advantage for all histologies except for pleomorphic cell carcinoma.

Exercise and lifestyle physical activity recommendations for people with multiple sclerosis throughout the disease course.

OBJECTIVES: To provide clinicians who treat multiple sclerosis (MS) patients with evidence-based or expert opinion-based recommendations for promoting exercise and lifestyle physical activity across disability levels. METHODS: The National MS Society ("Society") convened clinical and research experts in the fields of MS, exercise, rehabilitation, and physical activity to (1) reach consensus on optimal exercise and lifestyle physical activity recommendations for individuals with MS at disability levels 0-9.0 on the Expanded Disability Status Scale (EDSS) and (2) identify and address barriers/facilitators for participation. RECOMMENDATIONS: Based on current evidence and expert opinion, the Society makes the following recommendations, endorsed by the Consortium of Multiple Sclerosis Centers:Healthcare providers should endorse and promote the benefits/safety of exercise and lifestyle physical activity for every person with MS.Early evaluation by a physical or occupational therapist or exercise or sport scientist, experienced in MS (hereafter referred to as "specialists"), is recommended to establish an individualized exercise and/or lifestyle physical activity plan.Taking into account comorbidities and symptom fluctuations, healthcare providers should encourage ⩾150 min/week of exercise and/or ⩾150 min/week of lifestyle physical activity.Progress toward these targets should be gradual, based on the person's abilities, preferences, and safety.If disability increases and exercise/physical activity becomes more challenging, referrals to specialists are essential to ensure safe and appropriate prescriptions.When physical mobility is very limited, exercise should be facilitated by a trained assistant.

Multiple Myeloma, Version 3.2021, NCCN Clinical Practice Guidelines in Oncology.

Multiple myeloma is a malignant neoplasm of plasma cells that accumulate in bone marrow, leading to bone destruction and marrow failure. This manuscript discusses the management of patients with solitary plasmacytoma, smoldering multiple myeloma, and newly diagnosed multiple myeloma.

NCCN Guidelines Insights: Colorectal Cancer Screening, Version 2.2020.

The NCCN Guidelines for Colorectal Cancer (CRC) Screening describe various colorectal screening modalities as well as recommended screening schedules for patients at average or increased risk of developing sporadic CRC. They are intended to aid physicians with clinical decision-making regarding CRC screening for patients without defined genetic syndromes. These NCCN Guidelines Insights focus on select recent updates to the NCCN Guidelines, including a section on primary and secondary CRC prevention, and provide context for the panel's recommendations regarding the age to initiate screening in average risk individuals and follow-up for low-risk adenomas.

NCCN Guidelines Insights: Hematopoietic Growth Factors, Version 1.2020.

Management of febrile neutropenia (FN) is an integral part of supportive care for patients undergoing cancer treatment. The NCCN Guidelines for Hematopoietic Growth Factors provide suggestions for appropriate evaluation, risk determination, prophylaxis, and management of FN. These NCCN Guidelines are intended to guide clinicians in the appropriate use of growth factors for select patients undergoing treatment of nonmyeloid malignancies. These NCCN Guidelines Insights highlight important updates to the NCCN Guidelines regarding the incorporation of newly FDA-approved granulocyte-colony stimulating factor biosimilars for the prevention and treatment of FN.

Testicular Cancer, Version 2.2020, NCCN Clinical Practice Guidelines in Oncology.

Testicular cancer is relatively uncommon and accounts for <1% of all male tumors. However, it is the most common solid tumor in men between the ages of 20 and 34 years, and the global incidence has been steadily rising over the past several decades. Several risk factors for testicular cancer have been identified, including personal or family history of testicular cancer and cryptorchidism. Testicular germ cell tumors (GCTs) comprise 95% of malignant tumors arising in the testes and are categorized into 2 main histologic subtypes: seminoma and nonseminoma. Although nonseminoma is the more clinically aggressive tumor subtype, 5-year survival rates exceed 70% with current treatment options, even in patients with advanced or metastatic disease. Radical inguinal orchiectomy is the primary treatment for most patients with testicular GCTs. Postorchiectomy management is dictated by stage, histology, and risk classification; treatment options for nonseminoma include surveillance, systemic therapy, and nerve-sparing retroperitoneal lymph node dissection. Although rarely occurring, prognosis for patients with brain metastases remains poor, with >50% of patients dying within 1 year of diagnosis. This selection from the NCCN Guidelines for Testicular Cancer focuses on recommendations for the management of adult patients with nonseminomatous GCTs.

NCCN Guidelines Insights: Multiple Myeloma, Version 1.2020.

The NCCN Guidelines for Multiple Myeloma provide recommendations for diagnosis, workup, treatment, follow-up, and supportive care for patients with monoclonal gammopathy of renal significance, solitary plasmacytoma, smoldering myeloma, and multiple myeloma. These NCCN Guidelines Insights highlight some of the important updates and changes in the 1.2020 version of the NCCN Guidelines for Multiple Myeloma.

Consent in the Exam Room.

INTRODUCTION: Explicitly obtaining consent from a patient prior to starting a sensitive physical exam is essential to improve their experience with intimate examinations such as the genitourinary exam. AIM: The purpose of this article is to raise awareness among providers about how and why to obtain consent for intimate examinations. METHODS: The current literature on consent was reviewed and the opinion piece was created using current events and literature. RESULTS: Providers have a responsibility to consent patients for a sensitive exam. CONCLUSION: Explicitly obtaining consent from a patient priro to starting a sensitive physical exam such as a genitourinary exam is essential to improve the patient experience with such exams. Keller JM. Consent in the Exam Room. J Sex Med 2019;16:618-620.

Results of a Social Network Testing Intervention for HIV in Infectious Disease Clinics.

Social networks can be leveraged to identify undiagnosed HIV-infected individuals. The NC-LINK clinic-based testing initiative utilized these networks to achieve a 5% (95% CI 1.1-8.9%) positivity rate by providing free HIV testing to anyone who accompanied an HIV-infected patient to their clinic appointment. During 2013-2015, 120 individuals were tested at two clinics (N > 1000 patients each) in North Carolina, with 5 new and 6 total positive results. Of these, three linked to care within 30 days and all within 365 days. If expanded further, this initiative could significantly increase the number of HIV-infected individuals aware of their status.

Guidance of sentinel lymph node biopsy decisions in patients with T1-T2 melanoma using gene expression profiling.

AIM: Can gene expression profiling be used to identify patients with T1-T2 melanoma at low risk for sentinel lymph node (SLN) positivity? PATIENTS & METHODS: Bioinformatics modeling determined a population in which a 31-gene expression profile test predicted <5% SLN positivity. Multicenter, prospectively-tested (n = 1421) and retrospective (n = 690) cohorts were used for validation and outcomes, respectively. RESULTS: Patients 55-64 years and ≥65 years with a class 1A (low-risk) profile had SLN positivity rates of 4.9% and 1.6%. Class 2B (high-risk) patients had SLN positivity rates of 30.8% and 11.9%. Melanoma-specific survival was 99.3% for patients ≥55 years with class 1A, T1-T2 tumors and 55.0% for class 2B, SLN-positive, T1-T2 tumors. CONCLUSION: The 31-gene expression profile test identifies patients who could potentially avoid SLN biopsy.