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A new paradigm in human genetics is high frequencies of inter-individual variations in copy numbers of specific genomic DNA segments. Such common copy number variation (CNV) loci often contain genes engaged in host-environment interaction including those involved in immune effector functions. DNA sequences within a CNV locus often share a high degree of identity but beneficial or deleterious polymorphic variants are present among different individuals. Thus, common gene CNVs can contribute, both qualitatively and quantitatively, to a spectrum of phenotypic variants. In this review we describe the phenotypic and genotypic diversities of complement C4 created by copy number variations of RCCX modules (RP-C4-CYP21-TNX) and size dichotomy of C4 genes. A direct outcome of C4 CNV is the generation of two classes of polymorphic proteins, C4A and C4B, with differential chemical reactivities towards peptide or carbohydrate antigens, and a range of C4 plasma protein concentrations (from 15 to 70 mg/dl) among healthy subjects. Deliberate molecular genetic studies enabled development of definitive techniques to determine exact patterns of RCCX modular variations, copy numbers of long and short C4A and C4B genes by Southern blot analyses or by real-time quantitative PCR. It is found that in healthy European Americans, the total C4 gene copy number per diploid genome ranges from 2 to 6: 60.8% of people with four copies of C4 genes, 27.2% with less than four copies, and 12% with more than four copies. Such a distribution is skewed towards the low copy number side in patients with systemic lupus erythematosus (SLE), a prototypic autoimmune disease with complex etiology. In SLE, the frequency of individuals with less than four copies of C4 is significantly increased (42.2%), while the frequency of those with more than four copies is decreased (6%). This decrease in total C4 gene copy number in SLE is due to increases in homozygous and heterozygous deficiencies of C4A but not C4B. Therefore, it is concluded that lower copy number of C4 is a risk factor for and higher gene copy number of C4 is a protective factor against SLE disease susceptibility. Copyright © 2009 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Most patients with p16-positive oropharynx cancer (p16+OPC) receive contralateral elective nodal radiation therapy that improves regional control but increases acute and long-term toxicity. We hypothesize a validated volume reduction in the contralateral neck is effective with an improved toxicity profile in patients with p16+OPC receiving definitive or adjuvant radiation therapy. Patients with newly diagnosed p16+OPC without contralateral nodal involvement treated with primary proton or photon-based (chemo)radiation or adjuvant (chemo)radiation following Transoral Robotic Surgery (TORS) were eligible for enrollment. The reduced contralateral nodal volume included regions of level II and III based on high risk locations for contralateral nodal disease. The primary endpoint was elective out-of-field contralateral nodal failure. Dosimetric comparisons between standard versus reduced elective nodal volumes were analyzed. Acute toxicity was collected using CTCAE v4.0. Fifty-two patients were enrolled of which 36 (69.2%) received definitive (chemo)radiation. Sixteen (30.8%) patients underwent adjuvant radiation following TORS of which 5 (31.2%) received concurrent platinum-based chemotherapy for high risk features. Proton therapy was used in 38 (73.1%) patients. There were no contralateral nodal failures at a median follow up of 15 months (range 1-24 months). For the first 20 patients enrolled, dosimetric comparison of the reduced contralateral elective nodal volumes to consensus elective nodal volumes demonstrated a decrease in the mean dose (18.5 Gy to 14.1 Gy [p<0.05]) and V30 Gy (21.3% to 11.6% [p<0.01]) of the contralateral parotid dose. Significant differences were independent of radiation modality or technology. Acute grade 3 toxicity was observed in 13 (25%) patients including 6 (11.5%) who received a PEG tube during treatment. There were no grade 4-5 acute toxicities, and at 6 months follow up no patients had retained a PEG tube. S elective a voidance of nodal v olum e s at minimal r isk in the N0 contralateral neck of patients with p16-positive oropharynx cancer can be safely performed while maintaining excellent regional control. Both dose to contralateral organs at risk and toxicities were favorable. Maturation of follow-up is ongoing to further support this de-intensification strategy. [ABSTRACT FROM AUTHOR]

Purpose: Combined micro-PET/CT scanners are widely employed to investigate models of brain disorders in rodents using PET-based coregistration. We examined if CT-based coregistration could improve estimates of brain dimensions and consequently estimates of nondisplaceable binding potential (BP ND ) in rodent PET studies., Procedures: PET and CT scans were acquired on 5 female and 5 male CD-1 mice with 3-[ 18 F]fluoro-5-(2-pyridinylethynyl)benzonitrile ([ 18 F]FPEB), a radiotracer for the metabotropic glutamate receptor subtype 5 (mGluR5). In the proposed PET/CT (PTCT) approach, the tracer-specific standard volume was dimension-customized to each animal using the scaling factors from CT-to-standard CT coregistration to simplify PET-to-standard PET coregistration (i.e., 3 CT- and 6 PET-derived parameters). For comparison, conventional PET-based coregistration was performed with 9 (PT9) or 12 (PT12) parameters. PET frames were transferred to the standard space by the three approaches (PTCT, PT9, and PT12) to obtain regional time-activity curves (TACs) and BP ND in 14 standard volumes of interest (VOIs). Lastly, CT images of the animals were transferred to the standard space by CT-based parameters from PTCT and with the scaling factors replaced with those from PET-based PT9 to evaluate agreement of the skull to the standard CT., Results: The PET-based approaches showed various degrees of underestimations of scaling factors in the posterior-anterior-direction compared to PTCT, which resulted in negatively proportional overestimation of radioactivity in the cerebellum (reference region) up to 20%, and proportional, more prominent underestimation of BP ND in target regions down to -50%. The skulls of individual animals agreed with the standard skull for scaling factors from PTCT but not for the scaling factors from PT9, which suggested inaccuracy of the latter., Conclusions: The results indicated that conventional PET-based coregistration approaches could yield biased estimates of BP ND in proportion to errors of brain dimensions when applied to tracers for which the cerebellum serves as reference region. The proposed PTCT provides evidence of a quantitative improvement over PET-based approaches for brain studies using micro-PET/CT scanners., Competing Interests: Declarations. Ethical approval: All experimental protocols and procedures used in this study were reviewed and approved by the Johns Hopkins School of Medicine Animal Care and Use Committee. Consent for publication: Not indicated., (© 2024. The Author(s), under exclusive licence to World Molecular Imaging Society.)

Background: This study evaluates a novel multidisciplinary program providing expanded access to hepatitis C virus (HCV) treatment for rural Appalachian patients in South Carolina. This program identified patients via an opt-out emergency department screening program, and it aimed to achieve HCV cure by using community paramedics (CPs) to link and monitor patients from treatment initiation through 12-week sustained virologic response (SVR)., Methods: Patients aged ≥18 years who were HCV RNA positive were eligible for enrollment if they failed to appear for a scheduled HCV appointment or reported barriers to accessing office-based treatment. CPs provided home visits (initial and 4, 12, and 24 weeks) using a mobile Wi-Fi hotspot to support telemedicine appointments (compliant with the Health Insurance Portability and Accountability Act) and perform focused physical assessments, venipuncture, and coordinated home delivery of medications. Statistics described participant characteristics, prevalence of SVR, and patient satisfaction results at 12 weeks posttreatment., Results: Thirty-four patients were eligible for SVR laboratory tests by 31 August 2023; the majority were male (61.7%) and White (64.7%) with an average age of 56 years (SD, 11.7). Twenty-eight (82.4%) completed treatment and achieved 12-week SVR. Six (17.6%) were lost to follow-up. Two-thirds strongly agreed that they were satisfied with the overall care that they received, and half strongly agreed that their overall health had improved., Conclusions: This CP-augmented treatment program demonstrated success curing HCV for rural patients who lacked access to office-based treatment. Other health care systems may consider this novel delivery model to treat hard-to-reach individuals who are HCV positive., Competing Interests: Potential conflicts of interest. A. H. L. has served on advisory board for Merck Pharmaceuticals, AbbVie and Gilead Sciences. A. H. L. has received research grants from Merck Pharmaceuticals and Gilead Sciences. P. M. has received research grants from Gilead Sciences. No other authors declared any conflict of interest related to this work., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Purpose: Combined micro-PET/CT scanners are widely employed to investigate models of brain disorders in rodents using PET-based coregistration. We examined if CT-based coregistration could improve estimates of brain dimensions and consequently estimates of nondisplaceable binding potential (BP ND ) in rodent PET studies., Procedures: PET and CT scans were acquired on 5 female and 5 male CD-1 mice with PET and CT scans were acquired on 5 female and 5 male CD-1 mice with 3-[ 18 F]fluoro-5-(2-pyridinylethynyl)benzonitrile ([ 18 F]FPEB), a radiotracer for the metabotropic glutamate receptor subtype 5 (mGluR5). In the proposed PET/CT (PTCT) approach, the tracer-specific standard volume was dimension-customized to each animal using the scaling factors from CT-to-standard CT coregistration to simplify PET-to-standard PET coregistration (i.e., 3 CT- and 6 PET-derived parameters). For comparison, conventional PET-based coregistration was performed with 9 (PT9) or 12 (PT12) parameters. PET frames were transferred to the standard space by the three approaches (PTCT, PT9, and PT12) to obtain regional time-activity curves (TACs) and BP ND in 14 standard volumes of interest (VOIs). Lastly, CT images of the animals were transferred to the standard space by CT-based parameters from PTCT and with the scaling factors replaced with those from PET-based PT9 to evaluate agreement of the skull to the standard CT., Results: The PET-based approaches showed various degrees of underestimations of scaling factors in the posterior-anterior-direction compared to PTCT, which resulted in negatively proportional overestimation of radioactivity in the cerebellum (reference region) up to 20%, and proportional, more prominent underestimation of BP ND in target regions down to -50%. The skulls of individual animals agreed with the standard skull for scaling factors from PTCT but not for the scaling factors from PT9, which suggested inaccuracy of the latter., Conclusions: The results indicated that conventional PET-based coregistration approaches could yield biased estimates of BP ND due to erroneous estimates of brain dimensions when applied to tracers for which the cerebellum serves as reference region. The proposed PTCT provides evidence of a quantitative improvement over PET-based approaches for brain studies using micro-PET/CT scanners., Competing Interests: Declarations The authors have no conflicts of interest to declare.

11 C-RO-963, 11 C-RO-643, and 18 F-RO-948 (previously referred to as 11 C-RO6924963, 11 C-RO6931643, and 18 F-RO6958948, respectively) have been reported as promising PET tracers for tau imaging based on in vitro and preclinical PET data. Here we describe the first, to our knowledge, human evaluation of these novel radiotracers. Methods: Amyloid PET-positive Alzheimer disease (AD) subjects and younger controls each received 2 different tau tracers. Dynamic 90-min scans were obtained after bolus injection of 11 C-RO-963, 11 C-RO-643, or 18 F-RO-948. Arterial blood sampling was performed on 11 healthy controls and 11 AD subjects. Regions were defined on MR images, and PET data were quantified by plasma reference graphical analysis (for total distribution volume) and target cerebellum ratio (SUV ratios of 60- to 90-min frames). SUV ratio images were also analyzed voxelwise. Five older controls each underwent 2 scans with 18 F-RO-948 for evaluation of test-retest variability. Four AD subjects underwent a repeated 18 F-RO-948 scan 6-22 mo after the first scan. Six additional healthy controls (3 men and 3 women; age range, 41-67 y) each underwent 1 whole-body dosimetry scan with 18 F-RO-948. Results: In younger controls, SUV peak was observed in the temporal lobe with values of approximately 3.0 for 11 C-RO-963, 1.5 for 11 C-RO-643, and 3.5 for 18 F-RO-948. Over all brain regions and subjects, the trend was for 18 F-RO-948 to have the highest SUV peak , followed by 11 C-RO-963 and then 11 C-RO-643. Regional analysis of SUV ratio and total distribution volume for 11 C-RO-643 and 18 F-RO-948 clearly discriminated the AD group from the healthy control groups. Compartmental modeling confirmed that 11 C-RO-643 had lower brain entry than either 11 C-RO-963 or 18 F-RO-948 and that 18 F-RO-948 showed better contrast between (predicted) areas of high versus low tau accumulation. Thus, our subsequent analysis focused on 18 F-RO-948. Both voxelwise and region-based analysis of 18 F-RO-948 binding in healthy controls versus AD subjects revealed multiple areas where AD subjects significantly differed from healthy controls. Of 22 high-binding regions, 13 showed a significant group difference (after ANOVA, F (1,21) = 45, P < 10 -5 ). Voxelwise analysis also revealed a set of symmetric clusters where AD subjects had higher binding than healthy controls (threshold of P < 0.001, cluster size > 50). Conclusion: 18 F-RO-948 demonstrates characteristics superior to 11 C-RO-643 and 11 C-RO-963 for characterization of tau pathology in AD. Regional binding data and kinetic properties of 18 F-RO-948 compare favorably with other existing tau PET tracers., (© 2018 by the Society of Nuclear Medicine and Molecular Imaging.)

Background: The α7 nicotinic acetylcholine receptor increasingly has been implicated in normal brain physiology, as well as in neuropsychiatric disorders. The highly cortical distribution of α7 nicotinic acetylcholine receptor suggests a role in cognition., Methods: We expanded the first-in-human PET imaging of α7 nicotinic acetylcholine receptor with [18F]ASEM from 5 to 21 healthy nonsmoking volunteers and added a feasibility study in 6 male patients with schizophrenia. Study aims included: (1) confirmation of test-retest reproducibility of [18F]ASEM binding, (2) demonstration of specificity by competition with DMXB-A, an α7 nicotinic acetylcholine receptor partial agonist, (3) estimation of [18F]ASEM binding potentials and α7 nicotinic acetylcholine receptor density in vivo in humans, and (4) demonstrating the feasibility of studying α7 nicotinic acetylcholine receptor as a target for schizophrenia., Results: Test-retest PET confirmed reproducibility (>90%) (variability ≤7%) of [18F]ASEM volume of distribution (VT) estimates in healthy volunteers. Repeated sessions of PET in 5 healthy subjects included baseline and effect of inhibition after oral administration of 150 mg DMXB-A. From reduction of binding potentials, we estimated the dose-dependent occupancy of α7 nicotinic acetylcholine receptor by DMXB-A at 17% to 49% for plasma concentrations at 60 to 200 nM DMXB-A. In agreement with evidence postmortem, α7 nicotinic acetylcholine receptor density averaged 0.67 to 0.82 nM and inhibitor affinity constant averaged 170 to 385 nM. Median VT in a feasibility study of 6 patients with schizophrenia was lower than in healthy volunteers in cingulate cortex, frontal cortex, and hippocampus (P = 0.02, corrected for multiple comparions, Mann-Whitney test)., Conclusions: The current results confirm the reproducibility of [18F]ASEM VT estimates and the specificity of the tracer for α7 nicotinic acetylcholine receptor. Preliminary findings from our feasibility study of [18F]ASEM binding in patients with schizophrenia are suggestive and provide guidance for future studies with more subjects.

Interindividual gene copy-number variation (CNV) of complement component C4 and its associated polymorphisms in gene size (long and short) and protein isotypes (C4A and C4B) probably lead to different susceptibilities to autoimmune disease. We investigated the C4 gene CNV in 1,241 European Americans, including patients with systemic lupus erythematosus (SLE), their first-degree relatives, and unrelated healthy subjects, by definitive genotyping and phenotyping techniques. The gene copy number (GCN) varied from 2 to 6 for total C4, from 0 to 5 for C4A, and from 0 to 4 for C4B. Four copies of total C4, two copies of C4A, and two copies of C4B were the most common GCN counts, but each constituted only between one-half and three-quarters of the study populations. Long C4 genes were strongly correlated with C4A (R=0.695; P<.0001). Short C4 genes were correlated with C4B (R=0.437; P<.0001). In comparison with healthy subjects, patients with SLE clearly had the GCN of total C4 and C4A shifting to the lower side. The risk of SLE disease susceptibility significantly increased among subjects with only two copies of total C4 (patients 9.3%; unrelated controls 1.5%; odds ratio [OR] = 6.514; P=.00002) but decreased in those with > or =5 copies of C4 (patients 5.79%; controls 12%; OR=0.466; P=.016). Both zero copies (OR=5.267; P=.001) and one copy (OR=1.613; P=.022) of C4A were risk factors for SLE, whereas > or =3 copies of C4A appeared to be protective (OR=0.574; P=.012). Family-based association tests suggested that a specific haplotype with a single short C4B in tight linkage disequilibrium with the -308A allele of TNFA was more likely to be transmitted to patients with SLE. This work demonstrates how gene CNV and its related polymorphisms are associated with the susceptibility to a human complex disease.

Facial skin treatments with laser resurfacing, dermabrasion, and chemical peels were responsible for a significant portion of the 2.7 million cosmetic procedures performed in 1998. Perioral wrinkles are a common problem for which plastic surgical consultation is obtained. The aim of this study was to compare and quantify the advantages and disadvantages of laser resurfacing versus dermabrasion in the treatment of perioral wrinkles. Twenty female patients provided informed consent and participated in the study. Half of the perioral area was treated with dermabrasion and half was treated with the UltraPulse CO2 laser. The two procedures were compared using high-quality photographs; a biophysical evaluation of skin color, hydration, and mechanical properties; and patient evaluation of outcomes. Photographs were evaluated by 10 board-certified plastic surgeons who were blinded to the treatment methods. The laser treatment had a significantly higher erythema score at 1 month and a small but significantly greater improvement in perioral wrinkles at 6 months. Thirteen subjects selected the laser treatment as producing the best result, despite the greater intraoperative pain for this procedure. Biomechanical measurements suggest that the laser treatment produced a skin state more similar to skin in younger patients, presumably with higher levels and/or greater organization of the collagen and elastin. Patient preference was inferred from the resurfacing method that they would recommend to a friend. Although the laser was selected as the best result in a majority of cases, patient preference was equally distributed between the two treatments. The authors think that by studying and quantifying the biophysical changes that occur as a result of CO2 laser resurfacing, greater improvements in restoring actinic damage (e.g., wrinkles) can be achieved. Patients consider more than the objective skin changes from a resurfacing technique when making a recommendation to a friend.