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Point-of-care serological and direct antigen testing offers actionable insights for diagnosing challenging illnesses, empowering distributed health systems. Here, we report a POC-compatible serologic test for Lyme disease (LD), leveraging synthetic peptides specific to LD antibodies and a paper-based platform for rapid, and cost-effective diagnosis. Antigenic epitopes conserved across Borrelia burgdorferi genospecies, targeted by IgG and IgM antibodies, are selected to develop a multiplexed panel for detection of LD antibodies from patient sera. Multiple peptide epitopes, when combined synergistically with a machine learning-based diagnostic model achieve high sensitivity without sacrificing specificity. Blinded validation with 15 LD-positive and 15 negative samples shows 95.5% sensitivity and 100% specificity. Blind testing with the CDC’s LD repository samples confirms the test accuracy, matching lab-based two-tier results, correctly differentiating between LD and look-alike diseases. This LD diagnostic test could potentially replace the cumbersome two-tier testing, improving diagnosis and enabling earlier treatment while facilitating immune monitoring and surveillance. Lyme disease is the leading vector-borne disease in North America and Europe, but it lacks single tests for early diagnosis. Here, authors develop a rapid and low-cost serologic test using synthetic peptides, a paper-based assay, and machine learning.

Lyme Disease Biobank (LDB) enrolls participants with signs and symptoms of early Lyme disease (LD) from endemic areas and makes samples available to researchers developing more accurate diagnostics. From 2014 to 23, 466 cases and 367 controls were enrolled on Long Island, NY, and in Central Wisconsin. This study included 253 LDB participants who provided samples from an initial and a convalescent blood draw. Serologic testing, including a first-tier enzyme immunoassay and IgM and IgG immunoblotting, was performed on all samples; blots were interpreted using CDC criteria. At the first draw, 34% of samples from participants presenting with erythema migrans (EM) > 5 cm were positive by CDC's standard two-tiered testing (STTT) algorithm. IgG seroconversion was rare, only 4% of samples demonstrated seroconversion. While the majority of participants (78%) reported no LD symptoms at the second draw, 22% reported ongoing symptoms; the most common being joint pain, fatigue, and muscle pain. Only 35% of participants with ongoing symptoms reported seeing their provider about their symptoms. These results provide additional evidence that STTT is insensitive in early LD and seroconversion is rare after antibiotics. More than one-fifth of participants initially prescribed antibiotics reported ongoing LD symptoms. Therefore, healthcare professionals treating patients with early LD are encouraged to follow-up with their patients, determine whether they continue to experience symptoms, and consider immediate antibiotic re-treatment as appropriate. Early diagnosis, treatment, and follow-up of early LD patients has the potential to improve outcomes and reduce the burden of LD in the US.

Background Phelan-McDermid syndrome (PMS) is a rare neurodevelopmental disorder caused by 22q13 deletions that include the SHANK3 gene or pathogenic sequence variants in SHANK3 . It is characterized by global developmental delay, intellectual disability, speech impairment, autism spectrum disorder, and hypotonia; other variable features include epilepsy, brain and renal malformations, and mild dysmorphic features. Here, we conducted genotype-phenotype correlation analyses using the PMS International Registry, a family-driven registry that compiles clinical data in the form of family-reported outcomes and family-sourced genetic test results. Methods Data from the registry were harmonized and integrated into the i2b2/tranSMART clinical and genomics data warehouse. We gathered information from 401 individuals with 22q13 deletions including SHANK3 (n = 350, ranging in size from 10 kb to 9.1 Mb) or pathogenic or likely pathogenic SHANK3 sequence variants (n = 51), and used regression models with deletion size as a potential predictor of clinical outcomes for 328 phenotypes. Results Our results showed that increased deletion size was significantly associated with delay in gross and fine motor acquisitions, a spectrum of conditions related to poor muscle tone, renal malformations, mild dysmorphic features (e.g., large fleshy hands, sacral dimple, dysplastic toenails, supernumerary teeth), lymphedema, congenital heart defects, and more frequent neuroimaging abnormalities and infections. These findings indicate that genes upstream of SHANK3 also contribute to some of the manifestations of PMS in individuals with larger deletions. We also showed that self-help skills, verbal ability and a range of psychiatric diagnoses (e.g., autism, ADHD, anxiety disorder) were more common among individuals with smaller deletions and SHANK3 variants. Limitations Some participants were tested with targeted 22q microarrays rather than genome-wide arrays, and karyotypes were unavailable in many cases, thus precluding the analysis of the effect of other copy number variants or chromosomal rearrangements on the phenotype. Conclusions This is the largest reported case series of individuals with PMS. Overall, we demonstrate the feasibility of using data from a family-sourced registry to conduct genotype-phenotype analyses in rare genetic disorders. We replicate and strengthen previous findings, and reveal novel associations between larger 22q13 deletions and congenital heart defects, neuroimaging abnormalities and recurrent infections.

Lyme disease (LD), the leading tick-borne disease in the Northern hemisphere, is caused by spirochetes of several genospecies of the Borreliella burgdorferi sensu lato complex. LD is a multi-systemic and highly debilitating illness that is notoriously challenging to diagnose. The main drawbacks of the two-tiered serology, the only approved diagnostic test in the United States, include poor sensitivity, background seropositivity, and cross-reactivity. Recently, Raman spectroscopy (RS) was examined for its LD diagnostic utility by our earlier proof-of-concept study. The previous investigation analyzed the blood from mice that were infected with 297 and B31 strains of Borreliella burgdorferi sensu stricto ( s.s. ). The selected strains represented two out of the three major clades of B. burgdorferi s.s. isolates found in the United States. The obtained results were encouraging and prompted us to further investigate the RS diagnostic capacity for LD in this study. The present investigation has analyzed blood of mice infected with European genospecies, Borreliella afzelii or Borreliella garinii , or B. burgdorferi N40, a strain of the third major class of B. burgdorferi s.s. in the United States. Moreover, 90 human serum samples that originated from LD-confirmed, LD-negative, and LD-probable human patients were also analyzed by RS. The overall results demonstrated that blood samples from Borreliella -infected mice were identified with 96% accuracy, 94% sensitivity, and 100% specificity. Furthermore, human blood samples were analyzed with 88% accuracy, 85% sensitivity, and 90% specificity. Together, the current data indicate that RS should be further explored as a potential diagnostic test for LD patients.

Purpose: Disease advocacy organizations may assist in the conduct of research in a variety of ways. We sought to characterize how disease advocacy organizations participate in clinical research and perceive their contributions. Methods: Postal and electronic surveys administered to leaders of disease advocacy organizations for genetic conditions identified through the Genetic Alliance’s Disease InfoSearch. Results: Of the 201 disease advocacy organizations approached, 124 (62%) responded. In the past 2 years, 91% of these organizations had assisted in participant recruitment, 75% collected data, 60% provided a researcher with financial support, and 56% assisted with study design. Forty-five percent of these organizations also supported a research registry or biobank. Few disease advocacy organization leaders (12%) reported regrets about research studies they had supported. Most (68%) felt their involvement in clinical research had increased the amount of research on their condition and that researchers should consult organizations like theirs in deciding how to recruit participants (58%) and in selecting research topics (56%). Conclusion: In addition to providing financial support, disease advocacy organizations participate directly in multiple aspects of research, ranging from study design and patient recruitment to data collection and analysis. Leaders of these organizations feel strongly that scientists and research sponsors should engage them as partners in the conduct of clinical research. Genet Med 2012:14(2):223–228

Lyme disease (also known as Lyme borreliosis) is the most common vector-borne disease in the United States with an estimated 476,000 cases per year. While historically, the long-term impact of Lyme disease on patients has been controversial, mounting evidence supports the idea that a substantial number of patients experience persistent symptoms following treatment. The research community has largely lacked the necessary funding to properly advance the scientific and clinical understanding of the disease, or to develop and evaluate innovative approaches for prevention, diagnosis, and treatment. Given the many outstanding questions raised into the diagnosis, clinical presentation and treatment of Lyme disease, and the underlying molecular mechanisms that trigger persistent disease, there is an urgent need for more support. This review article summarizes progress over the past 5 years in our understanding of Lyme and tick-borne diseases in the United States and highlights remaining challenges.

Background and objectiveDiagnosis of early Lyme disease (LD) often relies on clinical recognition of the skin lesion, erythema migrans (EM), a diagnostic sign of disease when laboratory testing is insensitive. Because EM can present in morphologically distinct forms, its recognition by clinicians can be challenging. This study aimed to characterize the clinical spectrum of lesions in patients presenting with suspected early LD in an ambulatory care setting to identify features that might help clinicians to be better prepared to recognize EM lesions.MethodsImages of lesions from 69 participants suspected to have early LD were retrospectively evaluated by a dermatologist and a family practitioner with expertise in early LD. Reviewers made determinations on the diagnoses and morphological features of lesions. Agreement between reviewers and associations among lesion types and participant demographics, symptomology, and laboratory evidence of infection were examined using the kappa statistic and contingency tables, respectively.ResultsChallenges in diagnosing EM were evident in our study: initial concordance between reviewers was moderate [kappa statistic (95% CI): 0.45 (0.245 - 0.657)]. The final classification included 35 lesions (51%) that were agreed to be EM; 23 lesions (30%) were considered to be possible early EM or tick bite reactions, and 11 (16%) were thought not to be EM, but rather other diagnoses, including ringworm, allergic contact dermatitis, and mosquito bites. Only two lesions (6%) were observed with a classic bull’s eye or ring-within-a-ring pattern. Most EM lesions were uniform (51%), pink (74%), oval lesions (63%), with well-demarcated borders (92%). Early EM or tick bite reactions were typically <5 cm in size (74%), red (52%), round lesions (61%), with a punctum present (100%). Lesions thought not to be EM also tended to be pink or red (64%), round (55%), or uniform (45%) lesions, but also had raised (25%) or irregular borders (33%), which were not commonly observed in the reviewer-classified EM or tick bite reaction lesions. Participants with lesions classified as EM reported that they had the lesions for more days (p = 0.043) and reported more symptoms (p = 0.017) than participants with other lesions. Only 14 (20%) participants overall had positive laboratory evidence for LD; these included 13 (37%) of the participants with EM-classified lesions.ConclusionsEM commonly occurs in forms that are not the classic bull’s eye. Patients often present with lesions that may represent the very early stage of EM or tick bite reactions, and most patients will test negative on currently available laboratory tests, challenging clinicians in making an LD diagnosis or treatment decisions. Additional studies to further characterize the morphological features of EM and how variation in skin lesions may be perceived among clinicians would be helpful for developing guidelines on improving clinician recognition of EM.

The first biologic therapy for psoriasis was approved in 2003. Other approvals followed, including TNF-α inhibitors, and in addition to providing new treatment options that were greatly needed, these therapies increased our understanding of the immunopathogenesis of psoriasis. Clinical trial activity increased, but all biologic trials were placebo controlled with no active comparators. In 2009, ustekinumab, a new agent that targets the p40 subunit of cytokines IL-12 and IL-23, was approved. In 2010, the Active Comparator (CNTO1275/Enbrel) Psoriasis Trial (ACCEPT) was published, the first active comparator trial of psoriasis biologic agents, comparing ustekinumab and the TNF antagonist etanercept. Here, we describe the results of the ACCEPT trial and offer an expert commentary on the results and implications for psoriasis treatment and research.

The Genetic Alliance Registry and BioBank was founded in 2003 on the principal that a shared infrastructure would facilitate easy flow of resources and accelerate disease-specific research. Based on the Pseudoxanthoma Elasticum International Registry and BioBank, six disease advocacy organizations came together to identify the best solutions for advocacy organizations to promote and collect biological samples with associated clinical information from their members. This required a flexible system that could accommodate an extensive amount of data and samples, support new avenues of research, yet be adaptable to meet the needs of a variety of organizations, and straightforward to implement and use. After extensive landscape analyses, a cross-disease, infinitely expandable registry and biorepository was established. This article reports on this effort and shares the lessons learned.

Lyme disease (LD), caused by ( ), is the most common vector-borne disease in the United States. Methods to control the transmission of to humans via ticks are critical for prevention and elimination of LD. Previously, we showed that deletion of Borrelia hostadaptation Regulator ( mutant) and replacement of 8 conserved residues in Carbon Storage Regulator A of (CsrA , 8S mutant) resulted in upregulation of several lipoproteins due to increased levels of RpoS. Both strains were incapable of colonization in C3H/HeN mice. Clonal isolates lacking linear plasmid 25 derived from strain -B31 or B31-A3 incapable of infection served as control strains. Infection derived mouse serum and serum from Lyme disease patients exhibited reactivity to lysates and purified borrelial lipoproteins (PBLs) from these mutants. Proteomic analysis of PBLs from the mutants revealed similar and unique antigenic components. Two intradermal vaccinations with the live mutant strains induced anti-borrelial antibody responses and reduced load in different tissues compared to unvaccinated C3H/HeN mice following needle challenge with infectious strain B31-A3 strain. The mutant exhibited greater protective efficacy following needle challenge with or infected ( ) nymphs. Transmission of to naïve larvae was reduced from vaccinated mice compared to unvaccinated mice challenged with strain B31-A3. PBLs from mutant strains induced protective immunity in C3H/HeN mice against challenge with infected nymphs. Overall, non-infectious mutant strains can serve as a source of antigens for biologics to interfere with the natural life cycle of .