The transcription factor Foxp1 is a critical negative regulator of the differentiation of follicular helper T cells.

CD4(+) follicular helper T cells (T(FH) cells) are essential for germinal center (GC) responses and long-lived antibody responses. Here we report that naive CD4(+) T cells deficient in the transcription factor Foxp1 'preferentially' differentiated into T(FH) cells, which resulted in substantially enhanced GC and antibody responses. We found that Foxp1 used both constitutive Foxp1A and Foxp1D induced by stimulation of the T cell antigen receptor (TCR) to inhibit the generation of T(FH) cells. Mechanistically, Foxp1 directly and negatively regulated interleukin 21 (IL-21); Foxp1 also dampened expression of the costimulatory molecule ICOS and its downstream signaling at early stages of T cell activation, which rendered Foxp1-deficient CD4(+) T cells partially resistant to blockade of the ICOS ligand (ICOSL) during T(FH) cell development. Our findings demonstrate that Foxp1 is a critical negative regulator of T(FH) cell differentiation.

The Comprehensive Primary Care Plus Model and Health Care Spending, Service Use, and Quality.

Importance: Implemented in 18 regions, Comprehensive Primary Care Plus (CPC+) was the largest US primary care delivery model ever tested. Understanding its association with health outcomes is critical in designing future transformation models. Objective: To test whether CPC+ was associated with lower health care spending and utilization and improved quality of care. Design, Setting, and Participants: Difference-in-differences regression models compared changes in outcomes between the year before CPC+ and 5 intervention years for Medicare fee-for-service beneficiaries attributed to CPC+ and comparison practices. Participants included 1373 track 1 (1 549 585 beneficiaries) and 1515 track 2 (5 347 499 beneficiaries) primary care practices that applied to start CPC+ in 2017 and met minimum care delivery and other eligibility requirements. Comparison groups included 5243 track 1 (5 347 499 beneficiaries) and 3783 track 2 (4 507 499 beneficiaries) practices, matched, and weighted to have similar beneficiary-, practice-, and market-level characteristics as CPC+ practices. Interventions: Two-track design involving enhanced (higher for track 2) and alternative payments (track 2 only), care delivery requirements (greater for track 2), data feedback, learning, and health information technology support. Main Outcomes and Measures: The prespecified primary outcome was annualized Medicare Part A and B expenditures per beneficiary per month (PBPM). Secondary outcomes included expenditure categories, utilization (eg, hospitalizations), and claims-based quality-of-care process and outcome measures (eg, recommended tests for patients with diabetes and unplanned readmissions). Results: Among the CPC+ patients, 5% were Black, 3% were Hispanic, 87% were White, and 5% were of other races (including Asian/Other Pacific Islander and American Indian); 85% of CPC+ patients were older than 65 years and 58% were female. CPC+ was associated with no discernible changes in the total expenditures (track 1: $1.1 PBPM [90% CI, -$4.3 to $6.6], P = .74; track 2: $1.3 [90% CI, -$5 to $7.7], P = .73), and with increases in expenditures including enhanced payments (track 1: $13 [90% CI, $7 to $18], P < .001; track 2: $24 [90% CI, $18 to $31], P < .001). Among secondary outcomes, CPC+ was associated with decreases in emergency department visits starting in year 1, and in acute hospitalizations and acute inpatient expenditures in later years. Associations were more favorable for practices also participating in the Medicare Shared Savings Program and independent practices. CPC+ was not associated with meaningful changes in claims-based quality-of-care measures. Conclusions and Relevance: Although the timing of the associations of CPC+ with reduced utilization and acute inpatient expenditures was consistent with the theory of change and early focus on episodic care management of CPC+, CPC+ was not associated with a reduction in total expenditures over 5 years. Positive interaction between CPC+ and the Shared Savings Program suggests transformation models might be more successful when provider cost-reduction incentives are aligned across specialties. Further adaptations and testing of primary care transformation models, as well as consideration of the larger context in which they operate, are needed.

Transcription factor Foxp1 exerts essential cell-intrinsic regulation of the quiescence of naive T cells.

The molecular mechanisms that underlie T cell quiescence are poorly understood. Here we report that mature naive CD8(+) T cells lacking the transcription factor Foxp1 gained effector phenotype and function and proliferated directly in response to interleukin 7 (IL-7) in vitro. Foxp1 repressed expression of the IL-7 receptor α-chain (IL-7Rα) by antagonizing Foxo1 and negatively regulated signaling by the kinases MEK and Erk. Acute deletion of Foxp1 induced naive T cells to gain an effector phenotype and proliferate in lympho-replete mice. Foxp1-deficient naive CD8(+) T cells proliferated even in lymphopenic mice deficient in major histocompatibility complex class I. Our results demonstrate that Foxp1 exerts essential cell-intrinsic regulation of naive T cell quiescence, providing direct evidence that lymphocyte quiescence is achieved through actively maintained mechanisms that include transcriptional regulation.

Long-Term Effects of the Comprehensive Primary Care Model on Health Care Spending and Utilization.

BACKGROUND: The Centers for Medicare & Medicaid Services launched the 4-year Comprehensive Primary Care Initiative (CPC Classic) in 2012 and its 5-year successor, CPC Plus (CPC+), in 2017 to test whether improving primary care delivery in five areas-and providing practices with financial and technical support-reduced spending and improved quality. This is the first study to examine long-term effects of a primary care practice transformation model. OBJECTIVE: To test whether long-term primary care transformation-the 4-year CPC Classic and the first 2 years of its successor, CPC+-reduced hospitalizations, emergency department (ED) visits, and spending over 6 years. DESIGN: We used a difference-in-differences analysis to compare outcomes for beneficiaries attributed to CPC Classic practices with outcomes for beneficiaries attributed to comparison practices during the year before and 6 years after CPC Classic began. PARTICIPANTS: The study involved 565,674 Medicare fee-for-service beneficiaries attributed to 502 CPC Classic practices and 1,165,284 beneficiaries attributed to 908 comparison practices, with similar beneficiary-, practice-, and market-level characteristics as the CPC Classic practices. INTERVENTIONS: The interventions required primary care practices to improve 5 care areas and supported their transformation with substantially enhanced payment, data feedback, and learning support and, for CPC+, added health information technology support. MAIN MEASURES: Hospitalizations (all-cause), ED visits (outpatient and total), and Medicare Part A and B expenditures. KEY RESULTS: Relative to comparison practices, beneficiaries in intervention practices experienced slower growth in hospitalizations-3.1% less in year 5 and 3.5% less in year 6 (P < 0.01) and roughly 2% (P < 0.1) slower growth each year in total ED visits during years 3 through 6. Medicare Part A and B expenditures (excluding care management fees) did not change appreciably. CONCLUSIONS: The emergence of favorable effects on hospitalizations in years 5 and 6 suggests primary care transformation takes time to translate into lower hospitalizations. Longer tests of models are needed.

Proximal fibular nerve conduction studies to tibialis anterior: Optimal E2 (reference electrode) placement.

BACKGROUND: Several E2 (reference electrode) positions are described for fibular (peroneal) nerve conduction studies to tibialis anterior (TA). METHODS: This study compared the contribution of different E2 sites to the TA motor response, using remote referential recordings and different bipolar montages. RESULTS: The medial knee contributes minimal electrical activity to the bipolar TA recordings, whereas tibial, ankle, and toe references resulted in very similar, moderate amplitude contributions consistent with far field potentials. These observations were very similar in controls and in patients with lower leg symptoms and signs. CONCLUSIONS: Standard montages using distal leg or foot E2 sites result in lower amplitudes with distortion arising from the E2 electrode, compared with the TA-Knee montage. Optimal measurement of the TA motor response is achieved using a medial knee reference, without compromising measures of fibular nerve conduction across the knee.

Tissue-specific transcriptome analyses provide new insights into GPCR signalling in adult Schistosoma mansoni.

Schistosomes are blood-dwelling trematodes with global impact on human and animal health. Because medical treatment is currently based on a single drug, praziquantel, there is urgent need for the development of alternative control strategies. The Schistosoma mansoni genome project provides a platform to study and connect the genetic repertoire of schistosomes to specific biological functions essential for successful parasitism. G protein-coupled receptors (GPCRs) form the largest superfamily of transmembrane receptors throughout the Eumetazoan phyla, including platyhelminths. Due to their involvement in diverse biological processes, their pharmacological importance, and proven druggability, GPCRs are promising targets for new anthelmintics. However, to identify candidate receptors, a more detailed understanding of the roles of GPCR signalling in schistosome biology is essential. An updated phylogenetic analysis of the S. mansoni GPCR genome (GPCRome) is presented, facilitated by updated genome data that allowed a more precise annotation of GPCRs. Additionally, we review the current knowledge on GPCR signalling in this parasite and provide new insights into the potential roles of GPCRs in schistosome reproduction based on the findings of a recent tissue-specific transcriptomic study in paired and unpaired S. mansoni. According to the current analysis, GPCRs contribute to gonad-specific functions but also to nongonad, pairing-dependent processes. The latter may regulate gonad-unrelated functions during the multifaceted male-female interaction. Finally, we compare the schistosome GPCRome to that of another parasitic trematode, Fasciola, and discuss the importance of GPCRs to basic and applied research. Phylogenetic analyses display GPCR diversity in free-living and parasitic platyhelminths and suggest diverse functions in schistosomes. Although their roles need to be substantiated by functional studies in the future, the data support the selection of GPCR candidates for basic and applied studies, invigorating the exploitation of this important receptor class for drug discovery against schistosomes but also other trematodes.

Optimal reference electrode placement for accessory and axillary nerve conduction studies.

BACKGROUND: Various techniques are described for proximal motor nerve conduction studies (NCSs). We investigated alternative reference electrode (E2) locations for accessory and axillary NCSs. METHODS: Multi-channel recordings were made from trapezius or deltoid referred to different sites, and from those sites referred to a remote electrode. Responses were compared using grouped statistics, and correlation analysis. RESULTS: For accessory NCSs, all belly:E2 montages showed comparable responses but axillary NCSs were more variable. Low amplitude contamination was seen at the sternum and contralateral acromion but greater distortion using other potential E2 sites. In both accessory and axillary studies, the ipsilateral acromion showed moderate activity, which correlated with the belly:remote response. CONCLUSIONS: Variation in E2 electrode sites may significantly distort the measured compound muscle action potential (CMAP). For accessory and axillary NCS, a sternal reference has favorable characteristics. Other sites, such as ipsilateral acromion or deltoid insertion, may not yield a representative CMAP.

Primary Care Practice Transformation Introduces Different Staff Roles.

PURPOSE: Practices in the 4-year Comprehensive Primary Care (CPC) initiative changed staffing patterns during 2012-2016 to improve care delivery. We sought to characterize these changes and to compare practice patterns with those in similar non-CPC practices in 2016. METHODS: We conducted an online survey among selected US primary care practices. We statistically tested 2012-2016 changes in practice-reported staff composition among 461 CPC practices using 2-tailed t tests. Using logistic regression analysis, we compared differences in staff types between the CPC practices and 358 comparison practices that participated in the survey in 2016. RESULTS: In 2012, most CPC practices reported having physicians (100%), administrative staff (99%), and medical assistants (90%). By 2016, 84% reported having care managers/care coordinators (up from 24% in 2012), and 29% reported having behavioral health professionals, clinical psychologists, or social workers (up from 19% in 2014). There were also smaller increases (of less than 10 percentage points) in the share of practices having pharmacists, nutritionists, registered nurses, quality improvement specialists, and health educators. Larger and system-affiliated practices were more likely to report having care managers/care coordinators and behavioral health professionals. In 2016, relative to comparison practices, CPC practices were more likely to report having various staff types-notably, care managers/care coordinators (84% of CPC vs 36% of comparison practices), behavioral health professionals (29% vs 12%), and pharmacists (18% vs 4%). CONCLUSIONS: During the CPC initiative, CPC practices added different staff types to a fairly traditional staffing model of physicians with medical assistants. They most commonly added care managers/care coordinators and behavioral health staff to support the CPC model and, at the end of CPC, were more likely to have these staff members than comparison practices.

Two-Year Costs and Quality in the Comprehensive Primary Care Initiative.

BACKGROUND: The 4-year, multipayer Comprehensive Primary Care Initiative was started in October 2012 to determine whether several forms of support would produce changes in care delivery that would improve the quality and reduce the costs of care at 497 primary care practices in seven regions across the United States. Support included the provision of care-management fees, the opportunity to earn shared savings, and the provision of data feedback and learning support. METHODS: We tracked changes in the delivery of care by practices participating in the initiative and used difference-in-differences regressions to compare changes over the first 2 years of the initiative in Medicare expenditures, health care utilization, claims-based measures of quality, and patient experience for Medicare fee-for-service beneficiaries attributed to initiative practices and a group of matched comparison practices. RESULTS: During the first 2 years, initiative practices received a median of $115,000 per clinician in care-management fees. The practices reported improvements in approaches to the delivery of primary care in areas such as management of the care of high-risk patients and enhanced access to care. Changes in average monthly Medicare expenditures per beneficiary did not differ significantly between initiative and comparison practices when care-management fees were not taken into account (-$11; 95% confidence interval [CI], -$23 to $1; P=0.07; negative values indicate less growth in spending at initiative practices) or when these fees were taken into account ($7; 95% CI, -$5 to $19; P=0.27). The only significant differences in other measures were a 3% reduction in primary care visits for initiative practices relative to comparison practices (P<0.001) and changes in two of the six domains of patient experience--discussion of decisions regarding medication with patients and the provision of support for patients taking care of their own health--both of which showed a small improvement in initiative practices relative to comparison practices (P=0.006 and P<0.001, respectively). CONCLUSIONS: Midway through this 4-year intervention, practices participating in the initiative have reported progress in transforming the delivery of primary care. However, at this point these practices have not yet shown savings in expenditures for Medicare Parts A and B after accounting for care-management fees, nor have they shown an appreciable improvement in the quality of care or patient experience. (Funded by the Department of Health and Human Services, Centers for Medicare and Medicaid Services; ClinicalTrials.gov number, NCT02320591.).

The Effects of a Primary Care Transformation Initiative on Primary Care Physician Burnout and Workplace Experience.

BACKGROUND: Physician burnout is associated with deleterious effects for physicians and their patients and might be exacerbated by practice transformation. OBJECTIVE: Assess the effect of the Comprehensive Primary Care (CPC) initiative on primary care physician experience. DESIGN: Prospective cohort study conducted with about 500 CPC and 900 matched comparison practices. Mail surveys of primary care physicians, selected using cross-sectional stratified random selection 11 months into CPC, and a longitudinal design with sample replacement 44 months into CPC. PARTICIPANTS: Primary care physicians in study practices. INTERVENTION: A multipayer primary care transformation initiative (October 2012-December 2016) that required care delivery changes and provided enhanced payment, data feedback, and learning support. MAIN MEASURES: Burnout, control over work, job satisfaction, likelihood of leaving current practice within 2 years. KEY RESULTS: More than 1000 physicians responded (over 630 of these in CPC practices) in each round (response rates 70-81%, depending on round and research group). Physician experience outcomes were similar for physicians in CPC and comparison practices. About one third of physician respondents in CPC and comparison practices reported high levels of burnout in each round (32 and 29% in 2013 [P = 0.59], and 34 and 36% in 2016 [P = 0.63]). Physicians in CPC and comparison practices reported some to moderate control over work, with an average score from 0.50 to 0.55 out of 1 in 2013 and 2016 (CPC-comparison differences of - 0.04 in 2013 [95% CI - 0.08-0.00, P = 0.07], and - 0.03 in 2016 [95% CI - 0.03-0.02, P = 0.19]). In 2016, roughly three quarters of CPC and comparison physicians were satisfied with their current job (77 and 74%, P = 0.77) and about 15% planned to leave their practice within 2 years (14 and 15%, P = 0.17). CONCLUSIONS: Despite requiring substantial practice transformation, CPC did not affect physician experience. Research should track effects of other transformation initiatives on physicians and test new ways to address burnout. TRIAL REGISTRATION: ClinicalTrials.gov number, NCT02320591.

A Miniaturized Screen of a Schistosoma mansoni Serotonergic G Protein-Coupled Receptor Identifies Novel Classes of Parasite-Selective Inhibitors.

Schistosomiasis is a tropical parasitic disease afflicting ~200 million people worldwide and current therapy depends on a single drug (praziquantel) which exhibits several non-optimal features. These shortcomings underpin the need for next generation anthelmintics, but the process of validating physiologically relevant targets ('target selection') and pharmacologically profiling them is challenging. Remarkably, even though over a quarter of current human therapeutics target rhodopsin-like G protein coupled receptors (GPCRs), no library screen of a flatworm GPCR has yet been reported. Here, we have pharmacologically profiled a schistosome serotonergic GPCR (Sm.5HTR) implicated as a downstream modulator of PZQ efficacy, in a miniaturized screening assay compatible with high content screening. This approach employs a split luciferase based biosensor sensitive to cellular cAMP levels that resolves the proximal kinetics of GPCR modulation in intact cells. Data evidence a divergent pharmacological signature between the parasitic serotonergic receptor and the closest human GPCR homolog (Hs.5HTR7), supporting the feasibility of optimizing parasitic selective pharmacophores. New ligands, and chemical series, with potency and selectivity for Sm.5HTR over Hs.5HTR7 are identified in vitro and validated for in vivo efficacy against schistosomules and adult worms. Sm.5HTR also displayed a property resembling irreversible inactivation, a phenomenon discovered at Hs.5HTR7, which enhances the appeal of this abundantly expressed parasite GPCR as a target for anthelmintic ligand design. Overall, these data underscore the feasibility of profiling flatworm GPCRs in a high throughput screening format competent to resolve different classes of GPCR modulators. Further, these data underscore the promise of Sm.5HTR as a chemotherapeutically vulnerable node for development of next generation anthelmintics.

The Impact of a Health Information Technology-Focused Patient-centered Medical Neighborhood Program Among Medicare Beneficiaries in Primary Care Practices: The Effect on Patient Outcomes and Spending.

BACKGROUND: The Center for Medicare & Medicaid Innovation (CMMI) tests new models of paying for or delivering health care services and expands models that improve health outcomes while lowering medical spending. CMMI gave TransforMED, a national learning and dissemination contractor, a 3-year Health Care Innovation Award (HCIA) to integrate health information technology systems into physician practices. This paper estimates impacts of TransforMED's HCIA-funded program on patient outcomes and Medicare parts A and B spending. RESEARCH DESIGN: We compared outcomes for Medicare fee-for-service (FFS) beneficiaries served by 87 treatment practices to outcomes for Medicare FFS beneficiaries served by 286 matched comparison practices, adjusting for differences in outcomes between the 2 groups during a 1-year baseline period. We estimated impacts in 3 evaluation outcome domains: quality-of-care processes, service use, and spending. RESULTS: We estimated the program led to a 7.1% reduction in inpatient admissions and a 5.7% decrease in the outpatient emergency department visits. However, there was no evidence of statistically significant effects in outcomes in either the quality-of-care processes or spending domains. CONCLUSIONS: These results indicate that TransforMED's program reduced service use for Medicare FFS beneficiaries, but also show that the program did not have statistically significant favorable impacts in the quality-of-care processes or spending domains. These results suggest that providing practices with population health management and cost-reporting software-along with technical assistance for how to use them-can complement practices' own patient-centered medical home transformation efforts and add meaningfully to their impacts on service use.

Behavioral Health and the Comprehensive Primary Care (CPC) Initiative: findings from the 2014 CPC behavioral health survey.

BACKGROUND: Incorporating behavioral health care into patient centered medical homes is critical for improving patient health and care quality while reducing costs. Despite documented effectiveness of behavioral health integration (BHI) in primary care settings, implementation is limited outside of large health systems. We conducted a survey of BHI in primary care practices participating in the Comprehensive Primary Care (CPC) initiative, a four-year multi-payer initiative of the Centers for Medicare and Medicaid Services (CMS). We sought to explore associations between practice characteristics and the extent of BHI to illuminate possible factors influencing successful implementation. METHOD: We fielded a survey that addressed six substantive domains (integrated space, training, access, communication and coordination, treatment planning, and available resources) and five behavioral health conditions (depression, anxiety, pain, alcohol use disorder, and cognitive function). Descriptive statistics compared BHI survey respondents to all CPC practices, documented the availability of behavioral health providers, and primary care and behavioral health provider communication. Bivariate relationships compared provider and practice characteristics and domain scores. RESULTS: One hundred sixty-one of 188 eligible primary care practices completed the survey (86% response rate). Scores indicated basic to good baseline implementation of BHI in all domains, with lowest scores on communication and coordination and highest scores for depression. Higher scores were associated with: having any behavioral health provider, multispecialty practice, patient-centered medical home designation, and having any communication between behavioral health and primary care providers. CONCLUSIONS: This study provides useful data on opportunities and challenges of scaling BHI integration linked to primary care transformation. Payment reform models such as CPC can assist in BHI promotion and development.

'Death and axes': unexpected Ca²âº entry phenologs predict new anti-schistosomal agents.

Schistosomiasis is a parasitic flatworm disease that infects 200 million people worldwide. The drug praziquantel (PZQ) is the mainstay therapy but the target of this drug remains ambiguous. While PZQ paralyses and kills parasitic schistosomes, in free-living planarians PZQ caused an unusual axis duplication during regeneration to yield two-headed animals. Here, we show that PZQ activation of a neuronal Ca²âº channel modulates opposing dopaminergic and serotonergic pathways to regulate 'head' structure formation. Surprisingly, compounds with efficacy for either bioaminergic network in planarians also displayed antischistosomal activity, and reciprocally, agents first identified as antischistocidal compounds caused bipolar regeneration in the planarian bioassay. These divergent outcomes (death versus axis duplication) result from the same Ca²âº entry mechanism, and comprise unexpected Ca²âº phenologs with meaningful predictive value. Surprisingly, basic research into axis patterning mechanisms provides an unexpected route for discovering novel antischistosomal agents.

Distal acquired demyelinating symmetric (DADS) neuropathy associated with colorectal adenocarcinoma.

INTRODUCTION: Paraneoplastic neuropathies are well recognized as a remote effect of cancer, and subacute sensory neuronopathy is a recognized syndrome. Demyelinating neuropathies are relatively rare. Distal acquired demyelinating symmetric (DADS) neuropathy associated with lymphoproliferative disease has been reported previously. We present the association of DADS neuropathy with solid tumor. METHODS: We report the clinical presentation, electrophysiology, and progress of DADS neuropathy in a patient later found to have colorectal adenocarcinoma. RESULTS: A patient presented with subacute onset of symmetric distal sensory and motor symptoms. Electrophysiology was typical of DADS neuropathy. Anti-MAG antibodies were initially positive at low titer, and indirect immunofluorescence analysis for anti-nuclear antibodies revealed autoantibodies to centromere nuclear protein-F (CENP-F). There was clinical and electrophysiologic resolution after tumor resection. CONCLUSIONS: This case describes the presentation of DADS neuropathy as a paraneoplastic syndrome in a patient later found to have colorectal adenocarcinoma.

Staffing patterns of primary care practices in the comprehensive primary care initiative.

PURPOSE: Despite growing calls for team-based care, the current staff composition of primary care practices is unknown. We describe staffing patterns for primary care practices in the Centers for Medicare and Medicaid Services (CMS) Comprehensive Primary Care (CPC) initiative. METHODS: We undertook a descriptive analysis of CPC initiative practices' baseline staffing using data from initial applications and a practice survey. CMS selected 502 primary care practices (from 987 applicants) in 7 regions based on their health information technology, number of patients covered by participating payers, and other factors; 496 practices were included in this analysis. RESULTS: Consistent with the national distribution, most of the CPC initiative practices included in this study were small: 44% reported 2 or fewer full-time equivalent (FTE) physicians; 27% reported more than 4. Nearly all reported administrative staff (98%) and medical assistants (89%). Fifty-three percent reported having nurse practitioners or physician assistants; 47%, licensed practical or vocational nurses; 36%, registered nurses; and 24%, care managers/coordinators-all of these positions are more common in larger practices. Other clinical staff were reported infrequently regardless of practice size. Compared with other CPC initiative practices, designated patient-centered medical homes were more likely to have care managers/coordinators but otherwise had similar staff types. Larger practices had fewer FTE staff per physician. CONCLUSIONS: At baseline, most CPC initiative practices used traditional staffing models and did not report having dedicated staff who may be integral to new primary care models, such as care coordinators, health educators, behavioral health specialists, and pharmacists. Without such staff and payment for their services, practices are unlikely to deliver comprehensive, coordinated, and accessible care to patients at a sustainable cost.

Advances in AAV vector development for gene therapy in the retina.

Adeno-associated virus (AAV) is a small, non-pathogenic dependovirus that has shown great potential for safe and long-term expression of a genetic payload in the retina. AAV has been used to treat a growing number of animal models of inherited retinal degeneration, though drawbacks-including a limited carrying capacity, slow onset of expression, and a limited ability to transduce some retinal cell types from the vitreous-restrict the utility of AAV for treating some forms of inherited eye disease. Next generation AAV vectors are being created to address these needs, through rational design efforts such as the creation of self-complementary AAV vectors for faster onset of expression and specific mutations of surface-exposed residues to increase transduction of viral particles. Furthermore, directed evolution has been used to create, through an iterative process of selection, novel variants of AAV with newly acquired, advantageous characteristics. These novel AAV variants have been shown to improve the therapeutic potential of AAV vectors, and further improvements may be achieved through rational design, directed evolution, or a combination of these approaches, leading to broader applicability of AAV and improved treatments for inherited retinal degeneration.

Diagnosis of dysferlinopathy masked by a superimposed hypothyroid myopathy.

We report a woman in her 30s with dysferlinopathy whose diagnosis was masked by superimposed hypothyroidism. Laboratory studies revealed Hashimoto's thyroiditis and markedly raised serum creatine kinase (CK of 6255 U/L; reference range 0-170 U/L). Electromyography, nerve conduction studies and MRI of the hip and thigh were consistent with a diagnosis of hypothyroid myopathy, but thyroxine failed to resolve her clinical presentation or normalise the CK level. Immunohistochemical (IHC) staining of right vastus lateralis muscle biopsy revealed the selective absence of dysferlin leading to a diagnosis of limb-girdle muscular dystrophy type IIB. Dysferlinopathy is a challenging diagnosis due to a varied clinical picture and low incidence. Misdiagnosis is common even in uncomplicated presentations, and this case outlines the need for routine inclusion of IHC and a low threshold for genetic testing, in the workup of complex myopathy.

Canomad: report of a case with a 40-year history and autopsy. Is this a sensory ganglionopathy with neuromuscular junction blockade?

INTRODUCTION: An 80-year-old man had a 40-year history of chronic sensory ataxic neuropathy and 11 years of relapsing/remitting episodes of rapid deterioration with perioral paresthesiae and weakness of bulbar, respiratory, and limb muscles. METHODS: An immunoglobulin M (IgM) paraprotein was detected 12 years before death, and Waldenstrom macroglobulinemia was diagnosed on bone marrow biopsy 3 years before death. Chronic ataxic neuropathy with ophthalmoplegia, IgM paraprotein, cold agglutinins, and anti-disialyl antibodies (CANOMAD) was diagnosed. RESULTS: Comprehensive autopsy showed severe dorsal column atrophy and dorsal root ganglionopathy. A different pathology was identified in cranial and peripheral nerves, dorsal roots, and cauda equina, comprising infiltration of clonal B-lymphocytes within the endoneurium, perineurium, and leptomeninges. CONCLUSIONS: The autopsy provides evidence of the pathogenesis of the relapsing remitting component of CANOMAD, and we postulate that this may relate to the presence of clonal IgM anti-disiayl gangliosides secreting B-lymphocytes within nerves.