Deep brain stimulation in Latin America in comparison with the US and Europe in a real-world population: indications, demographics, techniques, technology, and adverse events.

OBJECTIVE: The aim of this study was to provide geographic comparisons of deep brain stimulation (DBS) procedures in Latin America with the US and Europe regarding primary indications, demographic information, clinical and device-related adverse events, technology used, and patient outcomes using the Medtronic Product Surveillance Registry data as of July 31, 2021. METHODS: Two thousand nine hundred twelve patients were enrolled in the registry (2782 received DBS and 1580 are currently active). Fourteen countries contributed 44,100 years of device experience to the registry. DBS centers in Latin America are located in Colombia (n = 3), Argentina (n = 1), Brazil (n = 1), and Mexico (n = 1). Fisher's exact test was used to compare the difference in proportions of categorical variables between regions. The Wilcoxon signed-rank test was used for the EQ-5D index score change from baseline to follow-up. RESULTS: The most common indication for DBS was Parkinson's disease across all regions. In Latin America, dystonia was the second most common indication, compared to essential tremor in other regions. There was a striking finding with respect to age-patients were an average of 10 years younger at DBS implantation in Latin America. This difference was most likely due to the greater number of patients with dystonia receiving the device implants. The intraoperative techniques were quite similar, showing the same level of quality and covering the main principles of the surgeries with some variations in the brand of frames, planning software, and microrecording systems. Rechargeable batteries were significantly more common in Latin America (72.37%) than in the US (6.44%) and Europe (9.9%). Staging of the DBS procedure differed, with only 11.84% in Latin America staging the procedure compared with 97.58% and 34.86% in the US and Europe, respectively. The EQ-5D score showed significant improvements in all regions during the first 6-12 months (p < 0.0001). However, the 24-month follow-up only showed an improvement in the scale for Latin America (p < 0.0001). CONCLUSIONS: DBS was performed in Latin America with similar indications, techniques, and technology as in the US and Europe. Important differences were found, with Latin America implementing more regular use of rechargeable devices, including younger patients at the time of surgery, and showing more sustained quality of life improvements at 24 months of follow-up. The authors hypothesize that these disparities stem from differences in resources among regions. However, more studies are needed to standardize DBS practice across the world to improve patients' quality of life and provide high-quality care.

Targeted Drug Delivery for Chronic Nonmalignant Pain: Longitudinal Data From the Product Surveillance Registry.

OBJECTIVES: To assist in assessment of therapy risks and benefits of targeted drug delivery (TDD) for chronic nonmalignant pain using registry data on product performance, adverse events, and elective device replacement. MATERIALS AND METHODS: The Product Surveillance Registry (PSR) (NCT01524276) is an ongoing prospective, long-term, multicenter registry enrolling consented patients implanted with an intrathecal drug delivery system. Patients are followed prospectively with participating investigators providing pump and catheter performance data for events related to the device, procedure, and therapy. Event descriptions include patient symptoms and outcomes. RESULTS: Registry data from the 4646 patients (59.7% female) treated with TDD for chronic, nonmalignant pain at 59 registry sites between August 2003 and October 2019, with over 17,000 patient-years (4646 patients with 44 months average follow-up), were analyzed. Registry discontinuation was largely (46.2% of discontinued patients) due to study site closure and patient death; exit due to an adverse or device event was limited to 10.2%. CONCLUSIONS: Treating chronic pain with escalating doses of strong systemic opioids often leads to inconsistent pain control, impaired function, untenable side effects, and reduced quality of life and this practice has contributed to the current opioid crisis in the United States. TDD has been an available therapy for these patients for greater than 30 years, and data from this real-world registry offer supporting evidence to the long-term safety of this therapy as an alternative to systemic opioids, as well as insights into patient acceptance and satisfaction.

Intrathecal Baclofen for Severe Spasticity: Longitudinal Data From the Product Surveillance Registry.

OBJECTIVE: To assist in the assessment of intrathecal baclofen (ITB) therapy risks and benefits by providing surgical intervention rate, safety, and elective device replacement rate data. MATERIALS AND METHODS: An ongoing prospective, long-term, multicenter Product Surveillance Registry (PSR) (NCT01524276) enrolled consented patients implanted with the SynchroMed II infusion system. Pump and catheter performance data were collected, with patients followed prospectively for events related to the device, procedure, and therapy. Investigators provided event descriptions, patient symptoms, and patient outcomes. RESULTS: We analyzed registry data from 1743 patients (77% adult, 46.8% female) treated with ITB for severe spasticity at 53 registry sites between August 2003 and October 2017, for an accumulated 6481 patient-years. Discontinuation from the registry was largely (58.6% of discontinued patients) due to study site closure and patient relocation; exit due to an adverse event was limited to 0.3%. After 10 years, 87.2% of adult and 76.3% of pediatric patients continued with ITB. Overall, 99.1% of pumps reaching end of battery life were replaced at the time of explant. CONCLUSIONS: ITB therapy for the treatment of severe spasticity requires surgical implantation of a programmable infusion system for chronic drug delivery. If complications arise, many necessitate surgical intervention for correction. For spinal and cerebral spasticity in pediatric and adult patients, discontinuation rates due to an adverse event were low (0.3%), and there was high acceptance (99.1%) of surgical intervention for therapy continuation. Patient/caregiver willingness to accept surgical and other risks for therapy continuation was extremely high.

Intrathecal Drug Delivery Systems for Cancer Pain: An Analysis of a Prospective, Multicenter Product Surveillance Registry.

BACKGROUND: The safety and efficacy of intrathecal drug delivery systems (IDDSs) for the treatment of cancer-related pain have been demonstrated in randomized controlled clinical trials (RCTs). Despite positive evidence for this therapy, IDDS remains underutilized to treat cancer pain. Real-world registry data augment existing safety and effectiveness data and are presented here to broaden awareness of this therapeutic option, needed for adequate cancer-related pain treatment, and as a viable tool addressing concerns with systemic opioid use. METHODS: This prospective, long-term, multicenter (United States, Western Europe, and Latin America) registry started in 2003 to monitor the performance of SynchroMed Infusion Systems. Patient-reported outcomes were added in 2013. Before data acquisition, all sites obtained Ethics Committee/Institutional Review Board approval and written patient consent. The study was registered (NCT01524276 at clinicaltrials.gov) before patients were enrolled. Patients who provided informed consent were enrolled in the registry at initial IDDS implant or replacement. RESULTS: Through July 2017, 1403 patients with cancer pain were enrolled and implanted. The average (minimum/maximum) age of patients was 59 years (13/93 years), with 56.6% female. The most frequent cancer types were lung, breast, colon/rectal, pancreatic, and prostate. The majority of patients whose registry follow-up ended (87%; 1141/1311) were followed through death, with 4.3% (n = 57) exiting due to device explant or therapy discontinuation; the remaining 113 (8.6%) discontinued for reasons such as transfer of care, lost to follow-up, and site closure. Pain scores within the cohort of patients providing baseline and follow-up data improved significantly at 6 (P = .0007; n = 103) and 12 (P = .0026; n = 55) months compared to baseline, with EuroQol with 5 dimensions (EuroQol-5D) scores showing significant improvement at 6 months (P = .0016; n = 41). Infection requiring surgical intervention (IDDS explant, replacement, pocket revision, irrigation and debridement, etc) was reported in 3.2% of patients. CONCLUSIONS: Adequate and improved pain control in patients with cancer, even in advanced stages, with concurrent quality of life maintenance is attainable. Results from this large-scale, multicenter, single-group cohort supplement existing RCT data that support IDDS as a safe and effective therapeutic option with a positive benefit-risk ratio in the treatment of cancer pain.

Closed fumarase C active-site structures reveal SS Loop residue contribution in catalysis.

Fumarase C (FumC) catalyzes the reversible conversion of fumarate to S-malate. Previous structural investigations within the superfamily have reported a dynamic structural segment, termed the SS Loop. To date, active-site asymmetry has raised the question of how SS Loop placement affects participation of key residues during the reaction. Herein, we report structural and kinetic analyses from Escherichia coli FumC variants to understand the contribution of SS Loop residues S318, K324, and N326. High-resolution X-ray crystallographic results reveal three distinct FumC active-site conformations; disordered-open, ordered-open, and the newly discovered ordered-closed. Surprisingly, each SS Loop variant has unaffected Michaelis constants coupled to reductions in turnover number. Based upon our structural and functional analyses, we propose structural and catalytic roles for each of the aforementioned residues.

Vitamin A and Hydrochlorothiazide Causing Severe Hypercalcemia in a Patient With Primary Hyperparathyroidism.

OBJECTIVE: To report a case of severe hypercalcemia, exacerbated by vitamin A supplementation and hydrochlorothiazide, in a patient with primary hyperparathyroidism. METHODS: Clinical and laboratory findings are presented along with response to therapy. RESULTS: A 68-year-old white female presented to the emergency department complaining of nausea, vomiting, and altered mental status. Laboratory findings revealed calcium 15.8 mg/dL (8.4-10.2), albumin 4.1 g/dL (3.8-4.8), and parathyroid hormone 62 pg/mL (14-64). Serum calcium improved after intravenous hydration with normal saline. Prior to this hospitalization, over-the-counter medications were significant for calcium (600 mg daily), vitamin A (11 000 IU daily), and vitamin D (800 IU daily).The patient's prescription medications were significant for hydrochlorothiazide (12.5 mg daily). Twenty-four-hour urine calcium was subsequently found to be 146 mg (35-250). Myeloma, lymphoma, and sarcoidosis were ruled out as the etiology for hypercalcemia. The diagnosis of primary hyperparathyroidism was confirmed. She was treated surgically for primary hyperparathyroidism. The right and left superior parathyroid showed hypercellular parathyroid on pathology. The patient was normocalcemic after surgery. CONCLUSION: Previous reports suggest that very high doses of vitamin A is required to cause hypercalcemia. This case suggests that in a setting of primary hyperparathyroidism and hydrochlorothiazide therapy, vitamin A may contribute to the development of severe hypercalcemia in patients who are on calcium and vitamin D supplements. Given their biologic effects, public awareness needs to be created regarding the injudicious use of vitamins.

Biochemical Characterization of Two Clinically-Relevant Human Fumarase Variants Defective for Oligomerization.

BACKGROUND: Fumarase, a significant enzyme of energy metabolism, catalyzes the reversible hydration of fumarate to L-malate. Mutations in the FH gene, encoding human fumarase, are associated with fumarate hydratase deficiency (FHD) and hereditary leiomyomatosis and renal cell cancer (HLRCC). Fumarase assembles into a homotetramer, with four active sites. Interestingly, residues from three of the four subunits within the homotetramer comprise each active site. Hence, any mutation affecting oligomerization is predicted to disrupt enzyme activity. METHODS: We constructed two variants of hexahistidine-tagged human recombinant fumarase, A308T and H318Y, associated with FHD and HLRCC, respectively. Both Ala308 and His318 lie within the fumarase intersubunit interface. We purified unmodified human fumarase and the two variants, and analyzed their enzymatic activities and oligomerization states in vitro. RESULTS: Both variants showed severely diminished fumarase activity. Steady-state kinetic analysis demonstrated that the variants were largely defective due to decreased turnover rate, while displaying Km values for L-malate similar to unmodified human recombinant fumarase. Blue native polyacrylamide gel electrophoresis and gel filtration experiments revealed that each variant had an altered oligomerization state, largely forming homodimers rather than homotetramers. CONCLUSION: We conclude that A308T and H318Y render human fumarase enzymatically inactive via defective oligomerization. Therefore, some forms of FHD and HLRCC can be linked to improperly folded quaternary structure.

Proteolysis of truncated hemolysin A yields a stable dimerization interface.

Wild-type and variant forms of HpmA265 (truncated hemolysin A) from Proteus mirabilis reveal a right-handed, parallel ß-helix capped and flanked by segments of antiparallel ß-strands. The low-salt crystal structures form a dimeric structure via the implementation of on-edge main-chain hydrogen bonds donated by residues 243-263 of adjacent monomers. Surprisingly, in the high-salt structures of two variants, Y134A and Q125A-Y134A, a new dimeric interface is formed via main-chain hydrogen bonds donated by residues 203-215 of adjacent monomers, and a previously unobserved tetramer is formed. In addition, an eight-stranded antiparallel ß-sheet is formed from the flap regions of crystallographically related monomers in the high-salt structures. This new interface is possible owing to additional proteolysis of these variants after Tyr240. The interface formed in the high-salt crystal forms of hemolysin A variants may mimic the on-edge ß-strand positioning used in template-assisted hemolytic activity.

Intrathecal Drug Delivery Systems (IDDS): The Implantable Systems Performance Registry (ISPR).

OBJECTIVES: The ISPR was initially created to monitor the product performance of Medtronic implanted intrathecal drug infusion and spinal cord systems available in the United States. MATERIALS AND METHODS: Data were collected from 50 representative sites implanting and following patients with intrathecal drug delivery systems across the United States between August 7, 2003 and January 31, 2014. Device performance over time was estimated using life table survival methods. RESULTS: Of the 6093 patients enrolled in the ISPR, 3405 (55.9%) were female and 2675 (43.9%) were male, and 13 (0.2%) did not provide gender data. The average age at enrollment was 52.9 years (SD =17.6 years) and average follow-up time was 29.6 months. Currently, the estimates of device survival from pump-related events exceed 90% for all pump models across the applicable follow-up time points. The majority of product performance events were catheter-related. At 5 years of follow-up, all applicable catheter models, with the exception of revised not as designed or grafted not as designed catheters, had greater than 81% survival from catheter-related events. CONCLUSIONS: The ISPR is designed to serve as an ongoing source of system and device-related information with a focus on "real-world" safety and product performance. ISPR data continue to be used to guide future product development efforts aimed at improving product reliability and quality.

Spinal Cord Stimulation (SCS)-The Implantable Systems Performance Registry (ISPR).

OBJECTIVES: The Implantable Systems Performance Registry (ISPR) was created to monitor the product performance of Medtronic Spinal Cord Stimulation (SCS) and implanted intrathecal drug infusion systems available in the United States. MATERIALS AND METHODS: Data were collected on 2605 patients from 44 centers from various geographic regions across the United States implanting and following patients with SCS systems between June 25, 2004 and January 31, 2014. Actuarial life table methods are used to estimate device performance over time. Of the 2605 patients, 1490 (57.2%) were female, 1098 (42.1%) were male and 17 (0.7%) did not provide gender data. The average age at enrollment was 56.3 years (range: 4-97, SD = 14.3) and average follow-up time was 20.1 months (SD = 22.5). RESULTS: Currently the estimates of device survival from neurostimulator-related events exceed 97% for all neurostimulator models across the applicable follow-up time points and all applicable extension models had greater than 95% survival from extension events. The majority of product performance events were lead-related. At 5 years of follow-up, all applicable lead families, with the exception of the Pisces-Quad LZ family, had greater than 75% survival from lead events. CONCLUSIONS: The ISPR is designed to serve as an ongoing source of system and device-related information with a focus on "real-world" safety and product performance. ISPR data continue to be used to guide future product development efforts aimed at improving product reliability and quality.

Sequential unfolding of the hemolysin two-partner secretion domain from Proteus mirabilis.

Protein secretion is a major contributor to Gram-negative bacterial virulence. Type Vb or two-partner secretion (TPS) pathways utilize a membrane bound ß-barrel B component (TpsB) to translocate large and predominantly virulent exoproteins (TpsA) through a nucleotide independent mechanism. We focused our studies on a truncated TpsA member termed hemolysin A (HpmA265), a structurally and functionally characterized TPS domain from Proteus mirabilis. Contrary to the expectation that the TPS domain of HpmA265 would denature in a single cooperative transition, we found that the unfolding follows a sequential model with three distinct transitions linking four states. The solvent inaccessible core of HpmA265 can be divided into two different regions. The C-proximal region contains nonpolar residues and forms a prototypical hydrophobic core as found in globular proteins. The N-proximal region of the solvent inaccessible core, however, contains polar residues. To understand the contributions of the hydrophobic and polar interiors to overall TPS domain stability, we conducted unfolding studies on HpmA265 and site-specific mutants of HpmA265. By correlating the effect of individual site-specific mutations with the sequential unfolding results we were able to divide the HpmA265 TPS domain into polar core, nonpolar core, and C-terminal subdomains. Moreover, the unfolding studies provide quantitative evidence that the folding free energy for the polar core subdomain is more favorable than for the nonpolar core and C-terminal subdomains. This study implicates the hydrogen bonds shared among these conserved internal residues as a primary means for stabilizing the N-proximal polar core subdomain.

Structural and functional studies of truncated hemolysin A from Proteus mirabilis.

In this study we analyzed the structure and function of a truncated form of hemolysin A (HpmA265) from Proteus mirabilis using a series of functional and structural studies. Hemolysin A belongs to the two-partner secretion pathway. The two-partner secretion pathway has been identified as the most common protein secretion pathway among Gram-negative bacteria. Currently, the mechanism of action for the two-partner hemolysin members is not fully understood. In this study, hemolysis experiments revealed a unidirectional, cooperative, biphasic activity profile after full-length, inactive hemolysin A was seeded with truncated hemolysin A. We also solved the first x-ray structure of a TpsA hemolysin. The truncated hemolysin A formed a right-handed parallel beta-helix with three adjoining segments of anti-parallel beta-sheet. A CXXC disulfide bond, four buried solvent molecules, and a carboxyamide ladder were all located at the third complete beta-helix coil. Replacement of the CXXC motif led to decreased activity and stability according to hemolysis and CD studies. Furthermore, the crystal structure revealed a sterically compatible, dry dimeric interface formed via anti-parallel beta-sheet interactions between neighboring beta-helix monomers. Laser scanning confocal microscopy further supported the unidirectional interconversion of full-length hemolysin A. From these results, a model has been proposed, where cooperative, beta-strand interactions between HpmA265 and neighboring full-length hemolysin A molecules, facilitated in part by the highly conserved CXXC pattern, account for the template-assisted hemolysis.

Development of the American Association of Diabetes Educators' Diabetes Self-management Assessment Report Tool.

PURPOSE: The purpose of this article is to describe the development and testing of a new tool for collecting patient information for diabetes self-management education (DSME): the Diabetes Self-management Assessment Report Tool (D-SMART). The D-SMART was designed through expert panel consensus based on a hybrid conceptual framework and is intended to serve multiple functions at the level of the patient, the program, and the field. METHODS: The D-SMART has completed 3 rounds of pilot testing and is currently undergoing a fourth round, with each round resulting in revisions to the original instrument. RESULTS: Findings from the pilot testing indicate that the instrument has acceptable reliability, validity, and sensitivity (or responsiveness) to change. A full-scale field test is currently under way, in which data from the D-SMART will be used to guide the delivery of services and to evaluate and enhance program functioning with a goal of improving education and care. Additional data from the field test are reported elsewhere, and further analyses are planned. CONCLUSIONS: The D-SMART provides educators with a tool that measures patients' behaviors and identifies those priorities for, and barriers to, change.

Structure of free fumarase C from Escherichia coli.

Previous crystal structures of fumarase C from Escherichia coli have noted two occupied dicarboxylate-binding sites termed the active site and the B site. Here, the first known fumarase C structure is reported in which both sites are unoccupied by bound ligand. This so-called ;free' crystal form shows conservation of the active-site water in a similar orientation to that reported in other fumarase C crystal structures. More importantly, a shift of His129 has been observed at the B site. This new crystallographic information suggests the use of water as a permanent member of the active site and the use of an imidazole-imidazolium conversion to control access at the allosteric B site.

Missense mutations in fumarate hydratase in multiple cutaneous and uterine leiomyomatosis and renal cell cancer.

Heterozygous germline mutations in fumarate hydratase (FH) predispose to the multiple cutaneous and uterine leiomyomatosis syndrome (MCUL), which, when co-existing with renal cancer, is also known as hereditary leiomyomatosis and renal cell cancer. Twenty-seven distinct missense mutations represent 68% of FH mutations reported in MCUL. Here we show that FH missense mutations significantly occurred in fully conserved residues and in residues functioning in the FH A-site, B-site, or subunit-interacting region. Of 24 distinct missense mutations, 13 (54%) occurred in the substrate-binding A-site, 4 (17%) in the substrate-binding B-site, and 7 (29%) in the subunit-interacting region. Clustering of missense mutations suggested the presence of possible mutational hotspots. FH functional assay of lymphoblastoid cell lines from 23 individuals with heterozygous FH missense mutations showed that A-site mutants had significantly less residual activity than B-site mutants, supporting data from Escherichia coli that the A-site is the main catalytic site. Missense FH mutations predisposing to renal cancer had no unusual features, and identical mutations were found in families without renal cancer, suggesting a role for genetic or environmental factors in renal cancer development in MCUL. That all missense FH mutations associating with MCUL/hereditary leiomyomatosis and renal cell cancer showed diminished FH enzymatic activity suggests that the tumor suppressor role of fumarate hydratase may relate to its enzymatic function.

Organelle and translocatable forms of glyoxysomal malate dehydrogenase. The effect of the N-terminal presequence.

Many organelle enzymes coded for by nuclear genes have N-terminal sequences, which directs them into the organelle (precursor) and are removed upon import (mature). The experiments described below characterize the differences between the precursor and mature forms of watermelon glyoxysomal malate dehydrogenase. Using recombinant protein methods, the precursor (p-gMDH) and mature (gMDH) forms were purified to homogeneity using Ni2+-NTA affinity chromatography. Gel filtration and dynamic light scattering have shown both gMDH and p-gMDH to be dimers in solution with p-gMDH having a correspondingly higher molecular weight. p-gMDH also exhibited a smaller translational diffusion coefficient (D(t)) at temperatures between 4 and 32 degrees C resulting from the extra amino acids on the N-terminal. Differential scanning calorimetry described marked differences in the unfolding properties of the two proteins with p-gMDH showing additional temperature dependent transitions. In addition, some differences were found in the steady state kinetic constants and the pH dependence of the K(m) for oxaloacetate. Both the organelle-precursor and the mature form of this glyoxysomal enzyme were crystallized under identical conditions. The crystal structure of p-gMDH, the first structure of a cleavable and translocatable protein, was solved to a resolution of 2.55 A. GMDH is the first glyoxysomal MDH structure and was solved to a resolution of 2.50 A. A comparison of the two structures shows that there are few visible tertiary or quaternary structural differences between corresponding elements of p-gMDH, gMDH and other MDHs. Maps from both the mature and translocatable proteins lack significant electron density prior to G44. While no portion of the translocation sequences from either monomer in the biological dimer was visible, all of the other solution properties indicated measurable effects of the additional residues at the N-terminal.

Crystallization of truncated hemolysin A from Proteus mirabilis.

Proteus species are second only to Escherichia coli as the most common causative agent of Gram-negative bacteria-based urinary-tract infections and many harbor several virulence factors that provide inherent uropathogenicity. One virulence factor stems from a two-partner secretion pathway comprised of hemolysin A and hemolysin B; upon hemolysin B-dependent secretion, hemolysin A becomes activated. This system is distinct from the classic type I secretion pathway exemplified by the hemolysin system within Escherichia coli. In order to describe the mechanism by which hemolysin A is activated for pore formation, an amino-terminal truncated form capable of complementing the non-secreted full-length hemolysin A and thereby restoring hemolytic activity has been constructed, expressed and purified. A room-temperature data set has been collected to 2.5 A resolution. The crystal belongs to the orthorhombic space group P2(1)2(1)2, with unit-cell parameters a = 34.47, b = 58.40, c = 119.74 A. The asymmetric unit is expected to contain a single monomer, which equates to a Matthews coefficient of 1.72 A3 Da(-1) and a solvent content of 28.3%.

The role of the allosteric B site in the fumarase reaction.

The role of a malate binding site in a concavity external to the more deeply situated active site has been a major mystery of the fumarase reaction. The malate, within 12 A of the active site, was bound by hydrogen bonds to two main-chain amides and to two basic residues, H129 and R126. Mutation of the His of this so-called B site of Escherichia coli fumarase had little effect on the overall initial rate kinetics of the enzyme, which has obscured an understanding of the critical role of the site. Contrary to the WT enzyme, which is rate-limited in the recycling of free enzyme isoforms that follows product release, the enzyme with both basic residues modified is rate-limited in the product release step itself. A loss of complexity in the mutated, but still functional, step is indicated by a greatly reduced sensitivity of its rate to changes in temperature. Unlike the inhibition by glycerol shown with normal enzyme and attributed to a viscogenic effect on the recycling rate, the product-release step of the B-site mutants is accelerated by glycerol, suggestive of a structural effect on the 12-A space between the A and B sites. It is proposed that the "extra" malate represents a stage in the transfer of substrate and product between the solvent and the "buried" active site of the enzyme.