The Efficacy and Tolerability of Irbesartan/Amlodipine Combination Therapy in Patients With Essential Hypertension Whose Blood Pressure Were not Controlled by Irbesartan Monotherapy.

PURPOSE: This study aimed to evaluate the efficacy and tolerability of irbesartan (IRB) and amlodipine (AML) combination therapy in patients with essential hypertension whose blood pressure (BP) was not controlled by IRB monotherapy. METHODS: Two multicenter, randomized, double-blind, placebo-controlled, phase III studies were conducted in Korea (the I-DUO 301 study and the I-DUO 302 study). After a 4-week run-in period with either 150 mg IRB (I-DUO 301 study) or 300 mg IRB (I-DUO 302 study), patients with uncontrolled BP (ie, mean sitting systolic BP [MSSBP] ≥140 mmHg to <180 mmHg and mean sitting diastolic BP <110 mmHg) were randomized to the placebo, AML 5 mg, or AML 10 mg group. A total of 428 participants were enrolled in the 2 I-DUO studies. In the I-DUO 301 study, 271 participants were randomized in a 1:1:1 ratio to receive either IRB/AML 150/5 mg, IRB/AML 150/10 mg, or IRB 150 mg/placebo. In the I-DUO 302 study, 157 participants were randomized in a 1:1 ratio to receive IRB/AML 300/5 mg or IRB 300 mg/placebo. The primary endpoint was the change in MSSBP from baseline to week 8. Tolerability was assessed according to the development of treatment-emergent adverse events (TEAEs) and clinically significant changes in physical examination, laboratory tests, pulse, and 12-lead electrocardiography. FINDINGS: In I-DUO 301, the mean (SD) changes of MSSBP at week 8 from baseline were -14.78 (12.35) mmHg, -21.47 (12.78) mmHg, and -8.61 (12.19) mmHg in the IRB/AML 150/5 mg, IRB/AML 150/10 mg, and IRB 150 mg/placebo groups, respectively. In I-DUO 302, the mean (SD) changes of MSSBP at week 8 from baseline were -13.30 (12.47) mmHg and -7.19 (15.37) mmHg in the IRB/AML 300/5 mg and IRB 300 mg/placebo groups, respectively. In both studies, all combination groups showed a significantly higher reduction in MSSBP than the IRB monotherapy groups (P < 0.001 for both). TEAEs occurred in 10.00%, 10.99%, and 12.22% of participants in the IRB/AML 150/5 mg, IRB/AML 150/10 mg, and IRB 150 mg/placebo groups, respectively, in I-DUO 301 and in 6.33% and 10.67% of participants in the IRB/AML 300/5 mg and IRB 300 mg/placebo groups, respectively, in I-DUO 302, with no significant between-group differences. Overall, there was one serious adverse event throughout I-DUO study. IMPLICATIONS: The combination of IRB and AML has superior antihypertensive effects compared with IRB alone over an 8-week treatment period, with placebo-like tolerability. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT05476354 (I-DUO 301), NCT05475665 (I-DUO 302).

Electronic Cigarette (E-Cig) Use in the Chronic Pain Population.

BACKGROUND: Since electronic cigarettes (E-Cigs) were introduced to the United States (US) in 2007 its use has increased. Like other tobacco products, E-Cigs too pose health risks. Studies have shown a correlation between pain and tobacco use, with the association being bidirectional. However, there is limited data on the effect of E-Cig use on chronic pain, as well as its association with opioid use. OBJECTIVES: To evaluate the use of tobacco products, including E-Cigs in a chronic pain population. STUDY DESIGN: This study was designed as a cross sectional survey. SETTING: This study was set in an urban academic teaching center. METHODS: After IRB approval, surveys of established chronic pain patients were conducted over 4 months. The survey and results were anonymous, without the collection of any identifiable information. The adult patients who had been treated in the pain practice for over 3 months were included in this study. The survey collected the patients' age, gender, history of tobacco usage, cigarette smoking, E-Cig and opioid use. RESULTS: A total of 312 patients were surveyed. 198 women (63.5%) and 114 men (36.5%). The average age was 58.2; ~59 years for men and ~58 years for women. Eighty-four patients (26.9%) were managing pain using chronic opioids; 46 women and 38 men. Nine women (4.5%) had tried E-Cigs in the past, but none (0%) were active users. Eighteen men (15.8%) had tried E-Cigs in the past with 9 (7.8%) being active users. Among the opioid managed patients, 6 (9.1%) had and were active users of E-Cigs and all 6 were men (20%). LIMITATIONS: The anonymous results collected through the survey may not be accurate as they cannot be validated. In addition to the small sample size, the entire study population is from an urban academic center which may not be generalizable to all chronic pain patients. Finally, the study does not evaluate the impact of tobacco or E-Cig use on pain level or functional status. CONCLUSION: In this study of chronic pain patients, cigarette smoking and E-Cig use was similar to the reported use in the general adult population in the US. The study showed a strong correlation between tobacco use, especially cigarettes and E-Cigs, and opioid use. As the use of E-Cigs becomes more mainstream, the association between E-Cig use, chronic pain, and opioid use should be monitored.

Advantages of whole-exome sequencing over immunomapping in 67 Brazilian patients with epidermolysis bullosa.

BACKGROUND: Epidermolysis bullosa (EB) is characterized by skin fragility and blistering. In Brazil, the diagnosis is usually obtained through immunomapping, which involves a skin biopsy. Most recently, whole exome sequencing (WES) has become an important tool for the diagnosis of the subtypes of EB, providing information on prognosis as well as allowing appropriate genetic counseling for the families. OBJECTIVE: To compare the results of immunomapping and molecular analysis and to describe the characteristics of a Brazilian cohort of patients with EB. METHODS: Patients were submitted to clinical evaluation and WES using peripheral blood samples. WES results were compared to those obtained from immunomapping testing from skin biopsies. RESULTS: 67 patients from 60 families were classified: 47 patients with recessive dystrophic EB (DEB), 4 with dominant DEB, 15 with EB simplex (EBS), and 1 with junctional EB (JEB). Novel causative variants were: 10/60 (16%) in COL7A1 associated with recessive DEB and 3 other variants in dominant DEB; one homozygous variant in KRT5 and another homozygous variant in PLEC, both associated with EBS. Immunomapping was available for 59 of the 67 patients and the results were concordant with exome results in 37 (62%), discordant in 13 (22%), and inconclusive in 9 patients (15%). STUDY LIMITATIONS: Even though EB is a rare disease, for statistical purposes, the number of patients evaluated by this cohort can still be considered limited; other than that, there was a significant difference between the proportion of types of EB (only one case with JEB, against more than 50 with DEB), which unfortunately represents a selection bias. Also, for a small subset of families, segregation (usually through Sanger sequencing) was not an option, usually due to deceased or unknown parent status (mostly the father). CONCLUSION: Although immunomapping has been useful in services where molecular studies are not available, this invasive method may provide a misdiagnosis or an inconclusive result in about 1/3 of the patients. This study shows that WES is an effective method for the diagnosis and genetic counseling of EB patients.

Prescription trends of opioid and non-opioid controlled prescription adjunctive analgesics prior to and after cervical spinal surgery: a retrospective cohort study.

OBJECTIVE: Cervical spine surgery (CSS) may be needed in those with refractory pain or neurologic deficits to improve outcomes in patients with cervical spine disease. However, consensus varies in the literature on the effect of surgery on opioid use. The objectives of this study were to analyze prescription rates of multiple controlled-substances before and after CSS and distinguish factors that may have contributed to opioid use after surgery. DESIGN: This is a retrospective cohort study analyzing prescription trends of various controlled substances in 632 patients who underwent CSS from 2019 to 2021. RESULTS: Opioids have the largest rise in prescriptions at 3- and 6-month time points after CSS. A significant association (p < 0.001) was found between opioid use one year prior to and one year after CSS. Exposure to opioids prior to surgery (OR 2.77, 95% CI 1.43, 5.51, p = 0.003) and higher morphine milligram equivalent (MME) dose (OR 1.02, 95% CI 1.01, 1.04, p = 0.012) were found to be associated to opioid use after surgery. Significantly more females were prescribed controlled substances (p = 0002). CONCLUSION: Higher MME dose and opioid exposure prior to surgery are important factors in predicting post-surgical opioid use.

One-year outcomes of total arch replacement and frozen elephant trunk using the E-vita Open NEO.

OBJECTIVES: In this cohort study, we aimed to assess the 1-year clinical outcomes of using the E-vita Open NEO™ hybrid prosthesis for total arch replacement with frozen elephant trunk (FET) to repair extensive aortic pathologies. METHODS: We reviewed individuals who underwent thoracic aortic surgery between April 2021 and March 2023 from the Gangnam Severance Aortic Registry. Exclusion criteria included ascending aortic replacement, 1 or 2 partial arch replacement, descending aortic replacement and total arch replacement without an FET. Finally, all consecutive patients who underwent total arch replacement and FET with E-vita Open NEO for aortic arch pathologies between April 2021 and March 2023 were included in this cohort study. The patients were divided into 3 groups based on their pathology: acute aortic dissection, chronic aortic dissection and thoracic aortic aneurysm. The primary end point was in-hospital mortality. The secondary end points during the postoperative period comprised stroke, spinal cord injury and redo sternotomy for bleeding. Additionally, the secondary end points during the follow-up period included the 1-year survival rate, 1-year freedom from all aortic procedures and 1-year freedom from unplanned aortic interventions. RESULTS: The study included 167 patients in total: 92 patients (55.1%) with acute aortic dissection, 20 patients (12.0%) with chronic aortic dissection and 55 patients (32.9%) with thoracic aortic aneurysm. The in-hospital mortality was 1.8% (n = 3). Strokes occurred in 1.8% (n = 3) of the patients, spinal cord injury in 1.8% (n = 3) and redo sternotomy for bleeding was performed in 3.0% (n = 5). There were no significant differences between the pathological groups. The median follow-up period (quartile 1-quartile 3) was 198 (37-373) days, with 1-year survival rates of 95.9%. At 1 year, the freedom from all aortic procedures and unplanned aortic interventions were 90.3% and 92.0%, respectively. CONCLUSIONS: The 1-year clinical outcomes of total arch replacement with FET using the E-vita Open NEO were favourable. Long-term follow-up is required to evaluate the durability of the FET.

Prevalence and characteristics of hepatitis delta virus infection in patients with hepatitis B in the United States: An analysis of the All-Payer Claims Database.

BACKGROUND AND AIMS: HDV leads to the most severe form of viral hepatitis; however, the prevalence of HDV is not well understood. Using real-world data from the All-Payer Claims Database, this study estimates the prevalence of HBV/HDV infection among the chronic HBV population and describes patient/clinical characteristics for adults with HBV/HDV infection in the United States. APPROACH AND RESULTS: Adults (≥18 years) with ≥1 inpatient claim or ≥2 outpatient claims for HDV infection or HBV in the All-Payer Claims Database from January 1, 2014, to December 31, 2020, were identified. HDV prevalence was calculated as the proportion of patients with HBV/HDV infection among total patients with HBV infection. Patient characteristics, socioeconomic status, advanced liver complications (eg, cirrhosis, HCC), and comorbidities were assessed. A total of 6719 patients were diagnosed with HBV/HDV among 144,975 with HBV and 12 months of continuous data, for a prevalence of 4.6%. At diagnosis, 31.7% of patients with HBV/HDV had advanced liver complications, including compensated cirrhosis (16.3%) and decompensated cirrhosis (10.4%). Diabetes (50.5%), hypertension (49.8%), and HIV infection (30.9%) were the top 3 comorbidities. CONCLUSIONS: In a large database capturing approximately 80% of the US-insured population, HBV/HDV infection prevalence was 4.6% among adults infected with HBV. Patients infected with HDV had high rates of baseline liver complications and other comorbidities at the time of diagnosis, suggesting potentially delayed diagnosis and/or treatment. Earlier identification of HBV/HDV infection among the population with HBV may provide opportunities to improve linkage to care and treatment, thereby reducing the risk of liver-related morbidity and mortality.

Association of hepatitis delta virus with liver morbidity and mortality: A systematic literature review and meta-analysis.

BACKGROUND AND AIMS: Studies have suggested that patients with chronic hepatitis B, either co- or superinfected, have more aggressive liver disease progression than those with the HDV. This systematic literature review and meta-analysis examined whether HDV RNA status is associated with increased risk of advanced liver disease events in patients who are HBsAg and HDV antibody positive. APPROACH AND RESULTS: A total of 12 publications were included. Relative rates of progression to advanced liver disease event for HDV RNA+/detectable versus HDV RNA-/undetectable were extracted for analysis. Reported OR and HRs with 95% CI were pooled using the Hartung-Knapp-Sidik-Jonkman method for random-effects models. The presence of HDV RNA+ was associated with an increased risk of any advanced liver disease event [random effect (95% CI): risk ratio: 1.48 (0.93, 2.33); HR: 2.62 (1.55, 4.44)]. When compared to the patients with HDV RNA- status, HDV RNA+ was associated with a significantly higher risk of progressing to compensated cirrhosis [risk ratio: 1.74 (1.24, 2.45)] decompensated cirrhosis [HR: 3.82 (1.60, 9.10)], HCC [HR: 2.97 (1.87, 4.70)], liver transplantation [HR: 7.07 (1.61, 30.99)], and liver-related mortality [HR: 3.78 (2.18, 6.56)]. CONCLUSIONS: The patients with HDV RNA+ status have a significantly greater risk of liver disease progression than the patients who are HDV RNA-. These findings highlight the need for improved HDV screening and linkage to treatment to reduce the risk of liver-related morbidity and mortality.

Health Care Resource Utilization and Total Costs of Care for Adult Patients With Relapsed or Refractory Acute Lymphoblastic Leukemia in the United States: A Retrospective Claims Analysis.

PURPOSE: Although immunotherapies such as blinatumomab and inotuzumab have led to improved outcomes, financial burden and health resource utilization (HRU) have increased for adult patients with relapsed or refractory B-cell acute lymphoblastic leukemia (R/R B-ALL). This study assessed real-world HRU and costs of care among adult patients with R/R B-ALL by line of therapy (LoT) in the United States. METHODS: We selected patients from the MarketScanⓇ Database (January 1, 2016 through December 31, 2020) as follows: ≥1 claims of ALL-indicated first-line (1L) therapies, ≥1 diagnosis of ALL before the index date (1L initiation date), 6-month continuous enrollment before the index date, second-line (2L) therapy initiation, ≥18 years old at 2L, no clinical trial enrollment, no diagnosis of other forms of non-Hodgkin's lymphoma, and no claim for daratumumab or nelarabine during the study period. Outcome measures included claim-based time to next treatment (TTNT), all-cause and adverse event (AE)-related HRU, and all-cause and AE-related costs. FINDINGS: The R/R B-ALL cohort (N = 203) was 60% male, median age of 41 years, and median Charlson Comorbidity Index score of 3.0. Mean (SD) follow-up was 17.8 (11.8) months. Of those who received 2L, 55.7% (113/203) required 3L, and 15% (30/203) initiated 4L+. Patients relapsed quickly, with a median TTNT of 170 days, 169 days, and 205 days for 2L, 3L, and 4L+, respectively. Hospitalization rates were high across each LoT (2L, 88%; 3L, 73%; 4L+, 73%), and the mean (SD) inpatient length of stay increased by LoT as follows: 8.6 (6.8) days for 2L, 10.6 (13.3) for 3L, and 11.6 (13.6) for 4L+. Mean (SD) overall costs were substantial within each LoT at $513,279 ($599,209), $340,419 ($333,555), and $390,327 ($332,068) for 2L, 3L, and 4L+, respectively. The mean (SD) overall/per-patient-per-month AE-related costs were $358,676 ($497,998) for 2L, $202,621 ($272,788) for 3L, and $210,539 ($267,814) for 4L+. Among those receiving blinatumomab or inotuzumab within each LoT, the mean (SD) total costs were $566,373 ($621,179), $498,070 ($376,260), and $512,908 ($159,525) for 2L, 3L, and 4L+, respectively. IMPLICATIONS: These findings suggest that adult patients with R/R B-ALL relapse frequently with standard of care and incur a substantial HRU and cost burden with each LoT. Those treated with blinatumomab or inotuzumab incurred higher total costs within each LoT compared with the overall R/R B-ALL cohort. Alternative therapies with longer duration of remission are urgently needed, and HRU should be considered for future studies examining the optimal sequencing of therapy.

Neuronal IGF-1 overexpression restores hippocampal newborn cell survival and recent CFC memory consolidation in Cav1.3 knock-out mice.

Insulin-like growth factor-1 (IGF-1) exogenously supplied in the brain was shown to enhance the survival of hippocampal dentate gyrus (DG) newborn cells and some cognitive functions of mice. This study aims to test whether IGF-1 requires Cav1.3 activity critically while enhancing newborn cell survival and cognitive functions. We used Cav1.3 KO mice, where both DG newborn cell survival and the recent (1 day) single-trial contextual fear conditioning (CFC) memory consolidation were impaired. To supply IGF-1, we overexpressed (OX) IGF-1 in DG mature neurons by injecting an adeno-associated virus (AAV-IGF-1-mCherry) into the hippocampal areas of Cav1.3 KO mice. Our results, first, confirmed the enhanced expression of IGF-1 in the DG granule cell layer by immunohistochemistry. Next, we found this IGF-1 OX resulted in fully restoring both the survival rate of DCX (+) newborn cells and the recent single-trial CFC memory formation in Cav1.3 KO mice. Our results show that IGF-1 can enhance the survival of DG immature newborn cells and the recent CFC memory formation in a Cav1.3 channel-independent manner in vivo, suggesting activation of complementary pathways including the Cav1.2 channel. The result will help the application of adult newborn cell-based therapy improve the cognitive functions of neurological disorders.

Health resource utilization and costs of care for adult patients with relapsed or refractory mantle cell lymphoma in the United States: a retrospective claims analysis.

OBJECTIVES: We assessed real-world healthcare resource utilization (HRU) and costs among US patients with relapsed or refractory mantle cell lymphoma (R/R MCL) by line of therapy (LoT). METHODS: We selected patients from MarketScan® (1/1/2016-12/31/2020): ≥1 claims of MCL-indicated first line (1L) therapies, ≥1 diagnoses of MCL pre-index date (1L initiation date), ≥6-month continuous enrollment pre-index date, second line (2L) therapy initiation, ≥18 years old at 2L, and no clinical trial enrollment. Outcomes included time to next treatment (TTNT), all-cause HRU, and costs. RESULTS: The cohort (N = 142) was 77.5% male, aged 62 years (median). Sixty-six percent and 23% advanced to 3L and 4L+, respectively. Mean (median) TTNT was 9.7 (5.9), 9.3 (5.0), and 6.3 (4.2) months for 2L, 3L, and 4L+, respectively. Mean (median) per patient per month (PPPM) costs were $29,999 ($21,313), $29,352 ($20,033), and $30,633 ($23,662) for 2L, 3L, and 4L+, respectively. Among those who received Bruton tyrosine kinase inhibitors, mean (median) PPPM costs were $24,702 ($17,203), $31,801 ($20,363), and $36,710 ($25,899) for 2L, 3L, and 4L+, respectively. CONCLUSIONS: During the period ending in 2020, patients relapsed frequently, incurring high HRU and costs across LoTs. More effective treatments with long-lasting remissions in R/R MCL may reduce healthcare burden.

Mantle cell lymphoma is a rare blood cancer of white blood cells. This type of cancer can be hard to treat, even with new treatments. In about 15% to 20% of people, the cancer will not get better or will come back within 2 years of starting treatment. When this happens, there are few good options for treatments that work. Using medical claims data, we looked at healthcare use and costs among US patients with mantle cell lymphoma that came back after treatment or did not respond to treatment. We found 142 patients who met the study criteria. Of these, 77.5% were men with a median age of 62 years. Sixty-six percent got a third of the treatment and 23% got a fourth treatment or more. The time until the next treatment was about 9­10 months for patients who got a second and third treatments.. It was about 6 months for people who got a fourth or more treatment. The average monthly cost of treatment was about $30,000 for those receiving a second or fourth or more treatment. It was slightly less for those who got a third treatment. For those who got Bruton's tyrosine kinase inhibitors, the monthly costs went up with each treatment they needed. Overall, we found that during the study period, patients with mantle cell lymphoma worsened quickly, received multiple treatments, and had high costs of care. Better treatments that work longer are needed.

Crotamine-based recombinant immunotoxin targeting HER2 for enhanced cancer cell specificity and cytotoxicity.

Crotamine, one of the major toxins present in the venom of the South American rattlesnake Crotalus durissus terrificus, exhibits potent cytotoxic properties and has been suggested for cancer therapy applications. However, its selectivity for cancer cells needs to be improved. This study designed and produced a novel recombinant immunotoxin, HER2(scFv)-CRT, composed of crotamine and single-chain Fv (scFv) derived from trastuzumab targeting human epidermal growth factor receptor 2 (HER2). The recombinant immunotoxin was expressed in Escherichia coli and purified using various chromatographic techniques. The cytotoxicity of HER2(scFv)-CRT was assessed in three breast cancer cell lines, demonstrating enhanced specificity and toxicity in HER2-expressing cells. These findings suggest that the crotamine-based recombinant immunotoxin has the potential to expand the repertoire of recombinant immunotoxin applications in cancer therapy.

Gut microbiota indole-3-propionic acid mediates neuroprotective effect of probiotic consumption in healthy elderly: A randomized, double-blind, placebo-controlled, multicenter trial and in vitro study.

BACKGROUND & AIMS: The beneficial effects of probiotic consumption on age-related decline in cerebral function have been previously reported in the literature; however, the mechanistic link between gut and brain interactions has not yet been fully elucidated. Therefore, this study aimed to identify the role of gut microbiota-derived metabolites in gut-brain interactions via blood metabolomic profiling analysis in clinical trials and in vitro mechanistic studies. METHODS: A randomized, double-blind, placebo-controlled, multicenter clinical trial was conducted in 63 healthy elderly individuals (≥65 years of age). Participants were administered either placebo (placebo group, N = 31) or probiotic capsules (Bifidobacterium bifidum BGN4 and Bifidobacterium longum BORI; probiotics group, N = 32) for 12 weeks. Global and targeted metabolomic profiling analyses of their blood samples were then performed using 1H nuclear magnetic resonance and liquid chromatography-mass spectrometry methods, both at baseline and at the end of the trial. Gut microbial analysis was conducted using the 16S ribosomal ribonucleic acid gene sequencing method. Subsequently, microglial BV2 cells were treated in vitro with indole-3-propionic acid (IPA) following lipopolysaccharide stimulation, and neuronal SH-SY5Y cells were treated with conditioned media from the BV2 cells. Finally, the levels of pro-inflammatory cytokines in BV2 cells and neurotrophins in SH-SY5Y cells were quantified using a real-time polymerase chain reaction or enzyme-linked immunosorbent assay. RESULTS: The metabolomic profiling analyses showed that probiotic consumption significantly altered the levels of metabolites involved in tryptophan metabolism (P < 0.01). Among these metabolites, gut microbiota-produced IPA had a 1.91-fold increase in the probiotics group (P < 0.05) and showed a significant relation to gut bacterial profiles (P < 0.01). Elevated IPA levels were also positively associated with the level of serum brain-derived neurotropic factor (BDNF) in the probiotics group (r = 0.28, P < 0.05), showing an inverse trend compared to the placebo group. In addition, in vitro treatment with IPA (5 µM) significantly reduced the concentration of proinflammatory TNF-α in activated microglia (P < 0.05), and neuronal cells cultured with conditioned media from IPA-treated microglia showed a significant increase in BDNF and nerve growth factor production (P < 0.05). CONCLUSIONS: These results show that gut microbiota-produced IPA plays a role in protecting the microglia from inflammation, thus promoting neuronal function. Therefore, this suggests that IPA is a significant mediator linking the interaction between the gut and the brain in the elderly with probiotic supplementation.

Biallelic variants in DNA2 cause poikiloderma with congenital cataracts and severe growth failure reminiscent of Rothmund-Thomson syndrome.

Rothmund-Thomson syndrome (RTS) is a rare, heterogeneous autosomal recessive genodermatosis, with poikiloderma as its hallmark. It is classified into two types: type I, with biallelic variants in ANAPC1 and juvenile cataracts, and type II, with biallelic variants in RECQL4, increased cancer risk and no cataracts. We report on six Brazilian probands and two siblings of Swiss/Portuguese ancestry presenting with severe short stature, widespread poikiloderma and congenital ocular anomalies. Genomic and functional analysis revealed compound heterozygosis for a deep intronic splicing variant in trans with loss of function variants in DNA2, with reduction of the protein levels and impaired DNA double-strand break repair. The intronic variant is shared by all patients, as well as the Portuguese father of the European siblings, indicating a probable founder effect. Biallelic variants in DNA2 were previously associated with microcephalic osteodysplastic primordial dwarfism. Although the individuals reported here present a similar growth pattern, the presence of poikiloderma and ocular anomalies is unique. Thus, we have broadened the phenotypical spectrum of DNA2 mutations, incorporating clinical characteristics of RTS. Although a clear genotype-phenotype correlation cannot be definitively established at this moment, we speculate that the residual activity of the splicing variant allele could be responsible for the distinct manifestations of DNA2-related syndromes.

An implantable ionic therapeutic platform for photodynamic therapy with wireless capacitive power transfer.

In this work, we describe the development of an implantable ionic device that can deliver a spatially targeted light source to tumor tissues in a controllable manner. The motivation behind our approach is to overcome certain limitations of conventional approaches where light is delivered from the outside of the body and only achieves low penetration depths. Also, to avoid the issues that come from the periodic need to replace the device's battery, we utilize a wireless power transfer system synchronized with light operation in an implantable structure. In our testing of this implanted, soft ionic, gel-based device that receives power wirelessly, we were able to clearly observe its capability to effectively deliver light in a harmonious and stable configuration to adjacent tissues. This approach reduces the mechanical inconsistencies seen in conventional systems that are induced by mismatches between the mechanical strength of conventional metallic components and that of biological tissues. The light delivering performance of our device was studied in depth under the various conditions set by adjusting the area of the gel receivers, the ion concentration and the ion types used in the gel components. The enhanced antitumor effects of our device were observed through in vitro cell tests, in comparison with treatments using the conventional approach of using direct light from outside the body. Full encapsulation using biocompatible elastomers enables our device to provide good functional stability, while implantation for about 3 weeks in the in vivo model showed the effective targeted photodynamic treatments made possible by our approach. Our advanced approach of designing the implantable platform based on ionic gel components allows us to iteratively irradiate a target with light whenever required, making the technology particularly suited to long-term treatment of residual tumors while facilitating further practical and clinical development.

Imagawa-Matsumoto syndrome: SUZ12-related overgrowth disorder.

The SUZ12 gene encodes a subunit of polycomb repressive complex 2 (PRC2) that is essential for development by silencing the expression of multiple genes. Germline heterozygous variants in SUZ12 have been found in Imagawa-Matsumoto syndrome (IMMAS) characterized by overgrowth and multiple dysmorphic features. Similarly, both EZH2 and EED also encode a subunit of PRC2 each and their pathogenic variants cause Weaver syndrome and Cohen-Gibson syndrome, respectively. Clinical manifestations of these syndromes significantly overlap, although their different prevalence rates have recently been noted: generalized overgrowth, intellectual disability, scoliosis, and excessive loose skin appear to be less prevalent in IMMAS than in the other two syndromes. We could not determine any apparent genotype-phenotype correlation in IMMAS. The phenotype of neurofibromatosis type 1 arising from NF1 deletion was also shown to be modified by the deletion of SUZ12, 560 kb away. This review deepens our understanding of the clinical and genetic characteristics of IMMAS together with other overgrowth syndromes related to PRC2. We also report on a novel IMMAS patient carrying a splicing variant (c.1023+1G>C) in SUZ12. This patient had a milder phenotype than other previously reported IMMAS cases, with no macrocephaly or overgrowth phenotypes, highlighting the clinical variation in IMMAS.

Toward a new taxonomy of obstetrical disease: improved performance of maternal blood biomarkers for the great obstetrical syndromes when classified according to placental pathology.

BACKGROUND: The major challenge for obstetrics is the prediction and prevention of the great obstetrical syndromes. We propose that defining obstetrical diseases by the combination of clinical presentation and disease mechanisms as inferred by placental pathology will aid in the discovery of biomarkers and add specificity to those already known. OBJECTIVE: To describe the longitudinal profile of placental growth factor (PlGF), soluble fms-like tyrosine kinase-1 (sFlt-1), and the PlGF/sFlt-1 ratio throughout gestation, and to determine whether the association between abnormal biomarker profiles and obstetrical syndromes is strengthened by information derived from placental examination, eg, the presence or absence of placental lesions of maternal vascular malperfusion. STUDY DESIGN: This retrospective case cohort study was based on a parent cohort of 4006 pregnant women enrolled prospectively. The case cohort of 1499 pregnant women included 1000 randomly selected patients from the parent cohort and all additional patients with obstetrical syndromes from the parent cohort. Pregnant women were classified into six groups: 1) term delivery without pregnancy complications (n=540; control); 2) preterm labor and delivery (n=203); 3) preterm premature rupture of the membranes (n=112); 4) preeclampsia (n=230); 5) small-for-gestational-age neonate (n=334); and 6) other pregnancy complications (n=182). Maternal plasma concentrations of PlGF and sFlt-1 were determined by enzyme-linked immunosorbent assays in 7560 longitudinal samples. Placental pathologists, masked to clinical outcomes, diagnosed the presence or absence of placental lesions of maternal vascular malperfusion. Comparisons between mean biomarker concentrations in cases and controls were performed by utilizing longitudinal generalized additive models. Comparisons were made between controls and each obstetrical syndrome with and without subclassifying cases according to the presence or absence of placental lesions of maternal vascular malperfusion. RESULTS: 1) When obstetrical syndromes are classified based on the presence or absence of placental lesions of maternal vascular malperfusion, significant differences in the mean plasma concentrations of PlGF, sFlt-1, and the PlGF/sFlt-1 ratio between cases and controls emerge earlier in gestation; 2) the strength of association between an abnormal PlGF/sFlt-1 ratio and the occurrence of obstetrical syndromes increases when placental lesions of maternal vascular malperfusion are present (adjusted odds ratio [aOR], 13.6 vs 6.7 for preeclampsia; aOR, 8.1 vs 4.4 for small-for-gestational-age neonates; aOR, 5.5 vs 2.1 for preterm premature rupture of the membranes; and aOR, 3.3 vs 2.1 for preterm labor (all P<0.05); and 3) the PlGF/sFlt-1 ratio at 28 to 32 weeks of gestation is abnormal in patients who subsequently delivered due to preterm labor with intact membranes and in those with preterm premature rupture of the membranes if both groups have placental lesions of maternal vascular malperfusion. Such association is not significant in patients with these obstetrical syndromes who do not have placental lesions. CONCLUSION: Classification of obstetrical syndromes according to the presence or absence of placental lesions of maternal vascular malperfusion allows biomarkers to be informative earlier in gestation and enhances the strength of association between biomarkers and clinical outcomes. We propose that a new taxonomy of obstetrical disorders informed by placental pathology will facilitate the discovery and implementation of biomarkers as well as the prediction and prevention of such disorders.

Achondroplasia in Latin America: practical recommendations for the multidisciplinary care of pediatric patients.

BACKGROUND: Achondroplasia is the most common bone dysplasia associated with disproportionate short stature, and other comorbidities, such as foramen magnum stenosis, thoracolumbar kyphosis, lumbar hyperlordosis, genu varum and spinal compression. Additionally, patients affected with this condition have higher frequency of sleep disorders, ear infections, hearing loss and slowed development milestones. Considering these clinical features, we aimed to summarize the regional experts' recommendations for the multidisciplinary management of patients with achondroplasia in Latin America, a vast geographic territory with multicultural characteristics and with socio-economical differences of developing countries. METHODS: Latin American experts (from Argentina, Brazil, Chile and Colombia) particiáted of an Advisory Board meeting (October 2019), and had a structured discussion how patients with achondroplasia are followed in their healthcare centers and punctuated gaps and opportunities for regional improvement in the management of achondroplasia. RESULTS: Practical recommendations have been established for genetic counselling, prenatal diagnosis and planning of delivery in patients with achondroplasia. An outline of strategies was added as follow-up guidelines to specialists according to patient developmental phases, amongst them neurologic, orthopedic, otorhinolaryngologic, nutritional and anthropometric aspects, and related to development milestones. Additionally, the role of physical therapy, physical activity, phonoaudiology and other care related to the quality of life of patients and their families were discussed. Preoperative recommendations to patients with achondroplasia were also included. CONCLUSIONS: This study summarized the main expert recommendations for the health care professionals management of achondroplasia in Latin America, reinforcing that achondroplasia-associated comorbidities are not limited to orthopedic concerns.

Portulaca oleracea L. Extract Regulates Hepatic Cholesterol Metabolism via the AMPK/MicroRNA-33/34a Pathway in Rats Fed a High-Cholesterol Diet.

This study examined the effect of extruded Portulaca oleracea L. extract (PE) in rats fed a high-cholesterol diet through the AMP-activated protein kinase (AMPK) and microRNA (miR)-33/34a pathway. Sprague-Dawley rats were randomized into three groups and fed either a standard diet (SD), a high-cholesterol diet containing 1% cholesterol and 0.5% cholic acid (HC), or an HC diet containing 0.8% PE for 4 weeks. PE supplementation improved serum, liver, and fecal lipid profiles. PE upregulated the expression of genes involved in cholesterol efflux and bile acids' synthesis such as liver X receptor alpha (LXRα), ATP-binding cassette subfamily G5/G8 (ABCG5/8), and cholesterol 7 alpha-hydroxylase (CYP7A1), and downregulated farnesoid X receptor (FXR) in the liver. In addition, hepatic gene expression levels of apolipoprotein A-l (apoA-1), paraoxonase 1 (PON1), ATP-binding cassette subfamily A1/G1 (ABCA1/G1), lecithin-cholesterol acyltransferase (LCAT), and scavenger receptor class B type 1 (SR-B1), which are related to serum high-density lipoprotein cholesterol metabolism, were upregulated by PE. Furthermore, hepatic AMPK activity in the PE group was higher than in the HC group, and miR-33/34a expression levels were suppressed. These results suggest that PE improves the cholesterol metabolism by modulating AMPK activation and miR-33/34a expression in the liver.