Multi-strain probiotic improves subjective sleep quality with no impact on body composition, hemodynamics, and physical activity.

The objective of the study was to examine the impact of a multi-strain probiotic (MSP) on sleep, physical activity, and body composition changes. We used a randomised, double-blind, placebo-controlled approach with 70 healthy men and women (31.0 ± 9.5 years, 173.0 ± 10.4 cm, 73.9 ± 13.8 kg, 24.6 ± 3.5 kg/m2) supplemented daily with MSP (4 × 109 live cells Limosilactobacillus fermentum LF16, Lacticaseibacillus rhamnosus LR06, Lactiplantibacillus plantarum LP01, and Bifidobacterium longum 04; Probiotical S.p.A., Novara, Italy) or placebo (PLA). In response to supplementation (after 0, 2, 4, and 6 weeks of supplementation) and 3 weeks after stopping supplementation, participants had subjective (Pittsburgh Sleep Quality Index, PSQI) and objective sleep indicators, body composition, daily physical activity and resting hemodynamics assessed. Subjective sleep quality indicators using the PSQI (sleep latency, sleep disturbance, and global PSQI score) improved ( P < 0.05) at various time points with MSP supplementation. Systolic blood pressure in PLA increased ( P < 0.05) after 6 weeks of supplementation with no change in MSP. No changes ( P > 0.05) in sleep (hours asleep, minutes awake, number of times awake) or physical activity (step count, minutes of sedentary activity, total active minutes) metrics assessed by the wearable device were observed. Additionally, no changes in resting heart rate, diastolic blood pressure, and body composition were discerned. In conclusion, MSP supplementation improved the subjective ability to fall asleep faster and disturbances experienced during sleep, which resulted in improved overall sleep quality as assessed by the PSQI. No differences in other sleep indicators, physical activity, hemodynamics, and body composition were observed during or following MSP supplementation. Registered at clinicaltrials.gov: NCT05343533.

Enhanced Nanobubble Formation: Gold Nanoparticle Conjugation to Qß Virus-like Particles.

Plasmonic gold nanostructures are a prevalent tool in modern hypersensitive analytical techniques such as photoablation, bioimaging, and biosensing. Recent studies have shown that gold nanostructures generate transient nanobubbles through localized heating and have been found in various biomedical applications. However, the current method of plasmonic nanoparticle cavitation events has several disadvantages, specifically including small metal nanostructures (≤10 nm) which lack size control, tuneability, and tissue localization by use of ultrashort pulses (ns, ps) and high-energy lasers which can result in tissue and cellular damage. This research investigates a method to immobilize sub-10 nm AuNPs (3.5 and 5 nm) onto a chemically modified thiol-rich surface of Qß virus-like particles. These findings demonstrate that the multivalent display of sub-10 nm gold nanoparticles (AuNPs) caused a profound and disproportionate increase in photocavitation by upward of 5-7-fold and significantly lowered the laser fluency by 4-fold when compared to individual sub-10 nm AuNPs. Furthermore, computational modeling showed that the cooling time of QßAuNP scaffolds is significantly extended than that of individual AuNPs, proving greater control of laser fluency and nanobubble generation as seen in the experimental data. Ultimately, these findings showed how QßAuNP composites are more effective at nanobubble generation than current methods of plasmonic nanoparticle cavitation.

Response to Neoadjuvant Targeted Therapy in Operable Head and Neck Cancer Confers Survival Benefit.

PURPOSE: Neoadjuvant targeted therapy provides a brief, preoperative window of opportunity that can be exploited to individualize cancer care based on treatment response. We investigated whether response to neoadjuvant therapy during the preoperative window confers survival benefit in patients with operable head and neck squamous cell carcinoma (HNSCC). PATIENTS AND METHODS: A pooled analysis of treatment-naïve patients with operable HNSCC enrolled in one of three clinical trials from 2009 to 2020 (NCT00779389, NCT01218048, NCT02473731). Neoadjuvant regimens consisted of EGFR inhibitors (n = 83) or anti-ErbB3 antibody therapy (n = 9) within 28 days of surgery. Clinical to pathologic stage migration was compared with disease-free survival (DFS) and overall survival (OS) while adjusting for confounding factors using multivariable Cox regression. Circulating tumor markers validated in other solid tumor models were analyzed. RESULTS: 92 of 118 patients were analyzed; all patients underwent surgery following neoadjuvant therapy. Clinical to pathologic downstaging was more frequent in patients undergoing neoadjuvant targeted therapy compared with control cohort (P = 0.048). Patients with pathologic downstage migration had the highest OS [89.5%; 95% confidence interval (CI), 75.7-100] compared with those with no stage change (58%; 95% CI, 46.2-69.8) or upstage (40%; 95% CI, 9.6-70.4; P = 0.003). Downstage migration remained a positive prognostic factor for OS (HR, 0.22; 95% CI, 0.05-0.90) while adjusting for measured confounders. Downstage migration correlated with decreased circulating tumor markers, SOX17 and TAC1 (P = 0.0078). CONCLUSIONS: Brief neoadjuvant therapy achieved pathologic downstaging in a subset of patients and was associated with significantly better DFS and OS as well as decreased circulating methylated SOX17 and TAC1.

Pilot study of fractional microneedling radiofrequency for hidradenitis suppurativa assessed by clinical response and histology.

BACKGROUND: Hidradenitis suppurativa (HS) is a devastating chronic inflammatory skin disease with frequent recurrences. Various systemic treatments and procedures have been used but the efficacy of fractional microneedling radiofrequency (FMR) has not been reported. AIM: To evaluate the clinical and histological efficacy of FMR in the treatment of HS lesions. METHODS: An 8-week, prospective, split-body, unblinded study was conducted, which enrolled 10 adult patients with mild to moderate HS to receive 3 sessions of FMR treatment biweekly. HS severity was assessed using the number and type of lesions, HS Physician Global Assessment (HS-PGA) and the modified Sartorius score (mSS). Skin biopsies were performed on participants to assess change in inflammation before and after FMR. RESULTS: Severity of HS was significantly reduced on the FMR-treated side of the body, but not on the control side. Inflammatory HS lesions were significantly reduced after 4 weeks, while HS-PGA and mSS were significantly decreased after 6 weeks. Immunohistochemistry staining showed decreased expression of inflammatory markers including neutrophil elastases, interleukin (IL)-8 and IL-17, tumour necrosis factor-α, transforming growth factor-ß1 and matrix metalloproteinases. CONCLUSION: FMR may be a viable treatment option for mild to moderate HS.

Measurement of hydraulic pressure on the sinus membrane for safer control during transcrestal sinus lifting.

The aim of this study was to determine the hydraulic pressures necessary to separate and lift the sinus membrane from the sinus floor in order to ensure a more controlled and safer hydraulic transcrestal sinus lifting surgery and prevent sinus membrane perforation. A flow-regulating hydrodynamic device with a pressure sensor was used in nine patients. The hydraulic pressure was found to increase steadily up to a mean peak of 25.0±13.0kPa, which is comparable to the medium suction power of ordinary vacuum cleaners. Subsequently, there was a short plateau followed by a sharp decrease in the hydraulic pressure.

Standardising clinical outcomes measures for adult clinical trials in Fabry disease: A global Delphi consensus.

BACKGROUND: Recent years have witnessed a considerable increase in clinical trials of new investigational agents for Fabry disease (FD). Several trials investigating different agents are currently in progress; however, lack of standardisation results in challenges to interpretation and comparison. To facilitate the standardisation of investigational programs, we have developed a common framework for future clinical trials in FD. METHODS AND FINDINGS: A broad consensus regarding clinical outcomes and ways to measure them was obtained via the Delphi methodology. 35 FD clinical experts from 4 continents, representing 3389 FD patients, participated in 3 rounds of Delphi procedure. The aim was to reach a consensus regarding clinical trial design, best treatment comparator, clinical outcomes, measurement of those clinical outcomes and inclusion and exclusion criteria. Consensus results of this initiative included: the selection of the adaptative clinical trial as the ideal study design and agalsidase beta as ideal comparator treatment due to its longstanding use in FD. Renal and cardiac outcomes, such as glomerular filtration rate, proteinuria and left ventricular mass index, were prioritised, whereas neurological outcomes including cerebrovascular and white matter lesions were dismissed as a primary or secondary outcome measure. Besides, there was a consensus regarding the importance of patient-related outcomes such as general quality of life, pain, and gastrointestinal symptoms. Also, unity about lysoGb3 and Gb3 tissue deposits as useful surrogate markers of the disease was obtained. The group recognised that cardiac T1 mapping still has potential but requires further development before its widespread introduction in clinical trials. Finally, patients with end-stage renal disease or renal transplant should be excluded unless a particular group for them is created inside the clinical trial. CONCLUSION: This consensus will help to shape the future of clinical trials in FD. We note that the FDA has, coincidentally, recently published draft guidelines on clinical trials in FD and welcome this contribution.

Morphology-Invariant Metallic Nanoparticles with Tunable Plasmonic Properties.

Current methods for tuning the plasmonic properties of metallic nanoparticles typically rely on alternating the morphology (i.e., size and/or shape) of nanoparticles. The variation of morphology of plasmonic nanoparticles oftentimes impairs their performance in certain applications. In this study, we report an effective approach based on the control of internal structure to engineer morphology-invariant nanoparticles with tunable plasmonic properties. Specifically, these nanoparticles were prepared through selective growth of Ag on the inner surfaces of preformed Ag-Au alloyed nanocages as the seeds to form Ag@(Ag-Au) shell@shell nanocages. Plasmonic properties of the Ag@(Ag-Au) nanocages can be conveniently and effectively tuned by varying the amount of Ag deposited on the inner surfaces, during which the overall morphology of the nanocages remains unchanged. To demonstrate the potential applications of the Ag@(Ag-Au) nanocages, they were applied to colorimetric sensing of human carcinoembryonic antigen (CEA) that achieved low detection limits. This work provides a meaningful concept to design and craft plasmonic nanoparticles.

Nickel-Platinum Nanoparticles as Peroxidase Mimics with a Record High Catalytic Efficiency.

While nanoscale mimics of peroxidase have been extensively developed over the past decade or so, their catalytic efficiency as a key parameter has not been substantially improved in recent years. Herein, we report a class of highly efficient peroxidase mimic-nickel-platinum nanoparticles (Ni-Pt NPs) that consist of nickel-rich cores and platinum-rich shells. The Ni-Pt NPs exhibit a record high catalytic efficiency with a catalytic constant (Kcat) as high as 4.5 × 107 s-1, which is ∼46- and 104-fold greater than the Kcat values of conventional Pt nanoparticles and natural peroxidases, respectively. Density functional theory calculations reveal that the unique surface structure of Ni-Pt NPs weakens the adsorption of key intermediates during catalysis, which boosts the catalytic efficiency. The Ni-Pt NPs were applied to an immunoassay of a carcinoembryonic antigen that achieved an ultralow detection limit of 1.1 pg/mL, hundreds of times lower than that of the conventional enzyme-based assay.

Combination treatment of copanlisib and gemcitabine in relapsed/refractory PTCL (COSMOS): an open-label phase I/II trial.

BACKGROUND: Current treatment options for peripheral T-cell lymphomas (PTCLs) in the relapsed/refractory setting are limited and demonstrate modest response rates with rare achievement of complete response (CR). PATIENTS AND METHODS: This phase I/II study (NCT03052933) investigated the safety and efficacy of copanlisib, a phosphatidylinositol 3-kinase-α/-δ inhibitor, in combination with gemcitabine in 28 patients with relapsed/refractory PTCL. Patients received escalating doses of intravenous copanlisib on days 1, 8, and 15, administered concomitantly with fixed-dose gemcitabine (1000 mg/m2 on days 1 and 8) in 28-day cycles. RESULTS: Dose-limiting toxicity was not observed in the dose-escalation phase and 60 mg copanlisib was selected for phase II evaluation. Twenty-five patients were enrolled in phase II of the study. Frequent grade ≥3 adverse events (AEs) included transient hyperglycemia (57%), neutropenia (45%), thrombocytopenia, (37%), and transient hypertension (19%). However, AEs were manageable, and none were fatal. The overall response rate was 72% with a CR rate of 32%. Median duration of response was 8.2 months, progression-free survival was 6.9 months, and median overall survival was not reached. Combination treatment produced a greater CR rate in patients with angioimmunoblastic T-cell lymphoma than those with PTCL-not otherwise specified (55.6% versus 15.4%, respectively, P = 0.074) and progression-free survival was significantly longer (13.0 versus 5.1 months, respectively, P = 0.024). In an exploratory gene mutation analysis of 24 tumor samples, TSC2 mutation was present in 25% of patients and occurred exclusively in responders. CONCLUSION: The combination of copanlisib and gemcitabine is a safe and effective treatment option in relapsed/refractory PTCLs and represents an important new option for therapy in this rare group of patients.

Preoperative evaluation of mammographic microcalcifications after neoadjuvant chemotherapy for breast cancer.

AIM: To assess the predictive value of preoperative residual mammographic microcalcifications for residual tumours after neoadjuvant chemotherapy (NAC) for breast cancer. MATERIALS AND METHODS: This single-centre retrospective study included breast cancer patients who underwent NAC and demonstrated suspicious microcalcifications within or near the tumour bed on mammography from June 2015 to August 2018. The residual microcalcifications and remnant lesion on magnetic resonance imaging (MRI) were correlated with histopathological findings of residual tumours and immunohistochemical markers. RESULTS: A total of 96 patients were included. Ten patients achieved pathological complete response (pCR) and previous suspicious microcalcifications were associated with benign pathology in 10.4% (10/96) of the patients. In the remaining 86 patients who did not achieve pCR, 61.5% (59/96) of the residual microcalcifications were associated with invasive or in situ carcinoma and 28.1% (27/96) with benign pathology. Hormone receptor-positive (HR+) patients had the highest proportion of residual malignant microcalcifications compared to HR- patients (48.9% versus 13.5%, respectively; p=0.019). MRI correlated better than residual microcalcifications on mammography in predicting residual tumour extent in all subtypes (ICC=0.709 versus 0.365). MRI also showed higher correlation with residual tumour size for the HR-/HER2+ and HR-/HER2- subtype (ICC=0.925 and 0.876, respectively). CONCLUSION: The extent of microcalcifications on mammography after NAC did not correlate with the extent of residual cancer in 38.5% of women. Regardless of the extent of microcalcifications, residual tumour extent on MRI after NAC and molecular subtype could be an accurate tool in evaluating residual cancer after NAC.

Making MRI available for patients with cardiac implantable electronic devices: growing need and barriers to change.

More than half of us will need a magnetic resonance imaging (MRI) scan in our lifetimes. MRI is an unmatched diagnostic test for an expanding range of indications including neurological and musculoskeletal disorders, cancer diagnosis, and treatment planning. Unfortunately, patients with cardiac pacemakers or defibrillators have historically been prevented from having MRI because of safety concerns. This results in delayed diagnoses, more invasive investigations, and increased cost. Major developments have addressed this-newer devices are designed to be safe in MRI machines under specific conditions, and older legacy devices can be scanned provided strict protocols are followed. This service however remains difficult to deliver sustainably worldwide: MRI provision remains grossly inadequate because patients are less likely to be referred, and face difficulties accessing services even when referred. Barriers still exist but are no longer technical. These include logistical hurdles (poor cardiology and radiology interaction at physician and technician levels), financial incentives (re-imbursement is either absent or fails to acknowledge the complexity), and education (physicians self-censor MRI requests). This article therefore highlights the recent changes in the clinical, logistical, and regulatory landscape. The aim of the article is to enable and encourage healthcare providers and local champions to build MRI services urgently for cardiac device patients, so that they may benefit from the same access to MRI as everyone else. KEY POINTS: • There is now considerable evidence that MRI can be provided safely to patients with cardiac implantable electronic devices (CIEDs). However, the volume of MRI scans delivered to patients with CIEDs is fifty times lower than that of the estimated need, and patients are approximately fifty times less likely to be referred. • Because scans for this patient group are frequently for cancer diagnosis and treatment planning, MRI services need to develop rapidly, but the barriers are no longer technical. • New services face logistical, educational, and financial hurdles which can be addressed effectively to establish a sustainable service at scale.

Notch1 inactivation promotes invasion and metastasis of nasopharyngeal carcinoma cells partly through Slug activation.

Nasopharyngeal carcinoma (NPC) is a rare form of the head and neck cancer of the epithelial lining of the nasopharynx and exhibits the highest metastatic rate among head and neck cancers. Underlying mechanisms of metastasis remain largely unknown. Here, we explored whether Notch1 affects the invasion and metastasis of NPC cells. In vitro migration and invasion capacities were evaluated after the knockdown of Notch1 expression in NPC cells. To investigate the role of Notch1 in in vivo metastasis, we examined the metastatic ability to the lungs following administration of cancer cells via mouse tail vein. The expression of epithelial-mesenchymal transition (EMT) markers associated with Notch1-mediated metastasis was investigated, and their roles in metastasis and relationship with Notch1 expression were investigated. Suppression of Notch1 expression increased the ability of NPC cells to invade Matrigel in vitro. Knockdown of Notch1 expression in NPC cells resulted in extensive lung metastasis in a mouse model and increased the mRNA expression of Slug in NPC cells. Slug-specific RNA interference resulted in the loss of the metastatic and invasion capacities in Notch1-suppressed NPC cells. These findings show that Notch1 has a significant suppressive role in the regulation of metastasis in NPCs, suggestive of its prudent use in clinical trials.

Is Polypharmacy Associated with Cognitive Frailty in the Elderly? Results from the Korean Frailty and Aging Cohort Study.

OBJECTIVES: Cognitive frailty-the coexistence of physical frailty and cognitive impairment-is a phenotype of frailty in the elderly. The coexistence of physical frailty and cognitive impairment, known as cognitive frailty, is one of the phenotypes of frailty in the elderly. Cognitive frailty predicts adverse health outcome more accurately than does physical frailty. In this study, we aim to determine whether the polypharmacy common among the elderly is linked with cognitive frailty. DESIGN, SETTING, AND PARTICIPANTS: The elderly, aged between 70 and 84 years, who participated in the cross-sectional Korean Frailty and Aging Cohort Study were included in the present study. MEASUREMENTS: Polypharmacy and hyperpolypharmacy were defined as the use of at least five and ten medications, respectively. Physical frailty was assessed by the Korean version of the FRAIL scale, and cognitive status was measured by the Trail Making Test part A, word list recall test, the Korean version of the Frontal Assessment Battery, and the Digit Span Backward test. RESULTS: Among the 2,392 participants, 26.8% and 4.1% took more than five and ten prescribed medications, respectively. Polypharmacy and hyperpolypharmacy participants tend to have more cognitive impairment and physical frailty. Participants with cognitive frailty had the highest polypharmacy rate regardless of medication type. After controlling for the potential confounders including severity of comorbidities, frailty was found to be significantly related to polypharmacy, as defined by prescribed as well as total medications, including non-prescribed medications. However, cognitive impairment only showed a linkage to polypharmacy of prescribed medications, which-according to the results of multivariable analysis- could increase cognitive frailty, with an odds ratio of 2.70. CONCLUSION: Although the elderly tend to depend on various medications, they should seriously consider the risk of polypharmacy for better health outcomes.

Predictive value of plasma neutrophil gelatinase-associated lipocalin in acute charcoal-burning carbon monoxide poisoning.

This study aimed to assess the feasibility of using the plasma neutrophil gelatinase-associated lipocalin (NGAL) level at the time of presentation in the emergency department (ED) to predict acute kidney injury (AKI) and the long-term neurological outcomes of acute charcoal-burning carbon monoxide (CO) poisoning. This retrospective study included 260 patients who suffered acute charcoal-burning CO poisoning. The median plasma NGAL concentration at the time of presentation in the ED after acute charcoal-burning CO poisoning was 78 (54-115) ng/ml. The NGAL level was an independent predictor of AKI development and could be used to stratify the severity of AKI. However, the area under the receiver operating characteristic curve (AUC) of the predictive model for AKI that included both the plasma NGAL level and clinical parameters was comparable to that of the predictive model including only the clinical parameters. The plasma NGAL level at the time of presentation in the ED was an independent factor predicting long-term neurological outcomes in patients who did not develop AKI. In these patients, the plasma NGAL level significantly improved the predictive accuracy of the model when used in combination with clinical parameters. In contrast, the plasma NGAL level was not associated with long-term neurological outcomes in patients who developed AKI. Measurement of the plasma NGAL level at the time ED presentation might improve the prediction of long-term neurological outcomes in patients who do not develop AKI after acute charcoal-burning CO poisoning. However, it might not offer additional benefit for AKI prediction compared to previously used markers.

Atrophic acne scar: a process from altered metabolism of elastic fibres and collagen fibres based on transforming growth factor-ß1 signalling.

BACKGROUND: Atrophic acne scar, a persistent sequela from acne, is undesirably troubling to many patients due to its cosmetic and psychosocial aspects. Although there have been some reports emphasizing the role of early inflammatory responses in atrophic acne scarring, evolving perspectives on the detailed pathogenic processes are promptly needed. OBJECTIVES: Examining the histological, immunological and molecular changes in early acne lesions susceptible to atrophic scarring can provide new insights to understand the pathophysiology of atrophic acne scar. METHODS: We experimentally validated several early fundamental hallmarks accounting for the transition of early acne lesions to atrophic scars by comparing molecular profiles of skin and acne lesions between patients who were prone to scar (APS) or not (ANS). RESULTS: In APS, compared with ANS, devastating degradation of elastic fibres and collagen fibres occurred in the dermis, followed by their incomplete recovery. Abnormally excessive inflammation mediated by innate immunity with T helper 17 and T helper 1 cells was observed. Epidermal proliferation was significantly diminished. Transforming growth factor (TGF)-ß1 was drastically elevated in APS, suggesting that aberrant TGF-ß1 signalling is an underlying modulator of all of these pathological processes. CONCLUSIONS: These results may provide a basis for understanding the pathogenesis of atrophic acne scarring. Reduction of excessive inflammation and TGF-ß1 signalling in early acne lesions is expected to facilitate the protection of normal extracellular matrix metabolism and ultimately the prevention of atrophic scar formation. What's already known about this topic? The dermis of atrophic acne scars shows alteration of extracellular matrix components such as collagen fibres. Inflammation in acne lesions is associated with the development of acne scars. What does this study add? Abnormalities in the metabolism of collagen fibres and elastic fibres were observed in the early developmental stages of acne lesions that were progressing into atrophic scars. Exacerbated inflammation and aberrant epidermal proliferation by increased transforming growth factor (TGF)-ß1 signalling may affect the abnormal extracellular matrix metabolism. What is the translational message? Abnormal changes in elastic fibres and collagen fibres are found in the early developmental process of acne in patients who are prone to atrophic scarring. An early treatment regimen strongly inhibiting inflammation and TGF-ß1 signalling to help the normal recovery of the extracellular matrix components is required to prevent atrophic scarring.

Prevalence and natural course of pseudotumours after small-head metal-on-metal total hip arthroplasty: a minimum 18-year follow-up study of a previous report.

AIMS: The present study investigated the five-year interval changes in pseudotumours and measured serum metal ions at long-term follow-up of a previous report of 28 mm diameter metal-on-metal (MoM) total hip arthroplasty (THA). PATIENTS AND METHODS: A total of 72 patients (mean age 46.6 years (37 to 55); 43 men, 29 women; 91 hips) who underwent cementless primary MoM THA with a 28 mm modular head were included. The mean follow-up duration was 20.3 years (18 to 24). All patients had CT scans at a mean 15.1 years (13 to 19) after the index operation and subsequent follow-up at a mean of 20.2 years (18 to 24). Pseudotumour volume, type of mass, and new-onset pseudotumours were evaluated using CT scanning. Clinical outcomes were assessed by Harris Hip Score (HHS) and the presence of groin pain. Serum metal ion (cobalt (Co) and chromium (Cr)) levels were measured at the latest follow-up. RESULTS: At final follow-up, pseudotumours were observed in 26/91 hips (28.6%). There was an increase in volume of the pseudotumour in four hips (15.4%), no change in volume in 21 hips (80.8%), and a decrease in volume in one hip (3.8%). There were no new-onset pseudotumours. There was no significant difference in HHS between patients with and without pseudotumours. At final follow-up, mean serum Co ion levels and median Co:Cr ratios were significantly greater in patients with pseudotumours, but the serum Cr ion levels were not significantly different. CONCLUSION: At a mean 20 years of follow-up, pseudotumours were observed in 26/91 hips (28.6%) with no new-onset pseudotumours during subsequent follow-up. Most pseudotumours in small-head MoM THA were static in volume and asymptomatic with normal serum metal ion levels. Cite this article: Bone Joint J 2019;101-B:317-324.

Vitamin D for the Immune System in Cystic Fibrosis (DISC): a double-blind, multicenter, randomized, placebo-controlled clinical trial.

BACKGROUND: Patients with cystic fibrosis (CF) have increased risk of vitamin D deficiency owing to fat malabsorption and other factors. Vitamin D deficiency has been associated with increased risk of pulmonary exacerbations of CF. OBJECTIVES: The primary objective of this study was to examine the impact of a single high-dose bolus of vitamin D3 followed by maintenance treatment given to adults with CF during an acute pulmonary exacerbation on future recurrence of pulmonary exacerbations. METHODS: This was a multicenter, double-blind, placebo-controlled, intent-to-treat clinical trial. Subjects with CF were randomly assigned to oral vitamin D3 given as a single dose of 250,000 International Units (IU) or to placebo within 72 h of hospital admission for an acute pulmonary exacerbation, followed by 50,000 IU of vitamin D3 or an identically matched placebo pill taken orally every other week starting at 3 mo after random assignment. The primary outcome was the composite endpoint of the time to next pulmonary exacerbation or death within 1 y. The secondary outcomes included circulating concentrations of the antimicrobial peptide cathelicidin and recovery of lung function as assessed by the percentage of predicted forced expiratory volume in 1 s (FEV1%). RESULTS: A total of 91 subjects were enrolled in the study. There were no differences between the vitamin D3 and placebo groups in time to next pulmonary exacerbation or death at 1 y. In addition, there were no differences in serial recovery of lung function after pulmonary exacerbation by FEV1% or in serial concentrations of plasma cathelicidin. CONCLUSIONS: Vitamin D3 initially given at the time of pulmonary exacerbation of CF did not alter the time to the next pulmonary exacerbation, 12-mo mortality, serial lung function, or serial plasma cathelicidin concentrations. This trial was registered at clinicaltrials.gov as NCT01426256.

Diagnosis and treatment of the cardiovascular consequences of Fabry disease.

Fabry disease (FD) has been a diagnostic challenge since it was first recognized in 1898, with patients traditionally suffering from considerable delay before a diagnosis is made. Cardiac involvement is the current leading cause of death in FD. A combination of improved enzyme assays, availability of genetic profiling, together with more organized clinical services for rare diseases, has led to a rapid growth in the prevalence of FD. The earlier and more frequent diagnosis of asymptomatic individuals before development of the phenotype has focussed attention on early detection of organ involvement and closer monitoring of disease progression. The high cost of enzyme replacement therapy at a time of constraint within many health economies, moreover, has challenged clinicians to target treatment effectively. This article provides an outline of FD for the general physician and summarizes the aetiology and pathology of FD, the cardiovascular consequences thereof, modalities used in diagnosis and then discusses current indications for treatment, including pharmacotherapy and device implantation.

Thickness and Sphericity Control of Hollow Hard Silica Shells through Iron (III) Doping: Low Threshold Ultrasound Contrast Agents.

Silica particles are convenient ultrasound imaging contrast agents because of their long imaging time and ease of modification; however, they require a relatively high insonation power for imaging and have low biodegradability. In this study, 2 µm ultrathin asymmetric hollow silica particles doped with iron (III) (Fe(III)-SiO2) are synthesized to produce biodegradable hard shelled particles with a low acoustic power threshold comparable with commercial soft microbubble contrast agents (Definity) yet with much longer in vivo ultrasound imaging time. Furthermore, high intensity focused ultrasound ablation enhancement with these particles shows a 2.5-fold higher temperature elevation than with Definity at the same applied power. The low power visualization improves utilization of the silica shells as an adjuvant in localized immunotherapy. The data are consistent with asymmetric engineering of hard particle properties that improve functionality of hard versus soft particles.