Safety and Immunogenicity of an Investigational Respiratory Syncytial Virus Vaccine (RSVPreF3) in Mothers and Their Infants: A Phase 2 Randomized Trial.

BACKGROUND: In a phase 1/2 study, a maternal respiratory syncytial virus vaccine candidate (RSVPreF3) demonstrated an acceptable safety profile and efficiently increased RSV-specific humoral immune responses in non-pregnant women. METHODS: In this phase 2 observer-blind, placebo-controlled, randomized clinical trial (NCT04126213), the safety of RSVPreF3 (60 or 120 µg), administered during late second or third trimester, was evaluated in 213 18- to 40-year-old healthy pregnant women through 6 months postdelivery and their offspring through infancy; immunogenicity was evaluated through day 43 postdelivery and day 181 postbirth, respectively. RESULTS: RSVPreF3 was well tolerated. No pregnancy-related or neonatal adverse events of special interest were considered vaccine/placebo related. In the 60 and 120 µg RSVPreF3 groups: (1) neutralizing antibody (nAb) titers in mothers increased 12.7- and 14.9-fold against RSV-A and 10.6- and 13.2-fold against RSV-B, respectively, 1 month postvaccination and remained 8.9-10.0-fold over prevaccination at day 43 postdelivery; (2) nAb titers were consistently higher compared to placebo recipients; (3) placental transfer ratios for anti-RSVPreF3 antibodies at birth were 1.62 and 1.90, respectively, and (4) nAb levels in infants were highest at birth and declined through day 181 postbirth. CONCLUSIONS: RSVPreF3 maternal vaccination had an acceptable safety risk profile and induced robust RSV-specific immune responses with successful antibody transfer to their newborns. CLINICAL TRIALS REGISTRATION: NCT04126213.

WHAT IS THE CONTEXT?: Infants, especially those less than 6 months of age, are at increased risk of lung infection caused by respiratory syncytial virus (RSV). However, this risk could be reduced with maternal vaccination against RSV during pregnancy. A previous clinical trial found that a vaccine candidate (named RSVPreF3) was well tolerated when given to non-pregnant women. WHAT IS NEW?: In pregnant women, RSVPreF3 was also well tolerated. Occurrence of unsolicited adverse events was similar between vaccine and placebo recipients. None of the serious adverse events or events of interest for pregnant women or newborns were considered related to the study intervention. One month after vaccination, mothers who received RSVPreF3 had 11­15 times higher levels of antibodies against RSV than before vaccination. These antibody levels remained similar until 43 days after delivery. In the infants born to mothers vaccinated during pregnancy with RSVPreF3, antibody levels were highest at birth, when levels were higher than in their mothers, and declined through day 181 postbirth. WHAT IS THE IMPACT?: RSVPreF3 had an acceptable safety risk profile in pregnant women and their babies. This vaccine induced potent immune responses against RSV, with maternal antibodies transferred to infants of the vaccinated mothers.

Electrochemically reconfigurable architected materials.

Architected materials can actively respond to external stimuli-such as mechanical forces, hydration and magnetic fields-by changing their geometries and thereby achieve novel functionalities. Such transformations are usually binary and volatile because they toggle between 'on' and 'off' states and require persistent external stimuli. Here we develop three-dimensional silicon-coated tetragonal microlattices that transform into sinusoidal patterns via cooperative beam buckling in response to an electrochemically driven silicon-lithium alloying reaction. In situ microscopy reveals a controllable, non-volatile and reversible structural transformation that forms multiple ordered buckling domains separated by distorted domain boundaries. We investigate the mechanical dynamics of individual buckling beams, cooperative coupling among neighbouring beams, and lithiation-rate-dependent distributions of domain sizes through chemo-mechanical modelling and statistical mechanics analysis. Our results highlight the critical role of defects and energy fluctuations in the dynamic response of architected materials. We further demonstrate that domain boundaries can be programmed to form particular patterns by pre-designing artificial defects, and that a variety of reconfigurational degrees of freedom can be achieved through micro-architecture design. This framework enables the design, fabrication, modelling, behaviour prediction and programming of electrochemically reconfigurable architected materials, and could open the way to beyond-intercalation battery electrodes, tunable phononic crystals and bio-implantable devices.

Corrigendum: Association of CTLA-4 Gene Variants with Response to Therapy and Long-term Survival in Metastatic Melanoma Patients Treated with Ipilimumab: An Italian Melanoma Intergroup Study.

[This corrects the article on p. 386 in vol. 8, PMID: 28446908.].

Association of CTLA-4 Gene Variants with Response to Therapy and Long-term Survival in Metastatic Melanoma Patients Treated with Ipilimumab: An Italian Melanoma Intergroup Study.

Ipilimumab (IPI) blocks CTLA-4 immune checkpoint resulting in T cell activation and enhanced antitumor immunity. IPI improves overall survival (OS) in 22% of patients with metastatic melanoma (MM). We investigated the association of CTLA-4 single nucleotide variants (SNVs) with best overall response (BOR) to IPI and OS in a cohort of 173 MM patients. Patients were genotyped for six CTLA-4 SNVs (-1661A>G, -1577G>A, -658C>T, -319C>T, +49A>G, and CT60G>A). We assessed the association between SNVs and BOR through multinomial logistic regression (MLR) and the prognostic effect of SNVs on OS through Kaplan-Meier method. Both -1577G>A and CT60G>A SNVs were found significantly associated with BOR. In particular, the proportion of responders was higher in G/G genotype while that of stable patients was higher in A/A genotype. The frequency of patients experiencing progression was similar in all genotypes. MLR evidenced a strong downward trend in the probability of responsiveness/progression, in comparison to disease stability, as a function of the allele A "dose" (0, 1, or 2) in both SNVs with reductions of about 70% (G/A vs G/G) and about 95% (A/A vs G/G). Moreover, -1577G/G and CT60G/G genotypes were associated with long-term OS, the surviving patients being at 3 years 29.8 and 30.8%, respectively, as compared to 12.9 and 14.4% of surviving patients carrying -1577G/A and CT60G/A, respectively. MM patients carrying -1577G/G or CT60G/G genotypes may benefit from IPI treatment in terms of BOR and long-term OS. These CTLA-4 SNVs may serve as potential biomarkers predictive of favorable outcome in this subset of patients.

Status of Anaplastic Lymphoma Kinase (ALK) in malignant mesothelioma.

BACKGROUND: Malignant mesothelioma (MM) is a particularly aggressive type of primary tumor, associated with exposure to asbestos, and characterized by high mortality. To date, there is no curative therapy for MM. The receptor anaplastic lymphoma kinase (ALK) was found to be mutated in many cases of cancer and used as a target in biological therapies. We investigated whether this pharmacological treatment could also be applicable to MM. MATERIALS AND METHODS: The state of ALK was analyzed by immunohistochemistry and fluorescent in situ hybridization in 63 MM tissue specimens. RESULTS: None of the 63 MM samples showed overexpression or translocation of ALK. CONCLUSION: Our preliminary data exclude the utility of analysis of the ALK gene in MM and suggest that ALK inhibitor therapy is not applicable to MM.

Ethnic differences in the use of intrapartum epidural analgesia.

BACKGROUND: Obstetric epidural analgesia (EA) is widely applied, but studies have reported that its use may be less extensive among immigrant women or those from minority ethnic groups. Our aim was to examine whether this was the case in our geographic area, which contains an important immigrant population, and if so, to describe the different components of this phenomenon. METHODS: Cross-sectional observational study. SETTING: general acute care hospital, located in Marbella, southern Spain. Analysis of computer records of deliveries performed from 2004 to 2010. Comparison of characteristics of deliveries according to the mothers' geographic origins and of vaginal deliveries noting whether EA was received, using univariate and bivariate statistical analysis and multiple logistic regression (MLR). RESULTS: A total of 21,034 deliveries were recorded, and 37.4% of these corresponded to immigrant women. EA was provided to 61.1% of the Spanish women and to 51.5% of the immigrants, with important variations according to geographic origin: over 52% of women from other European countries and South America received EA, compared with around 45% of the African women and 37% of the Asian women. These differences persisted in the MLR model after adjusting for the mother's age, type of labor initiation, the weight of the neonate and for single or multiple gestation. With the Spanish patients as the reference category, all the other countries of origin presented lower probabilities of EA use. This was particularly apparent for the patients from Asia (OR 0.38; 95%CI 0.31-0.46), Morocco (OR 0.49; 95%CI 0.43-0.54) and other Africa (OR 0.55; 95%CI 0.37-0.81). CONCLUSIONS: We observed a different use of EA in vaginal deliveries, according to the geographic origin of the women. The explanation for this involves a complex set of factors, depending both on the patient and on the healthcare staff.

Complications in immediate breast reconstruction after mastectomy.

OBJECTIVES: Immediate post-mastectomy breast reconstruction (IBR) is a procedure that has proven advantages, but it also entails risks. The aim of this study was to identify risk factors for reconstruction failure. METHODS: A review was made of all the IBR carried out at a general hospital from 2002 to 2009. Retrospective information was obtained about postoperative complications and the characteristics of patients and treatments applied. The minimum follow-up period was 9 months. Cox's regression analysis was performed on the variables related to the reconstruction failure requiring the removal of the prosthesis, with an explanatory model in which all the study variables were introduced and a predictive model that contained only the variables known before the intervention. RESULTS: A total of 115 IRB interventions carried out on 112 women with breast cancer were analyzed. The mean follow-up period was 25.5 months. In sixty cases (52.2 percent), there were no complications; in sixteen cases (13.9 percent) minor complications appeared, and in 39 (33.9 percent) the complications were moderate. In twenty-six cases (22.6 percent), a reconstruction failure occurred. Cox's regression model revealed that the reconstruction failures were related to the patient's age (Hazard Ratio 1.08), to neoadjuvant chemotherapy (HR 6.24) and to postoperative tamoxifen (HR 3.10). The predictive model included the age of the patient (HR 1.05) and the use of neoadjuvant chemotherapy (HR 5.11). CONCLUSIONS: A significant proportion of the patients receiving IBR developed reconstruction failure. Multivariate analysis identified three variables related to this complication, two of which were known before the intervention.

Granulocyte colony-stimulating factor attenuates left ventricular remodelling after acute anterior STEMI: results of the single-blind, randomized, placebo-controlled multicentre STem cEll Mobilization in Acute Myocardial Infarction (STEM-AMI) Trial.

AIMS: The aim of this study was to assess the effect of granulocyte colony-stimulating factor (G-CSF) on left ventricular (LV) function and volumes in patients with anterior ST-elevation myocardial infarction (STEMI) and depressed LV ejection fraction (EF). METHODS AND RESULTS: Sixty consecutive patients with anterior STEMI, undergoing primary angioplasty percutaneous coronary intervention (PCI), with symptom-to-reperfusion time of 2-12 h and EF ≤45% after PCI, were randomized to G-CSF 5 µg/kg b.i.d. subcutaneously (n = 24) or placebo (n = 25) for 5 days, starting <12 h after PCI. The primary endpoint was an increase from baseline to 6 months of 5% in left ventricular ejection fraction (LVEF), as measured by magnetic resonance imaging (MRI). Co-primary endpoint was a ≥20 mL difference in end-diastolic volume (EDV). Infarct size and perfusion were evaluated with late gadolinium enhancement (LGE) and gated (99m)Technetium Sestamibi single-photon emission computed tomography (SPECT). Left ventricular EDV and end-systolic volume (ESV) increased from baseline to 6 months in the placebo group (81.7 ± 24.4 to 94.4 ± 26.0 mL/m(2), P < 0.00005 and 45.2 ± 20.0 to 53.2 ± 23.8 mL/m(2), P = 0.016) but were unchanged in the G-CSF group (82.2 ± 20.3 to 85.7 ± 23.7 mL/m(2), P = 0.40 and 46.0 ± 18.2 to 48.4 ± 20.8 mL/m(2), P = 0.338). There were no significant differences in EF or perfusion between groups. A significant reduction in transmural LGE segments was seen at 6 months in the G-CSF vs. placebo groups (4.38 ± 2.9 to 3.3 ± 2.6, P = 0.04 and 4.2 ± 2.6 to 3.6 ± 2.7, P = 0.301, respectively). Significantly more placebo patients had a change in left ventricular end-diastolic volume abovethe median (9.3 mL/m(2)) when reperfusion time exceeded 180 min (median time-to-reperfusion) (P = 0.0123). Severe adverse events were similar between groups. CONCLUSION: Early G-CSF administration attenuates ventricular remodelling in patients with anterior STEMI and EF ≤45% after successful PCI.

Enhanced prognostic stratification of CAD patients with low ejection fraction by stress-rest Tc99m tetrofosmin gated-spect.

OBJECTIVE: This study was performed to assess whether post-stress and rest functional parameters, as measured by gated-SPECT, provide additional predictive value for long-term prognosis, over clinical and perfusion data in patients (pts.) with low left ventricular ejection fraction (LVEF). METHODS: 647 consecutive pts. underwent stress/rest gated-SPECT, and 497 were followed for a mean period of 516 +/- 264 days. Segmental perfusion and motion/thickening (post-stress and rest) were analysed visually, while EF and LV volumes were calculated using an automatic algorithm (QGS). The post-stress and rest ratio were determined for both end-diastolic (EDV) and end-systolic volume (ESV), while the post-stress LVEF change was calculated subtracting rest-EF from stress-EF. RESULTS: 84/497 pts. showed rest EF < 40%, and 15/84 (18%) experienced a cardiac event (3 cardiac deaths, 1 infarction, 3 hospitalized angina and 9 late revascularizations). The perfusion and functional parameters were not significantly more compromised in pts. with cardiac events compared with pts. without events. Post-stress ESV was the only index significantly higher in pts. with low EF and events compared with pts. with low EF without events (150 +/- 72 ml vs. 123 +/- 53 ml, P = 0.02). Univariate Cox analysis of clinical, perfusion and functional data showed that the best predictor of cardiac events was stress-ESV (score 6.5, P = 0.01), followed by rest-ESV, rest-EDV, stress-EDV and stress-LVEF. Multivariate analysis demonstrated that the addition of stress-ESV to stress-EF, yielded a significant increase in the global chi2 in the prediction of hard events (cardiac death/infarction) (score 4.634, P = 0.03). CONCLUSION: In patients with depressed LVEF, stress-ESV was the only independent predictor of long-term outcome.

[Enhanced prognostic stratification of cad patients with dilated left ventricle by stress and rest functional parameters and 99mTc-tetrofosmin Gated-SPECT].

PURPOSE: To evaluate whether the post-stress and rest functional parameters, measured by Gated-SPECT, have incremental prognostic value compared with perfusion parameters in predicting cardiac events (CE), in a population of CAD patients with dilated LV. MATERIALS AND METHODS: A total of 670 consecutive patients (mean age: 62; range 29-86 yrs.) underwent conventional diagnostic 2-day gated-SPECT with 99mTc-tetrofosmin (55% exercise stress test, 45% dip stress): 605 patients (mean age: 62 yrs., range: 34-86 yrs.) had known or suspected CAD, whereas 65 (mean age: 60 yrs, range: 29-80 yrs) had low pre-test likelihood of CAD (<10%), a normal post-stress perfusion scan and no hypertension. Fifty-three percent of CAD patients had a history of MI. Perfusion was analyzed on ungated images using 20 segments scored on a 5-point scale (0=normal, 4=no uptake), while wall thickening was assessed visually on stress/rest end-systolic images using a 4-point score (0=normal, 3=absence of WT). LVEF and volumes were calculated using an automatic algorithm. Post-stress and rest ratio were determined for both end-diastolic and end-systolic volume, while the post-stress LVEF change (d-LVEF) was calculated according to the following formula: (Stress LVEF-rest LVEF)/rest LVEF*100. RESULTS: By using a cutoff value of 126 ml for rest-EDV, and of 68 ml for rest-ESV we found a LV dilation in 129/605 patients (21%). These thresholds were the mean values plus two standard deviations obtained in the control group. 111/129 (86%) were followed up for a mean period of 147.0 months. 83 of 111 (75%) patients had a history of MI and forty three (39%) had undergone surgical revascularizations. During the follow-up, 21 events (5 cardiac deaths, 3 nonfatal MI, 13 late revascularizations) occurred. All post-stress perfusion and functional parameters were more compromised in patients with CE compared with patients without events, but only rest EDV, rest ESV, post-stress ESV and WT-SSS reached statistical significance (201 ml vs 176 ml; p=0.035; 137 ml vs 113 ml; p=0.047; 143 ml vs 117 ml; p=0.034, 19 vs 15; p=0.048, respectively). Multivariate Cox proportional analysis demonstrated that stress ESV added significantly prognostic information over WT-SSS in predicting CE (p=0.046). CONCLUSIONS: Stress ESV has incremental prognostic value compared with wall thickening in predicting CE, in CAD patients with dilated cardiomyopathy. Perfusion parameters failed to show prognostic information in these patients.

Geometry and bone mass in primary hyperparathyroidism assessed by peripheral Quantitative Computed Tomography (pQCT).

PURPOSE: Non-invasive measurement by peripheral quantitative computed tomography (pQCT) of bone geometry, biomechanics, and mineral content in patients (pts) with primary hyperparathyroidism (PHPT). MATERIALS AND METHODS: Total, trabecular and cortical mineral density (totBMD, cortBMD, trab BMD), bone geometrical properties (total area, trabecular area, cortical area, cortical/total area) and cortical thickness as biomechanical parameters, were assessed by pQCT at distal radius in 38 (32 F; 6 M) consecutive patients with PHPT (mean age: 62 yrs; range: 30-77). In a subgroup of 12 patients, bone mineral density (BMD) was also measured by means of dual X-ray absorptiometry (DXA) at the lumbar spine (L2-L4). RESULTS: Serum biochemical characteristics were: iPTH (269+/-214 pg/ml; range: 107-1438, normal: 30-65), Calcium (11.4+/-1.1 mg/dl; range: 10.6-13.5, normal: 8.1-10.4) and Alkaline Phosphatase (398+/- 392 U/L; range:173-1174, normal: 98-279). Compa-red with 87 healthy age-matched subjects, total, trabecular and cortical bone densities were reduced in all patients (TotBMD: 216+/-92 mg/cm(3) vs ctr 342+/-94, -37%, p<0.05; TrabBMD: 93+/-51 mg/cm(3) vs ctr 140+/-54, -34%, p <0.01; CorBMD: 711+/-178 mg/cm(3) vs ctr 802+/-175, -11%, p<0.02), such as cortical thickness (0.143+/-0.02 cm vs ctr 0.157+/-0.03, -9%, p<0.02). Among geometrical parameters, only cortical/total area was significant different in the two groups (0,29 vs 0.31; p<0.04). A strong correlation was found between peripheral trabecular bone density assessed by pQCT and axial bone mineral density measured by DXA at L2-L4 (r=0.80; p<0.01). CONCLUSIONS: pQCT measurements in PHPT showed: 1) osteopoenia in all bone compartments partly related to age and menopause; 2) reduced cortical density and cortical thickness consistent with "cancellization" of the inner cortex and lower ability of bone to absorb loading forces. DXA measurements showed osteopoenia also at the lumbar spine, a site rich in trabecular bone. PQCT allowing selective assessment of true volumetric cortical and trabecular bone density such as bone geometry, is proposable in clinical practice, in order to evaluate presurgical bone "status" and to monitor the response to parathyroidectomy.

Severe cortical and trabecular osteopenia in secondary hyperparathyroidism.

BACKGROUND: Peripheral quantitative computed tomography (pQCT) provides real volumetric bone density values, not only of the total, but also of trabecular and cortical bone, separately. In addition, it provides data on bone geometry that can be related to the risk of fracture. METHODS: Total, cortical, and trabecular volumetric bone mineral densities (BMD), as well as the main geometric parameters (cross-sectional area, cortical area, trabecular area, and cortical thickness) were assessed by pQCT at the distal radius in 24 hemodialysis patients affected by severe secondary hyperparathyroidism (PTH, mean +/- SD: 1444 +/- 695 pg/mL). The strength-strain index (SSI), a biomechanical parameter describing bone fragility, was also determined. RESULTS: Compared with a control group of 64 healthy age-matched subjects, volumetric BMD (mg/cm(3)) was significantly reduced in all patients (total BMD: 243 +/- 87 vs. 405 +/- 138, cortical BMD: 605 +/- 218 vs. 856 +/- 204, trabecular BMD: 95 +/- 51 vs. 182 +/- 75). Cortical area and cortical thickness showed significant modifications, while cross-sectional area did not. SSI was significantly reduced (547 +/- 125 vs. 927 +/- 306 mm(3)). PTH levels showed a significant inverse correlation with cortical BMD (r = -0.56), cortical thickness (r = -0.46), cortical area (r = -0.61), and SSI (r = -0.54). Quantitative analysis of bone demonstrated cortical porosity. CONCLUSIONS: In dialysis patients with severe secondary hyperparathyroidism, pQCT showed a significant cortical osteopenia, associated with geometric and mechanical bone impairment. Interestingly, we also found a comparable deficit of trabecular bone, which may be related to the very high PTH levels. Generalized cortical thinning, intracortical porosity and cortical-endosteal resorption ("trabecularization" of the cortical bone) are major determinants of reduced bone strength, which may be quantitated by pQCT.