Pregnancy outcomes and vaccine effectiveness during the period of omicron as the variant of concern, INTERCOVID-2022: a multinational, observational study.

BACKGROUND: In 2021, we showed an increased risk associated with COVID-19 in pregnancy. Since then, the SARS-CoV-2 virus has undergone genetic mutations. We aimed to examine the effects on maternal and perinatal outcomes of COVID-19 during pregnancy, and evaluate vaccine effectiveness, when omicron (B.1.1.529) was the variant of concern. METHODS: INTERCOVID-2022 is a large, prospective, observational study, involving 41 hospitals across 18 countries. Each woman with real-time PCR or rapid test, laboratory-confirmed COVID-19 in pregnancy was compared with two unmatched women without a COVID-19 diagnosis who were recruited concomitantly and consecutively in pregnancy or at delivery. Mother and neonate dyads were followed until hospital discharge. Primary outcomes were maternal morbidity and mortality index (MMMI), severe neonatal morbidity index (SNMI), and severe perinatal morbidity and mortality index (SPMMI). Vaccine effectiveness was estimated, adjusted by maternal risk profile. FINDINGS: We enrolled 4618 pregnant women from Nov 27, 2021 (the day after WHO declared omicron a variant of concern), to June 30, 2022: 1545 (33%) women had a COVID-19 diagnosis (median gestation 36·7 weeks [IQR 29·0-38·9]) and 3073 (67%) women, with similar demographic characteristics, did not have a COVID-19 diagnosis. Overall, women with a diagnosis had an increased risk for MMMI (relative risk [RR] 1·16 [95% CI 1·03-1·31]) and SPMMI (RR 1·21 [95% CI 1·00-1·46]). Women with a diagnosis, compared with those without a diagnosis, also had increased risks of SNMI (RR 1·23 [95% CI 0·88-1·71]), although the lower bounds of the 95% CI crossed unity. Unvaccinated women with a COVID-19 diagnosis had a greater risk of MMMI (RR 1·36 [95% CI 1·12-1·65]). Severe COVID-19 symptoms in the total sample increased the risk of severe maternal complications (RR 2·51 [95% CI 1·84-3·43]), perinatal complications (RR 1·84 [95% CI 1·02-3·34]), and referral, intensive care unit (ICU) admission, or death (RR 11·83 [95% CI 6·67-20·97]). Severe COVID-19 symptoms in unvaccinated women increased the risk of MMMI (RR 2·88 [95% CI 2·02-4·12]) and referral, ICU admission, or death (RR 20·82 [95% CI 10·44-41·54]). 2886 (63%) of 4618 total participants had at least a single dose of any vaccine, and 2476 (54%) of 4618 had either complete or booster doses. Vaccine effectiveness (all vaccines combined) for severe complications of COVID-19 for all women with a complete regimen was 48% (95% CI 22-65) and 76% (47-89) after a booster dose. For women with a COVID-19 diagnosis, vaccine effectiveness of all vaccines combined for women with a complete regimen was 74% (95% CI 48-87) and 91% (65-98) after a booster dose. INTERPRETATION: COVID-19 in pregnancy, during the first 6 months of omicron as the variant of concern, was associated with increased risk of severe maternal morbidity and mortality, especially among symptomatic and unvaccinated women. Women with complete or boosted vaccine doses had reduced risk for severe symptoms, complications, and death. Vaccination coverage among pregnant women remains a priority. FUNDING: None.

Placental apoptosis increased by hypoxia inducible Factor-1 stabilization is counteracted by leptin.

During pregnancy, apoptosis is a physiological event critical in the remodeling and aging of the placenta. Increasing evidence has pointed towards the relevance of hypoxia as modulator of trophoblast cell death. Previous reports have shown that leptin, a placental cytokine, promotes cell survival in both cell culture and placental explant models. The aim of this work is to establish the role of leptin in apoptosis under hypoxic condition in trophoblast cells. In this study, we evaluated the effect of cobalt chloride, a hypoxia mimicking agent that stabilizes the expression of hypoxia inducible factor-1 alpha (HIF-1α), on Swan-71 and human placental explants. Hypoxia chamber was also used to generate 2% oxygen. Apoptosis was determined by the presence of apoptotic nucleus, fragmentation of DNA and Caspase-3 and PARP-1 cleavage. The pro-apoptotic proteins BAX, BID, BAD and BAK and the anti-apoptotic effectors BCL-2, BCL-xL and MCL-1 were also analyzed. We found that HIF-1α stabilization increased the appearance of apoptotic nucleus, fragmentation of DNA, and Caspase-3 and PARP-1 cleavage. Hypoxia mimicking conditions enhanced the expression of pro-apoptotic effectors BAX, BID, BAD and BAK. HIF-1α stabilization also downregulated the level of BCL-2, BCL-xL and MCL-1. All these apoptotic parameters changes were reversed with leptin treatment. Moreover, we showed that leptin action on apoptosis modulation involves PI3K and MAPK signaling pathways. Obtained data demonstrate that HIF-1α stabilization induces apoptosis in human placenta and leptin counteracts this effect, reinforcing its role as a survival cytokine.

Maternal vaccination against COVID-19 and neonatal outcomes during Omicron: INTERCOVID-2022 study.

BACKGROUND: In early 2023, when Omicron was the variant of concern, we showed that vaccinating pregnant women decreased the risk for severe COVID-19-related complications and maternal morbidity and mortality. OBJECTIVE: This study aimed to analyze the impact of COVID-19 during pregnancy on newborns and the effects of maternal COVID-19 vaccination on neonatal outcomes when Omicron was the variant of concern. STUDY DESIGN: INTERCOVID-2022 was a large, prospective, observational study, conducted in 40 hospitals across 18 countries, from November 27, 2021 (the day after the World Health Organization declared Omicron the variant of concern) to June 30, 2022, to assess the effect of COVID-19 in pregnancy on maternal and neonatal outcomes and to assess vaccine effectiveness. Women diagnosed with laboratory-confirmed COVID-19 during pregnancy were compared with 2 nondiagnosed, unmatched women recruited concomitantly and consecutively during pregnancy or at delivery. Mother-newborn dyads were followed until hospital discharge. The primary outcomes were a neonatal positive test for COVID-19, severe neonatal morbidity index, severe perinatal morbidity and mortality index, preterm birth, neonatal death, referral to neonatal intensive care unit, and diseases during the neonatal period. Vaccine effectiveness was estimated with adjustment for maternal risk profile. RESULTS: We enrolled 4707 neonates born to 1577 (33.5%) mothers diagnosed with COVID-19 and 3130 (66.5%) nondiagnosed mothers. Among the diagnosed mothers, 642 (40.7%) were not vaccinated, 147 (9.3%) were partially vaccinated, 551 (34.9%) were completely vaccinated, and 237 (15.0%) also had a booster vaccine. Neonates of booster-vaccinated mothers had less than half (relative risk, 0.46; 95% confidence interval, 0.23-0.91) the risk of being diagnosed with COVID-19 when compared with those of unvaccinated mothers; they also had the lowest rates of preterm birth, medically indicated preterm birth, respiratory distress syndrome, and number of days in the neonatal intensive care unit. Newborns of unvaccinated mothers had double the risk for neonatal death (relative risk, 2.06; 95% confidence interval, 1.06-4.00) when compared with those of nondiagnosed mothers. Vaccination was not associated with any congenital malformations. Although all vaccines provided protection against neonatal test positivity, newborns of booster-vaccinated mothers had the highest vaccine effectiveness (64%; 95% confidence interval, 10%-86%). Vaccine effectiveness was not as high for messenger RNA vaccines only. Vaccine effectiveness against moderate or severe neonatal outcomes was much lower, namely 13% in the booster-vaccinated group (all vaccines) and 25% and 28% in the completely and booster-vaccinated groups, respectively (messenger RNA vaccines only). Vaccines were fairly effective in protecting neonates when given to pregnant women ≤100 days (14 weeks) before birth; thereafter, the risk increased and was much higher after 200 days (29 weeks). Finally, none of the neonatal practices studied, including skin-to-skin contact and direct breastfeeding, increased the risk for infecting newborns. CONCLUSION: When Omicron was the variant of concern, newborns of unvaccinated mothers had an increased risk for neonatal death. Neonates of vaccinated mothers had a decreased risk for preterm birth and adverse neonatal outcomes. Because the protective effect of COVID-19 vaccination decreases with time, to ensure that newborns are maximally protected against COVID-19, mothers should receive a vaccine or booster dose no more than 14 weeks before the expected date of delivery.

Clinical and microbiological features of positive blood culture episodes caused by non-fermenting gram-negative bacilli other than Pseudomonas and Acinetobacter species (2020-2023).

INTRODUCTION: Non-fermenting Gram-negative bacilli (NFGNB) other than Pseudomonas aeruginosa and Acinetobacter baumannii complex are pathogens of interest due to their ability to cause health-care associated infections and display complex drug resistance phenotypes. However, their clinical and microbiological landscape is still poorly characterized. METHODS: Observational retrospective study including all hospitalized patients presenting with a positive positive blood culture (BC) episode caused by less common NFGNB over a four-year period (January 2020-December 2023). Clinical-microbiological features and factors associated with mortality were investigated. RESULTS: Sixty-six less common NFGNB isolates other than Pseudomonas and Acinetobacter species causing 63 positive BC episodes were recovered from 60 patients. Positive BC episodes were predominantly sustained by Stenotrophomonas maltophilia (49.2%) followed by Achromobacter species (15.9%) that exhibited the most complex resistance phenotype. Positive BC episodes had bloodstream infection criteria in 95.2% of cases (60 out 63), being intravascular device (30.2%) and respiratory tract (19.1%) the main sources of infection. Fourteen-day, 30-day, and in-hospital mortality rates were 6.4%, 9.5%, and 15.9%, respectively. The longer time from admission to the positive BC episode, older age, diabetes, admission due to sepsis, and higher Charlson Comorbidity Index were identified as the main predictors of in-hospital mortality. CONCLUSIONS: Positive BC episodes sustained by NFGNB other than Pseudomonas and Acinetobacter species were predominantly sustained by Stenotrophomonas maltophilia and Achromobacter species, having bloodstream infection criteria in the vast majority of cases. Factors that have emerged to be associated with mortality highlighted how these species may have more room in prolonged hospitalisation and at the end of life for patients with chronic organ diseases.

Technology Assisted Rehabilitation Patient Perception Questionnaire (TARPP-Q): development and implementation of an instrument to evaluate patients' perception during training.

BACKGROUND: The introduction of technology-assisted rehabilitation (TAR) uncovers promising challenges for the treatment of motor disorders, particularly if combined with exergaming. Patients with neurological diseases have proved to benefit from TAR, improving their performance in several activities. However, the subjective perception of the device has never been fully addressed, being a conditioning factor for its use. The aims of the study were: (a) to develop a questionnaire on patients' personal experience with TAR and exergames in a real-world clinical setting; (b) to administer the questionnaire to a pilot group of neurologic patients to assess its feasibility and statistical properties. METHODS: A self-administrable and close-ended questionnaire, Technology Assisted Rehabilitation Patient Perception Questionnaire (TARPP-Q), designed by a multidisciplinary team, was developed in Italian through a Delphi procedure. An English translation has been developed with consensus, for understandability purposes. The ultimate version of the questionnaire was constituted of 10 questions (5 with multiple answers), totalling 29 items, exploring the patient's performance and personal experience with TAR with Augmented Performance Feedback. TARPP-Q was then administered pre-post training in an observational, feasible, multi-centric study. The study involved in-patients aged between 18 and 85 with neurological diseases, admitted for rehabilitation with TAR (upper limb or gait). FIM scale was run to control functional performance. RESULTS: Forty-four patients were included in the study. All patients answered the TARPP-Q autonomously. There were no unaccounted answers. Exploratory factor analyses identified 4 factors: Positive attitude, Usability, Hindrance perception, and Distress. Internal consistency was measured at T0. The values of Cronbach's alpha ranged from 0.72 (Distress) to 0.92 (Positive attitude). Functional Independence Measure (FIM®) scores and all TARPP-Q factors (Positive attitude, Usability, Hindrance perception, except for Distress (p = 0.11), significantly improved at the end of the treatment. A significant positive correlation between Positive attitude and Usability was also recorded. CONCLUSIONS: The TARPP-Q highlights the importance of patients' personal experience with TAR and exergaming. Large-scale applications of this questionnaire may clarify the role of patients' perception of training effectiveness, helping to customize devices and interventions.

Effects of prenatal exposure to maternal COVID-19 and perinatal care on neonatal outcome: results from the INTERCOVID Multinational Cohort Study.

BACKGROUND: The effect of COVID-19 in pregnancy on maternal outcomes and its association with preeclampsia and gestational diabetes mellitus have been reported; however, a detailed understanding of the effects of maternal positivity, delivery mode, and perinatal practices on fetal and neonatal outcomes is urgently needed. OBJECTIVE: To evaluate the impact of COVID-19 on fetal and neonatal outcomes and the role of mode of delivery, breastfeeding, and early neonatal care practices on the risk of mother-to-child transmission. STUDY DESIGN: In this cohort study that took place from March 2020 to March 2021, involving 43 institutions in 18 countries, 2 unmatched, consecutive, unexposed women were concomitantly enrolled immediately after each infected woman was identified, at any stage of pregnancy or delivery, and at the same level of care to minimize bias. Women and neonates were followed up until hospital discharge. COVID-19 in pregnancy was determined by laboratory confirmation and/or radiological pulmonary findings or ≥2 predefined COVID-19 symptoms. The outcome measures were indices of neonatal and perinatal morbidity and mortality, neonatal positivity and its correlation with mode of delivery, breastfeeding, and hospital neonatal care practices. RESULTS: A total of 586 neonates born to women with COVID-19 diagnosis and 1535 neonates born to women without COVID-19 diagnosis were enrolled. Women with COVID-19 diagnosis had a higher rate of cesarean delivery (52.8% vs 38.5% for those without COVID-19 diagnosis, P<.01) and pregnancy-related complications, such as hypertensive disorders of pregnancy and fetal distress (all with P<.001), than women without COVID-19 diagnosis. Maternal diagnosis of COVID-19 carried an increased rate of preterm birth (P≤.001) and lower neonatal weight (P≤.001), length, and head circumference at birth. In mothers with COVID-19 diagnosis, the length of in utero exposure was significantly correlated to the risk of the neonate testing positive (odds ratio, 4.5; 95% confidence interval, 2.2-9.4 for length of in utero exposure >14 days). Among neonates born to mothers with COVID-19 diagnosis, birth via cesarean delivery was a risk factor for testing positive for COVID-19 (odds ratio, 2.4; 95% confidence interval, 1.2-4.7), even when severity of maternal conditions was considered and after multivariable logistic analysis. In the subgroup of neonates born to women with COVID-19 diagnosis, the outcomes worsened when the neonate also tested positive, with higher rates of neonatal intensive care unit admission, fever, gastrointestinal and respiratory symptoms, and death, even after adjusting for prematurity. Breastfeeding by mothers with COVID-19 diagnosis and hospital neonatal care practices, including immediate skin-to-skin contact and rooming-in, were not associated with an increased risk of newborn positivity. CONCLUSION: In this multinational cohort study, COVID-19 in pregnancy was associated with increased maternal and neonatal complications. Cesarean delivery was significantly associated with newborn COVID-19 diagnosis. Vaginal delivery should be considered the safest mode of delivery if obstetrical and health conditions allow it. Mother-to-child skin-to-skin contact, rooming-in, and direct breastfeeding were not risk factors for newborn COVID-19 diagnosis, thus well-established best practices can be continued among women with COVID-19 diagnosis.

Occurrence of multi-carbapenemases producers among carbapenemase-producing Enterobacterales and in vitro activity of combinations including cefiderocol, ceftazidime-avibactam, meropenem-vaborbactam, and aztreonam in the COVID-19 era.

PURPOSE: To evaluate the prevalence of multi-carbapenemase-producing Enterobacterales (EB) and the activity of cefiderocol (CFDC), meropenem-vaborbactam (MEV), ceftazidime-avibactam (CZA), and combinations of CZA plus aztreonam (ATM), MEV plus ATM and CFDC plus CZA against them. METHODS: A collection of carbapenemase-producing EB clinical isolates (n = 1242) was investigated by lateral flow immunoassay NG-Test CARBA-5 and molecular testing. Cefiderocol MICs were determined using broth microdilution SensititreTM panel. MICs of CZA and MEV were determined by the gradient diffusion method. Antimicrobial synergy testing was performed using gradient diffusion strip crossing. RESULTS: KPC were the most frequent carbapenemases (83.2%), followed by VIM (9.2 %), OXA-48-like (4.3 %) and NDM enzymes (4.1%). Multi-carbapenemase producers were found in 10 (0.8%) isolates. Three combinations of two different carbapenemases were observed: KPC+VIM (n = 4), NDM+OXA-48-like (n = 4), and VIM+OXA-48-like (n = 2). CFDC showed potent activity against eight out of ten dual-carbapenemases producers, while resistance or reduced susceptibility was shown towards CZA and MEV. CFDC in combination with CZA showed no synergistic effects and only two additive effects on seven (87.5%) of the CFDC-susceptible strains. Conversely, CZA plus ATM and MEV plus ATM combinations were synergistic against all ATM-resistant strains regardless of dual-carbapenemases phenotype. CONCLUSIONS: The occurrence of multi-carbapenemase producers is not uncommon in Northern Italy area. MEV in combination with ATM might be considered as a potential therapeutic option, alternative to CZA plus ATM. CFDC susceptibility testing and synergy evaluation of ATM-based combinations should be performed in the lab routine to evaluate the most in vitro active antimicrobial regimen.

Direct detection of extended-spectrum-ß-lactamase-producers in Enterobacterales from blood cultures: a comparative analysis.

Accurate detection of extended-spectrum-ß-lactamase (ESBL)-producing Enterobacterales from bloodstream infection (BSI) is of paramount importance for both epidemiological and clinical purposes, especially for optimization of antibiotic stewardship interventions. Three phenotypic methods for the detection of ESBL phenotype in Klebsiella pneumoniae and Escherichia coli BSI were compared over a 4-month period (May-August 2021) in a main University Hospital from Northern Italy. The methods were the biochemical Rapid ESBL NP®, the immunological NG-Test CTX-M MULTI®, and the E-test technique based on ESBL E-test®. One hundred forty-two blood cultures (BCs) positive for K. pneumoniae or E. coli were included. ESBL and carbapenemase phenotype were detected in 26.1% (n = 37) and 16.9% (n = 24), respectively. The Rapid ESBL NP®, NG-Test CTX-M MULTI®, and direct ESBL E-test® positive and negative predictive values with 95% confidence intervals were 1 (0.87-1) and 0.97 (0.92-0.99), 1 (0.87-1) and 0.97 (0.92-0.99), and 1 (0.88-1) and 1 (0.96-1), respectively. The three phenotypic methods evaluated showed good performance in the detection of ESBL phenotype from K. pneumoniae- or E. coli-positive BCs. Rapid ESBL NP® and NG-test CTX-M® offer the important advantage of a turnaround time of 15 to 45 min, and the Rapid ESBL NP test in addition detects any type of ESBL producers.

Preeclampsia and COVID-19: results from the INTERCOVID prospective longitudinal study.

BACKGROUND: It is unclear whether the suggested link between COVID-19 during pregnancy and preeclampsia is an independent association or if these are caused by common risk factors. OBJECTIVE: This study aimed to quantify any independent association between COVID-19 during pregnancy and preeclampsia and to determine the effect of these variables on maternal and neonatal morbidity and mortality. STUDY DESIGN: This was a large, longitudinal, prospective, unmatched diagnosed and not-diagnosed observational study assessing the effect of COVID-19 during pregnancy on mothers and neonates. Two consecutive not-diagnosed women were concomitantly enrolled immediately after each diagnosed woman was identified, at any stage during pregnancy or delivery, and at the same level of care to minimize bias. Women and neonates were followed until hospital discharge using the standardized INTERGROWTH-21st protocols and electronic data management system. A total of 43 institutions in 18 countries contributed to the study sample. The independent association between the 2 entities was quantified with the risk factors known to be associated with preeclampsia analyzed in each group. The outcomes were compared among women with COVID-19 alone, preeclampsia alone, both conditions, and those without either of the 2 conditions. RESULTS: We enrolled 2184 pregnant women; of these, 725 (33.2%) were enrolled in the COVID-19 diagnosed and 1459 (66.8%) in the COVID-19 not-diagnosed groups. Of these women, 123 had preeclampsia of which 59 of 725 (8.1%) were in the COVID-19 diagnosed group and 64 of 1459 (4.4%) were in the not-diagnosed group (risk ratio, 1.86; 95% confidence interval, 1.32-2.61). After adjustment for sociodemographic factors and conditions associated with both COVID-19 and preeclampsia, the risk ratio for preeclampsia remained significant among all women (risk ratio, 1.77; 95% confidence interval, 1.25-2.52) and nulliparous women specifically (risk ratio, 1.89; 95% confidence interval, 1.17-3.05). There was a trend but no statistical significance among parous women (risk ratio, 1.64; 95% confidence interval, 0.99-2.73). The risk ratio for preterm birth for all women diagnosed with COVID-19 and preeclampsia was 4.05 (95% confidence interval, 2.99-5.49) and 6.26 (95% confidence interval, 4.35-9.00) for nulliparous women. Compared with women with neither condition diagnosed, the composite adverse perinatal outcome showed a stepwise increase in the risk ratio for COVID-19 without preeclampsia, preeclampsia without COVID-19, and COVID-19 with preeclampsia (risk ratio, 2.16; 95% confidence interval, 1.63-2.86; risk ratio, 2.53; 95% confidence interval, 1.44-4.45; and risk ratio, 2.84; 95% confidence interval, 1.67-4.82, respectively). Similar findings were found for the composite adverse maternal outcome with risk ratios of 1.76 (95% confidence interval, 1.32-2.35), 2.07 (95% confidence interval, 1.20-3.57), and 2.77 (95% confidence interval, 1.66-4.63). The association between COVID-19 and gestational hypertension and the direction of the effects on preterm birth and adverse perinatal and maternal outcomes, were similar to preeclampsia, but confined to nulliparous women with lower risk ratios. CONCLUSION: COVID-19 during pregnancy is strongly associated with preeclampsia, especially among nulliparous women. This association is independent of any risk factors and preexisting conditions. COVID-19 severity does not seem to be a factor in this association. Both conditions are associated independently of and in an additive fashion with preterm birth, severe perinatal morbidity and mortality, and adverse maternal outcomes. Women with preeclampsia should be considered a particularly vulnerable group with regard to the risks posed by COVID-19.

Feasibility of Conducting a Trial Assessing Benefits and Risks of Planned Caesarean Section Versus Planned Vaginal Birth: A Cross-Sectional Study.

INTRODUCTION: Though interest is growing for trials comparing planned delivery mode (vaginal delivery [VD]; cesarean section [CS]) in low-risk nulliparous women, appropriate study design is unclear. Our objective was to assess feasibility of three designs (preference trial [PCT], randomized controlled trial [RCT], partially randomized patient preference trial [PRPPT]) for a trial comparing planned delivery mode in low-risk women. METHODS: A cross-sectional survey of low-risk, nulliparous pregnant women (N = 416) and healthcare providers (N = 168) providing prenatal care and/or labor/delivery services was conducted in Argentina (2 public, 2 private hospitals). Proportion of pregnant women and providers willing to participate in each design and reasons for not participating were determined. RESULTS: Few women (< 15%) or professionals (33.3%) would participate in an RCT, though more would participate in PCTs (88% women; 65.9% professionals) or PRPPTs (44.4% public, 63.4% private sector women; 44.0% professionals). However, most women would choose vaginal delivery in the PCT and PRPPT (> 85%). Believing randomization unacceptable (RCT, PRPPT) and desiring choice of delivery mode (RCT) were women's reasons for not participating. For providers, commonly cited reasons for not participating included unacceptability of performing CS without medical indication, difficulty obtaining informed consent, discomfort enrolling patients (all designs), and violating women's right to choose (RCT). CONCLUSIONS FOR PRACTICE: Important limitations were found for each trial design evaluated. The necessity of stronger evidence regarding delivery mode in low-risk women suggests consideration of additional designs, such as a rigorously designed cohort study or an RCT within an obstetric population with equivocal CS indications.

Robot-Assisted Gait Training in Patients with Multiple Sclerosis: A Randomized Controlled Crossover Trial.

Background and Objectives: Gait disorders represent one of the most disabling aspects in multiple sclerosis (MS) that strongly influence patient quality of life. The improvement of walking ability is a primary goal for rehabilitation treatment. The aim of this study is to evaluate the effectiveness of robot-assisted gait training (RAGT) in association with physiotherapy treatment in patients affected by MS in comparison with ground conventional gait training. Study design: Randomized controlled crossover trial. Materials and Methods: Twenty-seven participants affected by MS with EDSS scores between 3.5 and 7 were enrolled, of whom seventeen completed the study. They received five training sessions per week over five weeks of conventional gait training with (experimental group) or without (control group) the inclusion of RAGT. The patients were prospectively evaluated before and after the first treatment session and, after the crossover phase, before and after the second treatment session. The evaluation was based on the 25-foot walk test (25FW, main outcome), 6 min walk test (6MWT), Tinetti Test, Modified Ashworth Scale, and modified Motricity Index for lower limbs. We also measured disability parameters using Functional Independence Measure and Quality of Life Index, and instrumental kinematic and gait parameters: knee extensor strength, double-time support, step length ratio; 17 patients reached the final evaluation. Results: Both groups significantly improved on gait parameters, motor abilities, and autonomy recovery in daily living activities with generally better results of RAGT over control treatment. In particular, the RAGT group improved more than control group in the 25FW (p = 0.004) and the 6MWT (p = 0.022). Conclusions: RAGT is a valid treatment option that in association with physiotherapy could induce positive effects in MS-correlated gait disorders. Our results showed greater effectiveness in recovering gait speed and resistance than conventional gait training.

Crosstalk between estradiol and NFκB signaling pathways on placental leptin expression.

Pregnancy success requires a proper fetal maternal interaction at the establishment of implantation. Leptin has been described as a multitasking cytokine in pregnancy, particularly in the placenta, where it acts as an autocrine hormone. The expression of leptin in normal trophoblastic cells is regulated by different endogenous signals. We have previously reported that 17ß-estradiol upregulates placental leptin expression through genomic and non-genomic mechanisms. To improve the knowledge of estrogen receptor mechanisms in regulating leptin gene expression, we examined transcription nuclear factor kappa B (NFκB) effect on estradiol leptin induction in human BeWo cell line and human term placental explants. We demonstrated that estradiol induction effect on leptin expression is blocked by the inhibition of NFκB signaling. We also found that the overexpression of p65 subunit, the active form of NFκB, induces leptin expression. Moreover, downregulation of estrogen receptor alpha (ERα), through a specific siRNA, abolished NFκB effect on leptin expression. We also demonstrated that ERα enhanced NFκB signaling pathway activation in trophoblastic cells. Estradiol treatment significantly increased p65 expression and phosphorylation of the inhibitory protein κB alpha (IκBα). A reporter plasmid containing NFκB elements was also induced in response to estradiol stimulation. Localization experiments revealed that estradiol treatment induced nuclear localization of overexpressed p65. Moreover, the overexpression of ERα produced a complete displacement of p65 protein to the nucleus. Finally, immunoprecipitation experiments showed the presence of a complex containing ERα and NFκB. All these evidences suggest a cooperative behavior between ERα and NFκB transcription factors to induce leptin transcription.

Fibromyalgia and the concept of resilience.

The concept of resilience varies according to the context in which it is used. Resilience is broadly defined as a protective factor that makes people less vulnerable to future adverse life events, in this implying the previous occurrence of an adverse event that has to be confronted before individual equilibrium can be restored. This definition can be applied to fibromyalgia and other chronic pain situations. Resilience is profoundly related to reaction to acute or chronic stress, and is therefore involved in the stress response system. Corticotropin-releasing factor can be considered a fundamental biological element of resilience, which also involves neural mechanisms such as the hypothalamic-pituitary-adrenal (HPA) axis, the locus coeruleus/norepinephrine system, the mesolimbic reward circuit and the fear circuit. Resilience also has a genetic basis: certain genetic characteristics, affect the degree of vulnerability to chronic stress. The number of psychiatric symptoms in healthy adults with high resilience scores do not change when they are exposed to stressing life events, whereas less resilient people develop additional symptoms. This is a typical clinical feature of fibromyalgia. Although resilience could be a therapeutic target for any chronic pain condition, it is an under-developed area of research, particularly in the light of the emerging interactions of positive emotions, physical health, and changes in pro-inflammatory cytokine levels. Given the lack of any pharmacological treatment capable of controlling more than 30-50% of the cases of chronic pain, there is a need to discover new therapeutic targets and strategies capable of changing a non-resilient phenotype into a more resilient phenotype, especially in the case of chronic pain conditions that cannot be explained by a lesion or a disease affecting the somatosensory system. This holds true of fibromyalgia, which is characterised by a complex combination of positive signs and symptoms that vary enormously from person to person depending on a wide range of pathophysiological changes in which genotype and, more importantly, environmental factors may play a major role in developing a more or less resilient personality.

Hyperbaric oxygen treatment of fibromyalgia: a prospective observational clinical study.

OBJECTIVES: Fibromyalgia (FM) is a syndrome of unknown aetiology that is characterised by widespread musculoskeletal pain, fatigue and disordered sleep, and often associated with neuropsychiatric and cognitive symptoms. Current treatment options are only partially effective, but hyperbaric oxygen therapy (HBOT) seems to be capable of relieving some of the symptoms. The aim of this study was to evaluate the efficacy and safety of HBOT after fewer sessions than generally used, chosen on the basis of pre-clinical and clinical data showing its rapid and sustained antinociceptive effect. METHODS: Patients with FM underwent HBOT (100% oxygen at 2.5 ata with air breaks) administered on three days per week for a total of twenty 90-minute sessions. Pain, fatigue, the quality of sleep, symptoms of anxiety and depression, and the patients' health-related quality of life were prospectively assessed before and after ten and twenty sessions. RESULTS: Twenty-eight of the 32 study patients completed the 20 HBOT sessions. Pain scores and the symptoms of anxiety (but not those of depression) significantly improved after both 10 and 20 sessions, whereas fatigue and FM symptom severity scores significantly improved only after 20 sessions. There was no significant change in the quality of sleep. The adverse effects were limited. CONCLUSIONS: These findings support the view that HBOT is an effective, rapid and safe means of treating various symptoms of FM.

Neuromuscular efficiency in fibromyalgia is improved by hyperbaric oxygen therapy: looking inside muscles by means of surface electromyography.

OBJECTIVES: Neuromuscular efficiency (NME) is impaired in fibromyalgia (FM). Hyperbaric oxygen therapy (HBOT) is a medical treatment using 100% of oxygen through an oxygen mask. HBOT in FM induces changes in cortical excitability and a secondary reduction in pain and muscle fatigue. However, there are still no direct data indicating changes in muscle fatigue. The aim of this study was to assess whether the reduction in muscle fatigue so far attributed to a central effect of HBOT can be directly detected by means of non-invasive sEMG as a change in NME. METHODS: The study was an observational longitudinal study on changes in NME induced by 20 sessions of HBOT at 2.4 atmosphere, in 22 patients with FM (3M; 19F) (age 49.8±9.5; height 164.7±7.5; weight 63.8±12.7). sEMG was recorded in single differential configuration from the biceps brachii muscle during the 30-second fatiguing contractions using linear arrays of eight adhesive electrodes. RESULTS: Evaluations made before and immediately after the first session showed that maximal strength did not change (T0 49±20 N, T1 49±19 N, p=0.792), thus suggesting that HBOT did not induce muscle fatigue or potentiation. After 20 sessions of HBOT, NME increased from 1.6±1.1 to 2.1±0.8 (p=0.050), whereas maximal strength, EMG amplitude and muscle fibre CV did not change. CONCLUSIONS: HBOT did not improve muscle strength or change muscle fibre content, but improved the ability of the central motor command to generate the same effort (MVC) with fewer recruited fibres. Our sEMG findings underlined a modified central mechanism related to fibre type recruitment order, thus suggesting that muscle fatigue is not primarily a muscular problem, as also demonstrated by other authors with different methods.

T helper 1 response is correlated with widespread pain, fatigue, sleeping disorders and the quality of life in patients with fibromyalgia and is modulated by hyperbaric oxygen therapy.

OBJECTIVES: Hyperbaric oxygen therapy (HBOT) has been used as treatment for different clinical conditions, including fibromyalgia (FM). HBOT modulates brain activity, ameliorates chronic pain and modifies the ratio of immune cells. Clinical studies have provided evidence that FM is associated with immune system dysregulation. In the present study we aimed to evaluate the effect of HBOT on immune system and on the quality of life-style of FM patients. METHODS: Patients with primary FM and controls were treated with HBOT. Physical, emotional and social assessment, quality of sleep, tender points, intensity score, WPI and symptom severity were evaluated before and after HBOT. Furthermore, a characterisation of CD4 T lymphocytes and their cytokine production was performed by flow cytometry. The expression of TNF-α, IFN-γ, IL-17, IL-9 and IL-22 was also assessed by RT-PCR. Finally, the serum levels of serotonin were evaluated by ELISA. RESULTS: Our results confirm the participation of immune system in the pathogenesis of FM and highlight the impact of HBOT treatment, with particular regard to the changes on proinflammatory cytokines production by CD4 T cells subsets. CONCLUSIONS: FM patients show a Th1 signature and the activation of this subset is modulated by HBOT.

Critical Illness Polyneuropathy (CIP): a multicenter study on functional outcome.

OBJECTIVES: To describe the functional recovery of consecutive inpatients with Critical Illness Polyneuropathy (CIP) at the time-point of the discharge from rehabilitation units according to Barthel Index scores. To examine whether age, gender, pre-ICU admission diagnosis, tracheostomy performance, heterotopic ossification development and duration of neuro-rehabilitation treatment are among the prognostic factors that can predict the functional outcome in studied patients. METHODS: A retrospective observational clinical study from January 2010 to December 2014 in three rehabilitation units in Greece. RESULTS: Sixteen subjects (57.1%) had >60 BI discharge scores, showing a prospect in gaining further independence. Females presented a tendency for better functional outcome vs males (73.8 ± 12.6 vs 58.6 ± 23.4, p=0.082). Respiratory, septic and neurologic patients demonstrated better rates of functional improvement after the rehabilitation process vs cardiac patients (p minor than 0.001, p=0.009 and p=0.019, respectively vs p=0,072). Heterotopic ossification development proved to be an adverse independent prognostic factor of functional outcome (47.8 ± 25.7 vs 68.8 ± 17.7, p=0.023). CONCLUSIONS: A proportion of included patients experienced severe disability with poor prospect of further functional development and return to work at the discharge from the rehabilitation units. According to the present study, which is the first that focuses only on CIP and its outcome, specific prognostic factors can be defined. Our results can be used as pilot data for larger studies, so that firmer conclusions can be drawn.

100 Hz Localized vibration increases ipsilateral cerebellar areas activity during a motor task in healthy subjects: Three Cases Report.

SUMMARY: Background and Purpose. The exact mechanism thought which Localized vibration (LV) acts on the motor system at the suprasegmental level is still poorly understood. In this paper we have reported three cases of healthy men exposed to 100 Hz localized vibration during a motor task. Case Description. This case report describes 3 healthy men (age 23 years). Outcomes. During fMRI participants were engaged in a right-hand self-paced finger tapping (FT) task, with and without a 100 Hz LV of the right hand. After standard images preprocessing and normalization, a fix-effect GLM analysis was used to test the effect of vibratory stimulation on motor network. A bilateral activation, greater in the left hemisphere than in the right one, in the frontal premotor and supplementary motor areas (SMA), central gyrus (M1), postcentral gyrus, was found without any statistical significance between conditions. Activation in the left lenticular nucleus and thalamus was also found without differences between conditions. When using the FT activation map as a mask, the analysis showed that only the right cerebellum correlate positively with the vibratory stimulation. Discussion. Using fMR a localized vibratory stimulus was found to significantly increase the activity in homo-lateral motor cerebellar areas during a motor task. This finding aims to trigger new studies on how a LV can influence motor recovery in neurorehabilitation and to (re) consider the role of cerebellum in the rehabilitation strategy.

One year in review 2017: fibromyalgia.

Fibromyalgia (FM) is a complex syndrome characterised by chronic pain, fatigue and functional symptoms. Widespread pain is often its most typical feature, whereas other manifestations may be associated to various extents. Its aetiopathogenesis is still a matter of debate, but various pharmacological and non-pharmacological therapies are currently available for its treatment. We review the literature concerning the most recent findings relating to the aetiopathogenesis, assessment and treatment of FM published between January 2016 and January 2017.

Topical Treatments for Localized Neuropathic Pain.

PURPOSE OF REVIEW: Topical therapeutic approaches in localized neuropathic pain (LNP) syndromes are increasingly used by both specialists and general practitioners, with a potentially promising effect on pain reduction. In this narrative review, we describe the available compounds for topical use in LNP syndromes and address their potential efficacy according to the literature. RECENT FINDINGS: Local anaesthetics (e.g., lidocaine, bupivacaine and mepivacaine), as well as general anaesthetic agents (e.g., ketamine), muscle relaxants (e.g., baclofen), capsaicin, anti-inflammatory drugs (e.g., diclofenac), salicylates, antidepressants (e.g., amitriptyline and doxepin), α2 adrenergic agents (e.g., clonidine), or even a combination of them have been tested in various applications for the treatment of LNP. Few of them have reached a sufficient level of evidence to support systematic use as treatment options. Relatively few systemic side effects or drug-drug interactions and satisfactory efficacy seem to be the benefits of topical treatments. More well-organized and tailored studies are necessary for the further conceptualization of topical treatments for LNP.