Mucosal-associated invariant T cells are functionally impaired in pediatric and young adult patients following allogeneic hematopoietic stem cell transplantation and their recovery correlates with clinical outcomes.

Mucosal-associated invariant T (MAIT) cells are innate-like T-cells implicated in the response to fungal and bacterial infections. Their contribution to restoring T-cell immunity and influencing hematopoietic stem cell transplant (HSCT) outcomes remains poorly understood. We retrospectively studied MAIT-cell recovery in 145 consecutive children and young adults with hematological malignancies undergoing allo-HSCT, between April/2019 and May/2022, from unrelated matched donor (MUD, n=52), with standard graft-versus-host-disease (GvHD) prophylaxis, or HLA-haploidentical (Haplo, n=93) donor after in vitro αßT/CD19-cell depletion, without post-HSCT pharmacological prophylaxis. With a median follow-up of 33 months (12-49), overall survival (OS), disease-free survival (DFS) and non-relapse mortality (NRM) were 79.5%, 72% and 7%, respectively; GvHD-free, Relapse-free Survival (GRFS) was 63%, while cumulative incidence of relapse was 23%. While WWT-cells reconstituted 1-2 years post-HSCT, MAIT-cells showed delayed recovery and prolonged functional impairment, characterized by expression of activation (CD25, CD38), exhaustion (PD1, TIM3) and senescence (CD57) markers, and suboptimal ex vivo response. OS, DFS and NRM were not affected by MAIT-cells. Interestingly, higher MAIT-cells at day+30 correlated with higher incidence of grade II-IV acute GvHD (19% vs 7%, p=0.06). Furthermore, a greater MAIT-cell count tended to be associated with a higher incidence of chronic GvHD (17% vs 6%, p=0.07) resulting in lower GRFS (55% vs 73%, p=0.05). Higher MAIT-cells also correlated with greater cytomegalovirus (CMV) reactivation and lower late blood stream infections (BSI) (44% vs 24%, p=0.02 and 9% vs 18%, p=0.08, respectively). Future studies are needed to confirm the impact of early MAIT-cell recovery on cGvHD, CMV reactivation and late BSI.

Contrast Agents during Pregnancy: Pros and Cons When Really Needed.

Many clinical conditions require radiological diagnostic exams based on the emission of different kinds of energy and the use of contrast agents, such as computerized tomography (CT), positron emission tomography (PET), magnetic resonance (MR), ultrasound (US), and X-ray imaging. Pregnant patients who should be submitted for diagnostic examinations with contrast agents represent a group of patients with whom it is necessary to consider both maternal and fetal effects. Radiological examinations use different types of contrast media, the most used and studied are represented by iodinate contrast agents, gadolinium, fluorodeoxyglucose, gastrographin, bariumsulfate, and nanobubbles used in contrast-enhanced ultrasound (CEUS). The present paper reports the available data about each contrast agent and its effect related to the mother and fetus. This review aims to clarify the clinical practices to follow in cases where a radiodiagnostic examination with a contrast medium is indicated to be performed on a pregnant patient.

PN-HPT® (Polynucleotides Highly Purified Technology) in facial middle third rejuvenation. Exploring the potential.

BACKGROUND: Wasting of soft tissues leads to flattening and deflation of the aging midface skin. Polynucleotides Highly Purified Technology (PN-HPT® ) demonstrated dermal hydration and elasticity as well as fibroblasts vitality and activity. AIMS: To probe the value of PN-HPT® in middle third rejuvenation in an open-design, exploratory prospective cohort study in 40 real-life ambulatorily treated women. METHODS: Three treatment sessions-at baseline (2-ml prefilled syringe containing 10 mg/ml PN-HPT® , 10 mg/ml hyaluronic acid, 200 mM mannitol) as intradermic gel, and after 3 weeks (2-ml prefilled syringe containing 20 mg/ml PN-HPT® intradermic gel) and 6 weeks (same treatment as baseline). The protocol allowed supplemental treatment with specifically formulated PN-HPT® (7.5 mg/ml) when needed in periocular and eyelid areas. ASSESSMENTS: sequential photographs of the facial middle third at baseline, third treatment session and 6-8 weeks after the third treatment session; scoring of overall skin quality and texture, skin quality determinants (wrinkles and skin roughness, skin elasticity, skin brightness), scar appearance, and subjective satisfaction with impromptu 10-cm Visual Analogue Scales. RESULTS: Significant improvement of overall skin quality and texture (from 7.0 ± 1.06 at baseline session to 7.8 ± 0.99 at follow-up), associated with highly significant improvements of wrinkles and skin roughness, elasticity, and brightness (-17.1%, +39.6%, and +51.1%, respectively). The severity scores of post-acne scars decreased from 7.6 ± 1.32 to 4.2 ± 2.13. Individual satisfaction score at the end of treatment: 0.8 ± 0.28. CONCLUSIONS: PN-HPT® candidate as a valuable option for facial middle third rejuvenation. Further trials will hopefully confirm these early results.

Thymic Function and T-Cell Receptor Repertoire Diversity: Implications for Patient Response to Checkpoint Blockade Immunotherapy.

The capacity of T cells to recognize and mount an immune response against tumor antigens depends on the large diversity of the T-cell receptor (TCR) repertoire generated in the thymus during the process of T-cell development. However, this process is dramatically impaired by immunological insults, such as that caused by cytoreductive cancer therapies and infections, and by the physiological decline of thymic function with age. Defective thymic function and a skewed TCR repertoire can have significant clinical consequences. The presence of an adequate pool of T cells capable of recognizing specific tumor antigens is a prerequisite for the success of cancer immunotherapy using checkpoint blockade therapy. However, while this approach has improved the chances of survival of patients with different types of cancer, a large proportion of them do not respond. The limited response rate to checkpoint blockade therapy may be linked to a suboptimal TCR repertoire in cancer patients prior to therapy. Here, we focus on the role of the thymus in shaping the T-cell pool in health and disease, discuss how the TCR repertoire influences patients' response to checkpoint blockade therapy and highlight approaches able to manipulate thymic function to enhance anti-tumor immunity.

Targeting cancer stem cells in medulloblastoma by inhibiting AMBRA1 dual function in autophagy and STAT3 signalling.

Medulloblastoma (MB) is a childhood malignant brain tumour comprising four main subgroups characterized by different genetic alterations and rate of mortality. Among MB subgroups, patients with enhanced levels of the c-MYC oncogene (MBGroup3) have the poorest prognosis. Here we identify a previously unrecognized role of the pro-autophagy factor AMBRA1 in regulating MB. We demonstrate that AMBRA1 expression depends on c-MYC levels and correlates with Group 3 patient poor prognosis; also, knockdown of AMBRA1 reduces MB stem potential, growth and migration of MBGroup3 stem cells. At a molecular level, AMBRA1 mediates these effects by suppressing SOCS3, an inhibitor of STAT3 activation. Importantly, pharmacological inhibition of autophagy profoundly affects both stem and invasion potential of MBGroup3 stem cells, and a combined anti-autophagy and anti-STAT3 approach impacts the MBGroup3 outcome. Taken together, our data support the c-MYC/AMBRA1/STAT3 axis as a strong oncogenic signalling pathway with significance for both patient stratification strategies and targeted treatments of MBGroup3.

Maternal outcomes and risk factors for COVID-19 severity among pregnant women.

Pregnant women may be at higher risk of severe complications associated with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which may lead to obstetrical complications. We performed a case control study comparing pregnant women with severe coronavirus disease 19 (cases) to pregnant women with a milder form (controls) enrolled in the COVI-Preg international registry cohort between March 24 and July 26, 2020. Risk factors for severity, obstetrical and immediate neonatal outcomes were assessed. A total of 926 pregnant women with a positive test for SARS-CoV-2 were included, among which 92 (9.9%) presented with severe COVID-19 disease. Risk factors for severe maternal outcomes were pulmonary comorbidities [aOR 4.3, 95% CI 1.9-9.5], hypertensive disorders [aOR 2.7, 95% CI 1.0-7.0] and diabetes [aOR2.2, 95% CI 1.1-4.5]. Pregnant women with severe maternal outcomes were at higher risk of caesarean section [70.7% (n = 53/75)], preterm delivery [62.7% (n = 32/51)] and newborns requiring admission to the neonatal intensive care unit [41.3% (n = 31/75)]. In this study, several risk factors for developing severe complications of SARS-CoV-2 infection among pregnant women were identified including pulmonary comorbidities, hypertensive disorders and diabetes. Obstetrical and neonatal outcomes appear to be influenced by the severity of maternal disease.

Covid-19 in children: A brief overview after three months experience.

Severe Acute Respiratory Syndrome - Coronavirus - 2 (SARS-CoV-2) and its related Coronavirus Disease - 19 (COVID-19) has become a health emergency worldwide. The medical community has been concerned since the beginning of the outbreak about the potential impact of COVID-19 in children, especially in those with underlying chronic diseases. Fortunately, COVID-19 has been reported to be less severe in children than in adults. However, epidemiologic and clinical data are scarce. Children show unique features of SARS-CoV-2 involvement that may account for the low rate of infection and death in this age group. The purpose of this review is to summarize the most relevant evidence of COVID-19 in children highlighting similarities and differences with adults.

Valacyclovir in primary maternal CMV infection for prevention of vertical transmission: A case-series.

BACKGROUND: No treatment is currently approved for cytomegalovirus infection in pregnancy. Valacyclovir has been studied in symptomatic cytomegalovirus infected fetuses and seems to reduce the risk of serious sequelae. OBJECTIVES: We used off-label valacyclovir on pregnant women with primary cytomegalovirus infection to reduce the risk of fetal infection. STUDY DESIGN: We treated 12 pregnant women with 8 g/day valacyclovir after diagnosis of cytomegalovirus infection until amniocentesis. We continued treatment until delivery in case of fetal infection. We periodically performed serology and virology tests on the women from referral until delivery and monitored them for adverse effects while on treatment. All women underwent late amniocentesis. We followed up infants for 5-28 months. RESULTS: At the time of amniocentesis, we observed a transmission rate of 17 %, and at birth we observed a transmission rate of 42 %. Two women with negative amniocentesis and infected newborns had viremia reactivation after valacyclovir discontinuation. We observed no symptomatic infections at birth and one isolated sensory-neural hearing loss at follow-up. CONCLUSIONS: This is the first series of antiviral treatment in women with a diagnosis of cytomegalovirus infection before amniocentesis. Valacyclovir may control cytomegalovirus infection while it is administered and reduce transmission at amniocentesis. Late transmission after treatment discontinuation is a risk. We advocate the need for a controlled trial of valacyclovir therapy starting from diagnosis of maternal infection until delivery, regardless of prenatal diagnosis of infection.

Managing fertile women under lithium treatment: the challenge of a Teratology Information Service.

BACKGROUND: The objective of the present study is to review the literature regarding the management of fertile patients under lithium treatment for bipolar disorder and to report the experience of our Teratology Information Service over the past thirteen years in managing women treated with lithium during preconception, pregnancy and breastfeeding. METHODS: This research focuses on a selective review of the literature and a retrospective survey has been carried out on fertile women under lithium treatment who called our service at A. Gemelli University Hospital in Rome from May 2002 to December 2015. RESULTS: A total of 140 women under lithium treatment called our TIS. A complete follow-up has been performed on 34 patients: 29 called during pregnancy and 5 called during preconception. None of the patients called during breastfeeding, while half of the patients were taking concomitant drugs during pregnancy. One major cardiac malformation (hypoplastic left heart syndrome) has been reported. No minor malformations have been detected. Twenty-one patients delivered a living child, with one premature neonate. Two patients underwent voluntary interruption of pregnancy and six patients had early spontaneous abortion. In one patient, intrauterine growth retardation occurred, but with no adverse neonatal outcomes. Four neonates experienced transient respiratory distress at birth. Two children developed mild to severe language delay, but normal motor development. CONCLUSIONS: Lithium treatment in fertile women is a very delicate topic, where risks and benefits of discontinuing therapy when women plan to become pregnant should be accurately evaluated. Thorough peri-conceptional counselling is crucial for the outcome of pregnancy and for maternal health status during preconception, gestation and breastfeeding.

Chronic exposure to high doses of selenium in the first trimester of pregnancy: Case report and brief literature review.

BACKGROUND: Obstetricians usually prescribe supplements during pregnancy without actual indication. The use of selenium during pregnancy has increased, due to its function in several antioxidant mechanisms. CASE: A pregnant woman received 200,000 micrograms (µg) per day of a selenium galenic formulation, since gestational week (g.w.) 7 to 12, due to a prescription error. The patient experienced nausea, vomiting, hand and foot paresthesia, followed by fatigue, loss of fingernails and hair. The woman was referred to our Fetal and Maternal Medicine Unit for surveillance. The mother's blood selenium levels went back to normal 13 weeks after arrest and the baby was born at term, without complications. Clinical evaluation and imaging studies were normal at one month of age. CONCLUSION: This is the first case of severe chronic selenium intoxication during the first trimester of pregnancy. In the present case, no consequences of congenital defects or pregnancy complications occurred. However, since vitamins, minerals, and food supplements may be harmful and prescription errors occur, obstetricians should avoid prescribing supplements in the absence of maternal deficiency.

Glaucoma Drug Therapy in Pregnancy: Literature Review and Teratology Information Service (TIS) Case Series.

BACKGROUND: There are many contradictions about pregnancy and fetal/neonatal outcomes after topical use of timolol alone or timolol in combination with other antiglaucoma medications. METHODS: Seventy-five pregnant women exposed to antiglaucoma medications were followed prospectively by phone interviews. 27 women used timolol as monotherapy, 48 women used timolol as a part of multidrug therapy. We selected a control group of 187 healthy pregnant women. RESULTS: Topical use of timolol alone or timolol in combination with other antiglaucoma medications does not influence pregnancy or fetal/neonatal outcomes. CONCLUSION: Beta-blocker is the first choice treatment for glaucoma in pregnancy but, when necessary, multidrug therapy should not to be excluded.

Screening and management of maternal colonization with Streptococcus agalactiae: an Italian cohort study.

INTRODUCTION: Streptococcus agalactiae (Group B streptococcus [GBS]) is the most common cause of sepsis and meningitis in infants <3 months of age. Intrapartum antibiotic prophylaxis (IAP) is effective in preventing the transmission of GBS to newborns. The Centers for Disease Control and Prevention (CDC) guidelines suggest vaginal and rectal cultures to assess GBS colonization between 35 and 37 weeks' gestation. METHODS: Between July and December 2013, we identified 535 women admitted to the Obstetric and Gynecology Unit of Cardarelli Hospital (Campobasso, Italy) for delivery. We evaluated the indications for IAP, complete execution of IAP, and neonatal outcomes. RESULTS: Our sample included 468 women and 475 live births. Correct screening for GBS was executed in 241 cases (51.5%), the number of women colonized was 96 (30.2%), and 136 women had indications to receive IAP, but only 68 (50%) received adequate treatment. CONCLUSIONS: GBS colonization status should be determined by collecting both vaginal and rectal specimens at 35-37 weeks' gestation. Inadequate screening for GBS and incorrect IAP led to an increased incidence of early-onset disease in newborns. Local public health agencies should promote surveillance and educational programs to prevent neonatal GBS infections.

Folic acid use in planned pregnancy: an Italian survey.

It is well known that periconceptional folic acid supplementation decreases the risk of neural tube defects. The aim of this study was to evaluate the attitudes and practices of women with planned pregnancies regarding periconceptional folic acid intake and to identify factors associated with the use of this supplement. During 2 years of observation, we surveyed women with planned pregnancies who called our Teratology Information Service. A total of 500 women were surveyed: 217 (43.4%) took folic acid before becoming pregnant, and 283 (56.6%) did not take it. The women who took folic acid before becoming pregnant had a high education level and received preconception counselling. Our results suggest that less than half of Italian women took folic acid before they became pregnant although they were trying to conceive. Knowledge about the benefits of this vitamin is inadequate also among women who planned the pregnancy and the level of information received from their physicians.

Syphilis Infection during pregnancy: fetal risks and clinical management.

Congenital syphilis is still a cause of perinatal morbidity and mortality. Untreated maternal infection leads to adverse pregnancy outcomes, including early fetal loss, stillbirth, prematurity, low birth weight, neonatal and infant death, and congenital disease among newborns. Clinical manifestations of congenital syphilis are influenced by gestational age, stage of maternal syphilis, maternal treatment, and immunological response of the fetus. It has been traditionally classified in early congenital syphilis and late congenital syphilis. Diagnosis of maternal infection is based on clinical findings, serological tests, and direct identification of treponemes in clinical specimens. Adequate treatment of maternal infection is effective for preventing maternal transmission to the fetus and for treating fetal infection. Prenatal diagnosis of congenital syphilis includes noninvasive and invasive diagnosis. Serological screening during pregnancy and during preconception period should be performed to reduce the incidence of congenital syphilis.

Clopidogrel treatment during pregnancy: a case report and a review of literature.

Management of ischemic heart disease in pregnant women is still difficult, as there is little experience with many of the newer treatments such as clopidogrel. The safety of clopidogrel in pregnancy is unknown, especially in combination with aspirin. Its use during gestation has been described in a few case reports. We describe the case of a 36-year-old woman in her 9th week of pregnancy with a history of chronic hypertension, dyslipidemia and CAD, who required antiplatelet treatment. Clopidogrel and aspirin were administrated until one week before delivery and a healthy child was born at 36 weeks of pregnancy by caesarean section, without any complication.

Smoke, alcohol consumption and illicit drug use in an Italian population of pregnant women.

OBJECTIVE: High-risk behaviours are associated with an increased risk of adverse pregnancy outcomes. Exposure to drugs, infection or radiation is a cause of concern for pregnant women, who contact Teratology Information Services (TIS) to have a counseling but with an accurate medical history is possible to detect additional behavioural risk factors that can significantly interfere with pregnancy outcome. The aim of this study is to describe risk behaviours in a population of Italian women calling our TIS and to identify related maternal factors. STUDY DESIGN: Between December 2008 and January 2010 we collected data from 503 pregnant women calling our TIS (Telefono Rosso, Rome). We investigated about smoke, alcohol and abuse substances addiction and we also collected demographic data. RESULTS: Of the 503 women consenting to participate 34% were found to have an additional risk marker during the current pregnancy. Within this group were 22.7% (n=119) who reported smoking, the 17.7% (n=89) admitted to drink and 2 women (0.4%) used illicit drugs. In 13.7% of cases (n=69) reason for calling represented an exposure to teratogenic agents. Unmarried status and previous induced abortion represent a risk factor for all high-risk behaviours. Lower education (p<0.001) and use of neurological drugs (p<0.001) are related with cigarette consumption. A lower parity was a risk factor for alcohol assumption (p=0.04). Women with high-risk behaviours tend to be exposed to more than a risk factor. CONCLUSIONS: Teratogen Information Services are an important system to identify women with pregnancy risk markers. These services should have the ability to provide risk reduction information to women who smoke cigarettes or with alcohol or drug use. In addition to the phone based information these women may benefit from referral back to their physician for assessment and management of substance use/abuse during pregnancy. Substance abuse risks are often underestimated by pregnant women. Single mothers or women with an history of terminations of pregnancy represents an high-risk population. Physicians should inform their patients about possible risks related to high-risk behaviours during preconception counseling or during the first obstetric visit.

Antiepileptic drugs during pregnancy: pharmacokinetics and transplacental transfer.

Epilepsy represents the most common maternal neurological disorder requiring continuous treatment during pregnancy. Maintaining optimum seizure control is an important objective in pregnancy, and the majority of women with epilepsy will need to continue antiepileptic drugs (AEDs). AEDs are frequently used to treat several other conditions, such as headaches and mood disorders. They have been associated with an increased risk of congenital malformations, minor anomalies, congenital syndrome and development disorders. This risk seems to be higher among women using polypharmacy and valproic acid. Neural tube defects are associated with valproic acid and carbamazepine exposure. New AEDs seem to have a less teratogenic effect, but human experience is still limited. The purpose of this review is to provide an update on AED exposure in pregnancy, focusing on pharmacokinetics and transplacental transport.

Use of the Internet by women seeking information about potentially teratogenic agents.

OBJECTIVE: The aim of this study was to evaluate if the Internet provides evidence-based information to women seeking information about teratogenic risk factors and women's risk perception. Furthermore, we evaluated the possible risk related to teratogen exposure in the study sample and analysed age, gravidity, educational level, geographic location, marital status and type of exposure compared to a control group made up of women who did not use the Internet to search for teratogen-related information. STUDY DESIGN: Between October 2008 and June 2009, a questionnaire was administered to pregnant women calling our Teratology Information Service concerning a suspected teratogenic exposure. RESULTS: Fifty-seven percent (n=116) of callers had used the Internet to find medical information about their exposure, while 43% (n=87) had not. Internet users had a medium-high level of education and consulted the Internet because of its convenience, usually early in their pregnancy. We verified the accuracy of the information the women obtained from the Internet and found that 59.5% (n=69) of women received evidence-based answers; 18.1% (n=21) were informed that their exposure was dangerous when it was not; 4.3% (n=5) were wrongly reassured; and the rest (n=18) were not able to interpret the data they found or found no relevant information. CONCLUSIONS: Internet use during pregnancy is a widespread phenomenon as the Internet offers the opportunity to share apprehensions and doubts with other women, but it can often lead to increased and unjustified anxiety. Medical information published on websites cannot be considered a substitute for informed medical advice, and patients should not take any action before consulting with a health care professional.