Crimean-Congo hemorrhagic fever virus (CCHFV) is a tick-borne nairovirus with a wide geographic spread that can cause severe and lethal disease. No specific medical countermeasures are approved to combat this illness. The CCHFV L protein contains an ovarian tumor (OTU) domain with a cysteine protease thought to modulate cellular immune responses by removing ubiquitin and ISG15 post-translational modifications from host and viral proteins. Viral deubiquitinases like CCHFV OTU are attractive drug targets, as blocking their activity may enhance cellular immune responses to infection, and potentially inhibit viral replication itself. We previously demonstrated that the engineered ubiquitin variant CC4 is a potent inhibitor of CCHFV replication in vitro. A major challenge of the therapeutic use of small protein inhibitors such as CC4 is their requirement for intracellular delivery, e.g., by viral vectors. In this study, we examined the feasibility of in vivo CC4 delivery by a replication-deficient recombinant adenovirus (Ad-CC4) in a lethal CCHFV mouse model. Since the liver is a primary target of CCHFV infection, we aimed to optimize delivery to this organ by comparing intravenous (tail vein) and intraperitoneal injection of Ad-CC4. While tail vein injection is a traditional route for adenovirus delivery, in our hands intraperitoneal injection resulted in higher and more widespread levels of adenovirus genome in tissues, including, as intended, the liver. However, despite promising in vitro results, neither route of in vivo CC4 treatment resulted in protection from a lethal CCHFV infection.

UNASSIGNED: Twin pregnancy is associated with higher risks of adverse perinatal outcomes for both the mother and the babies. Among the many challenges in the follow-up of twin pregnancies, the mode of delivery is the last but not the least decision to be made, with the main influencing factors being amnionicity and fetal presentation. The aim of the study was to compare perinatal outcomes in two European centers using different protocols for twin birth in case of non-cephalic second twin; the Italian patients being delivered mainly by cesarean section with those in Belgium being routinely offered the choice of vaginal delivery (VD).
UNASSIGNED: This was a dual center international retrospective observational study. The population included 843 women with a twin pregnancy ≥ 32 weeks (dichorionic or monochorionic diamniotic pregnancies) and a known pregnancy outcome. The population was stratified according to chorionicity. Demographic and pregnancy data were reported per pregnancy, whereas neonatal outcomes were reported per fetus. We used multiple logistic regression models to adjust for possible confounding variables and to compute the adjusted odds ratio (adjOR) for each maternal or neonatal outcome.
UNASSIGNED: The observed rate of cesarean delivery was significantly higher in the Italian cohort: 85% for dichorionic pregnancies and 94.4% for the monochorionic vs 45.2% and 54.4% respectively in the Belgian center (p-value < 0.001). We found that Belgian cohort showed significantly higher rates of NICU admission, respiratory distress at birth and Apgar score of < 7 after 5 min. Despite these differences, the composite severe adverse outcome was similar between the two groups.
UNASSIGNED: In this study, neither the presentation of the second twin nor the chorionicity affected maternal and severe neonatal outcomes, regardless of the mode of delivery in two tertiary care centers, but VD was associated to a poorer short-term neonatal outcome.

Neurodevelopment is a highly organized and complex process involving lasting and often irreversible changes in the central nervous system. Inherited disorders of neurotransmission (IDNT) are a group of genetic disorders where neurotransmission is primarily affected, resulting in abnormal brain development from early life, manifest as neurodevelopmental disorders and other chronic conditions. In principle, IDNT (particularly those of monogenic causes) are amenable to gene replacement therapy via precise genetic correction. However, practical challenges for gene replacement therapy remain major hurdles for its translation from bench to bedside. We discuss key considerations for the development of gene replacement therapies for IDNT. As an example, we describe our ongoing work on gene replacement therapy for succinic semialdehyde dehydrogenase deficiency, a GABA catabolic disorder.

BACKGROUND: Transplantation of neural stem cells improves ischemic stroke outcomes in rodent models and is currently in the clinical test stage. However, the optimal delivery route to achieve improved efficacy remains undetermined.
OBJECTIVE: This study aims to evaluate three more clinically feasible delivery routes: intravenous (IV), intranasal (IN), and intracerebroventricular (ICV). We compared the therapeutic efficacies of the three routes of transplanting human neural stem cells (hNSCs) into mice with permanent middle cerebral artery obstruction (pMCAO).
METHODS: Behavioral tests and cresyl violet staining were used to evaluate the therapeutic efficacies of functional recovery and lesion volumes. The expression of proinflammatory cytokines and neurotrophic factors was measured by real-time PCR. The distribution and differentiation of hNSCs were determined by immunofluorescence staining. The effect on endogenous neurogenesis and astrocyte function were determined by immunofluorescence staining and western blot.
RESULTS: hNSC transplantation using the three routes improved behavioral outcomes and reduced lesion volumes; IV transplantation of hNSCs results in earlier efficacy and improves the inflammatory microenvironment. The long-term distribution and differentiation of transplanted hNSCs in the peri-infarct areas can only be evaluated using ICV delivery. IV and ICV transplantation of hNSCs promote neurogenesis and modulate the dual function of astrocytes in the peri-infarct areas.
CONCLUSIONS: IV and IN delivery is suitable for repeated administration of hNSCs to achieve improved prognosis. Comparatively, ICV transplantation provides long-term efficacy at lower doses and fewer administration times.

Sensorineural hearing loss (SNHL), a highly prevalent sensory impairment, results from a multifaceted interaction of genetic and environmental factors. As we continually gain insights into the molecular basis of auditory development and the growing compendium of deafness genes identified, research on gene therapy for SNHL has significantly deepened. Adeno-associated virus (AAV), considered a relatively secure vector for gene therapy in clinical trials, can deliver various transgenes based on gene therapy strategies such as gene replacement, gene silencing, gene editing, or gene addition to alleviate diverse types of SNHL. This review delved into the preclinical advances in AAV-based gene therapy for SNHL, spanning hereditary and acquired types. Particular focus is placed on the dual-AAV construction method and its application, the vector delivery route of mouse inner ear models (local, systemic, fetal, and cerebrospinal fluid administration), and the significant considerations in transforming from AAV-based animal model inner ear gene therapy to clinical implementation.

OBJECTIVE: The HPA-axis is programmed during early infancy, but a lot is unknown about the programming of the HPA-axis in prematurely born or small for gestational age (SGA) children. Therefore, the aim of this preliminary study was to investigate the influence of prematurity and variables associated with birth on cortisol levels in young children.
METHODS: Cortisol was measured in a cross-sectional design in 38 premature born participants (<37 weeks of gestation), aged between 3 - 9 years old. Correlates of prematurity (degree of prematurity and birth delivery route) were investigated in relationship with cortisol levels with regression analysis.
RESULTS: Corrected for sex, delivery by C-section was associated with lower cortisol levels in the children (ß = -.42, p = .028), with an explained variance of 34%.
CONCLUSIONS: Birth delivery route by C-section is associated with lowered (or flattened) cortisol levels in children born prematurely. This is clinically relevant and might have important implications, because an HPA-axis disturbance might lead to developmental problems later on in life. However, future research is necessary to investigate the underlying indications for performing a C-section, which will help to understand factors that influence the HPA-axis development in children born prematurely.

Efficient delivery of therapeutics across the blood-brain barrier (BBB) for the treatment of central nervous system (CNS) tumors is a major challenge to the development of safe and efficacious therapies. Locoregional drug delivery platforms offer an improved therapeutic index by achieving high drug concentrations in the target tissue with negligible systemic exposure. Intrathecal (intraventricular) [IT] and convection-enhanced delivery [CED] are two clinically relevant methods being employed for various CNS malignancies. Both of these standalone platforms suffer from passive post-administration distribution forces, sometimes limiting the desired distribution for tumor therapy. Focused ultrasound and microbubble-mediated blood-brain barrier opening (FUS-BBBO) is a recent modality used for enhanced drug delivery. It is postulated that coupling of FUS with these alternative delivery routes may provide benefits. Multimodality FUS may provide the desired ability to increase the depth of parenchymal delivery following IT administration and provide a means for contour directionality with CED. Further, the transient enhanced permeability achieved with FUS-BBBO is well established, but drug residence and transit times, important to clinical dose scheduling, have not yet been defined. The present investigation comprises two discrete studies: 1. Conduct a comprehensive quantitative evaluation to elucidate the effect of FUS-BBBO as it relates to varying routes of administration (IT and IV) in its capacity to facilitate drug penetration within the striatal-thalamic region. 2. Investigate the impact of combining FUS-BBBO with CED on drug distribution, with a specific focus on the temporal dynamics of drug retention within the target region.
Firstly, we quantitatively assessed how FUS-BBBO coupled with IT and IV altered fluorescent dye (Dextran 2000 kDa and 70 kDa) distribution and concentration in a predetermined striatal-thalamic region in naïve mice. Secondly, we analyzed the pharmacokinetic effects of using FUS mediated BBB disruption coupled with CED by measuring the volume of distribution and time-dependent concentration of the dye.
Our results indicate that IV administration coupled with FUS-BBBO successfully enhances delivery of dye into the pre-defined sonication targets. Conversely, measurable dye in the sonication target was consistently less after IT administration. FUS enhances the distribution volume of dye after CED. Furthermore, a shorter time of residence was observed when CED was coupled with FUS-BBBO application when compared to CED alone.
1. Based on our findings, IV delivery coupled with FUS-BBBO is a more efficient means for delivery to deep targets (i.e. striatal-thalamic region) within a predefined spatial conformation compared to IT administration. 2. FUS-BBBO increases the volume of distribution (Vd) of dye after CED administration, but results in a shorter time of residence. Whether this finding is reproducible with other classes of agents (e.g., cytotoxic agents, antibodies, viral particles, cellular therapies) needs to be studied.

Mesenchymal stem cells (MSCs) are novel, promising agents for treating ocular surface disorders. MSCs can be isolated from several tissues and delivered by local or systemic routes. They produce several trophic factors and cytokines, which affect immunomodulatory, transdifferentiating, angiogenic, and pro-survival pathways in their local microenvironment via paracrine secretion. Moreover, they exert their therapeutic effect through a contact-dependent manner.
In this review, we discuss the characteristics, sources, delivery methods, and applications of MSCs in ocular surface disorders. We also explore the potential application of MSCs to inhibit senescence at the ocular surface.
Therapeutic application of MSCs in ocular surface disorders are currently under investigation. One major research area is corneal epitheliopathies, including chemical or thermal burns, limbal stem cell deficiency, neurotrophic keratopathy, and infectious keratitis. MSCs can promote corneal epithelial repair and prevent visually devastating sequelae of non-healing wounds. However, the optimal dosages and delivery routes have yet to be determined and further clinical trials are needed to address these fundamental questions.

BACKGROUND: Medical literature supports planned cesarean delivery for breech presentation at term because of observed reductions in neonatal morbidity and mortality compared with vaginal breech delivery.
OBJECTIVE: This study aimed to compare perinatal outcomes of singleton pregnancies with breech presentation at term according to the different delivery protocols of 2 teaching hospitals, where vaginal breech delivery (protocol 1) or cesarean delivery (protocol 2) is routinely offered, respectively.
METHODS: A retrospective matched cohort study was conducted between January 2015 and May 2021. A total of 1079 women were eligible for analysis. After matching for possible confounding factors, the final analysis was performed on 257 patients in each group. The primary outcomes were a composite of adverse obstetrical outcomes and a composite of neonatal adverse outcomes.
RESULTS: Overall, 1079 women were eligible for analysis. After matching for possible confounding factors, the final analysis was performed on 257 patients in each group. The composite of adverse obstetrical outcomes was similar in the 2 groups (24.1% vs 24.5%; P=1.000); however, the composite of neonatal adverse outcomes was significantly higher for protocol 1 (17.9% vs 1.2%; P<.001). No neonatal death or birth trauma was reported in either group. The rates of neonatal intensive care unit admission (4.3% vs 0.4%; P=.004), respiratory distress at birth (17.5% vs 1.2%; P<.001), and Apgar scores of <7 after 5 minutes (5.8% vs 0.4%; P<.001) were significantly higher for protocol 1.
CONCLUSIONS: Short-term, nonsevere adverse neonatal outcomes were significantly increased in the protocol 1 group. These must be balanced against the possible negative effects of cesarean delivery on long-term infant and maternal health.

mRNA vaccines have been revolutionary in combating the COVID-19 pandemic in the past two years. They have also become a versatile tool for the prevention of infectious diseases and treatment of cancers. For effective vaccination, mRNA formulation, delivery method and composition of the mRNA carrier play an important role. mRNA vaccines can be delivered using lipid nanoparticles, polymers, peptides or naked mRNA. The vaccine efficacy is influenced by the appropriate delivery materials, formulation methods and selection of a proper administration route. In addition, co-delivery of several mRNAs could also be beneficial and enhance immunity against various variants of an infectious pathogen or several pathogens altogether. Here, we review the recent progress in the delivery methods, modes of delivery and patentable mRNA vaccine technologies.