Evaluating the impact of HIV pre-exposure prophylaxis on pregnancy, infant, and maternal health outcomes in Malawi: PrIMO study protocol.

BACKGROUND: Incident HIV during the perinatal period significantly impedes elimination of Mother-to-Child HIV Transmission (eMTCT) efforts. Pre-Exposure Prophylaxis (PrEP) effectively reduces HIV acquisition, and new agents like injectable Cabotegravir (CAB-LA) offer potential advantages for pregnant and breastfeeding women. The Pregnancy, Infant, and Maternal health Outcomes (PrIMO) study will compare rates of composite adverse pregnancy outcomes, and infant adverse events, growth and neurodevelopment between mother-infant dyads receiving CAB-LA and those receiving oral PrEP in Malawi. METHODS: PrIMO is an observational cohort study involving: (1) the development of a PrEP Pregnancy Registry for longitudinal surveillance of pregnant women on PrEP in Malawi; and (2) the enrolment of a prospective safety cohort of 621 pregnant women initiating oral PrEP or CAB-LA and their subsequent infants. The registry will include all women continuing or initiating PrEP during pregnancy across targeted sites in Lilongwe and Blantyre districts. The safety cohort will enrol a subset of those women and their infants from Bwaila District Hospital in Lilongwe, Malawi. We hypothesize that CAB-LA's safety will be comparable to daily oral PrEP regarding adverse pregnancy outcomes, maternal/infant adverse events, and infant development. Participants in the cohort will choose either oral PrEP or CAB-LA and will be followed until 52 weeks post-delivery. Safety data will be collected from all mother-infant pairs and qualitative interviews will be conducted with a subset of purposively selected women (n = 50) to assess the acceptability of each PrEP modality. DISCUSSION: The PrIMO study will provide critical data on the safety of CAB-LA in pregnant and breastfeeding women and their infants. Results will guide clinical recommendations as the Malawi Ministry of Health prepares for the rollout of CAB-LA to this population. Evaluation of Registry implementation will inform its expansion to a nationwide safety monitoring system for PrEP use during pregnancy, with implications for similar systems in the region. TRIAL REGISTRATION NUMBER: NCT06158126. The study was prospectively registered (5 December 2023) in ClinicalTrials.gov.

Low Contrast Acuity Outcomes After SMILE and LASIK.

PURPOSE: To compare early visual quality of small incision lenticule extraction (SMILE) versus laser in situ keratomileusis (LASIK) in terms of low contrast acuity. METHODS: A secondary analysis was performed using a harmonized dataset derived from two completed prospective cohort studies on active-duty military service members undergoing either SMILE (n = 37), wavefront-guided (WFG) LASIK (n = 51), or wavefront-optimized (WFO) LASIK (n = 56). Night vision and photopic and mesopic low contrast visual acuity (LCVA) up to 3 months postoperatively were compared between groups. RESULTS: Compared to SMILE-treated eyes, WFG LASIK-treated eyes had significantly better night vision and photopic LCVA at 1 month postoperatively (beta = -0.039, P = .016; beta = -0.043, P = .007, respectively). WFO LASIK-treated eyes had significantly better photopic LCVA at 1 month postoperatively (beta = -0.039, P = .012) but had worse mesopic LCVA at 3 months postoperatively (beta = 0.033, P = .015) versus SMILE-treated eyes. CONCLUSIONS: SMILE and LASIK, on either a WFG or WFO laser platform, yielded excellent outcomes, but LCVA seemed to recover quicker following LASIK compared to SMILE. [J Refract Surg. 2024;40(9):e667-e671.].

Expanding density-correlation machine learning representations for anisotropic coarse-grained particles.

Physics-based, atom-centered machine learning (ML) representations have been instrumental to the effective integration of ML within the atomistic simulation community. Many of these representations build off the idea of atoms as having spherical, or isotropic, interactions. In many communities, there is often a need to represent groups of atoms, either to increase the computational efficiency of simulation via coarse-graining or to understand molecular influences on system behavior. In such cases, atom-centered representations will have limited utility, as groups of atoms may not be well-approximated as spheres. In this work, we extend the popular Smooth Overlap of Atomic Positions (SOAP) ML representation for systems consisting of non-spherical anisotropic particles or clusters of atoms. We show the power of this anisotropic extension of SOAP, which we deem AniSOAP, in accurately characterizing liquid crystal systems and predicting the energetics of Gay-Berne ellipsoids and coarse-grained benzene crystals. With our study of these prototypical anisotropic systems, we derive fundamental insights on how molecular shape influences mesoscale behavior and explain how to reincorporate important atom-atom interactions typically not captured by coarse-grained models. Moving forward, we propose AniSOAP as a flexible, unified framework for coarse-graining in complex, multiscale simulation.

Neuroprotection of low dose carbon monoxide in Parkinson's disease models commensurate with the reduced risk of Parkinson's among smokers.

Paradoxically, cigarette smoking is associated with a reduced risk of Parkinson's Disease (PD). This led us to hypothesize that carbon monoxide (CO) levels, which are constitutively but modestly elevated in smokers, might contribute to neuroprotection. Using rodent models of PD based on α-synuclein (αSyn) accumulation and oxidative stress, we show that low-dose CO mitigates neurodegeneration and reduces αSyn pathology. Oral CO administration activated signaling cascades mediated by heme oxygenase-1 (HO-1), which have been implicated in limiting oxidative stress, and in promoting αSyn degradation, thereby conferring neuroprotection. Consistent with the neuroprotective effect of smoking, HO-1 levels in cerebrospinal fluid were higher in human smokers compared to nonsmokers. Moreover, in PD brain samples, HO-1 levels were higher in neurons without αSyn pathology. Thus, CO in rodent PD models reduces pathology and increases oxidative stress responses, phenocopying possible protective effects of smoking evident in PD patients. These data highlight the potential for low-dose CO-modulated pathways to slow symptom onset and limit pathology in PD patients.

Cytotoxic and radical activities of metal-organic framework modified with iron oxide: Biological and physico-chemical analyses.

Metal-organic framework (MOF) modified with iron oxide, Fe3O4-MOF, is a perspective drug delivery agent, enabling magnetic control and production of active hydroxyl radicals, •OH, via the Fenton reaction. This paper studies cytotoxic and radical activities of Fe-containing nanoparticles (NPs): Fe3O4-MOF and its components - bare Fe3O4 and MOF (MIL-88B). Luminous marine bacteria Photobacteriumphosphoreum were used as a model cellular system to monitor bioeffects of the NPs. Neither the NPs of Fe3O4-MOF nor MOF showed cytotoxic effects in a wide range of concentrations (<10 mg/L); while Fe3O4 was toxic at >3·10-3 mg/L. The NPs of Fe3O4 did not affect the bacterial bioluminescence enzymatic system; their toxic effect was attributed to cellular membrane processes. The integral content of reactive oxygen species (ROS) was determined using a chemiluminescence luminol assay. Bacteria mitigated excess of ROS in water suspensions of Fe3O4-MOF and MOF, maintaining bioluminescence intensity closer to the control; this resulted in low toxicity of these NPs. We estimated the activity of •OH radicals in the NPs samples with physical and chemical methods - spin capture technology (using electron paramagnetic resonance spectroscopy) and methylene blue degradation. Physico-chemical interpretation of cellular responses is provided in terms of iron content, iron ions release and •OH radical production.

Continuing benefits of the Montreal Protocol and protection of the stratospheric ozone layer for human health and the environment.

The protection of Earth's stratospheric ozone (O3) is an ongoing process under the auspices of the universally ratified Montreal Protocol and its Amendments and adjustments. A critical part of this process is the assessment of the environmental issues related to changes in O3. The United Nations Environment Programme's Environmental Effects Assessment Panel provides annual scientific evaluations of some of the key issues arising in the recent collective knowledge base. This current update includes a comprehensive assessment of the incidence rates of skin cancer, cataract and other skin and eye diseases observed worldwide; the effects of UV radiation on tropospheric oxidants, and air and water quality; trends in breakdown products of fluorinated chemicals and recent information of their toxicity; and recent technological innovations of building materials for greater resistance to UV radiation. These issues span a wide range of topics, including both harmful and beneficial effects of exposure to UV radiation, and complex interactions with climate change. While the Montreal Protocol has succeeded in preventing large reductions in stratospheric O3, future changes may occur due to a number of natural and anthropogenic factors. Thus, frequent assessments of potential environmental impacts are essential to ensure that policies remain based on the best available scientific knowledge.

Development of a sampling protocol for collecting leaf surface material for multiphase chemistry studies.

Plant leaves and water drops residing on them interact with atmospheric oxidants, impacting the deposition and emission of trace gases and mediating leaf damage from air pollution. Characterizing the chemical composition and reactivity of the water-soluble material on leaf surfaces is thus essential for improving our understanding of atmosphere-biosphere interactions. However, the limited knowledge of sources and nature of these chemicals challenges sampling decisions. This work investigates how sampling variables and environmental factors impact the quantity and composition of water-soluble material sampled from wet leaves and proposes a flexible protocol for its collection. The ratio of solvent volume-to-leaf area, the solvent-to-leaf contact time, and environmental parameters - including the occurrence of rain, plant location and its metabolism - drive solute concentration in leaf soaks. Despite minor variations, UV-vis absorption spectra of leaf soaks are comparable to authentic raindrops collected from the same tree and share features with microbial dissolved organic matter - including overall low aromaticity, low chromophore content, and low average molecular weight. In addition to guiding the development of a sampling protocol, our data corroborate recent hypotheses on the amount, origin, nature, and reactivity of water-soluble organics on wet leaves, providing new directions of research into this highly interdisciplinary topic.

The rule of four: anomalous distributions in the stoichiometries of inorganic compounds.

Why are materials with specific characteristics more abundant than others? This is a fundamental question in materials science and one that is traditionally difficult to tackle, given the vastness of compositional and configurational space. We highlight here the anomalous abundance of inorganic compounds whose primitive unit cell contains a number of atoms that is a multiple of four. This occurrence-named here the rule of four-has to our knowledge not previously been reported or studied. Here, we first highlight the rule's existence, especially notable when restricting oneself to experimentally known compounds, and explore its possible relationship with established descriptors of crystal structures, from symmetries to energies. We then investigate this relative abundance by looking at structural descriptors, both of global (packing configurations) and local (the smooth overlap of atomic positions) nature. Contrary to intuition, the overabundance does not correlate with low-energy or high-symmetry structures; in fact, structures which obey the rule of four are characterized by low symmetries and loosely packed arrangements maximizing the free volume. We are able to correlate this abundance with local structural symmetries, and visualize the results using a hybrid supervised-unsupervised machine learning method.

4-Amidophenol Quinone Methide Precursors: Effective and Broad-Scope Nonoxime Reactivators of Organophosphorus-Inhibited Cholinesterases and Resurrectors of Organophosphorus-Aged Acetylcholinesterase.

Acetylcholinesterase (AChE) inhibition by organophosphorus (OP) compounds poses a serious health risk to humans. While many therapeutics have been tested for treatment after OP exposure, there is still a need for efficient reactivation against all kinds of OP compounds, and current oxime therapeutics have poor blood-brain barrier penetration into the central nervous system, while offering no recovery in activity from the OP-aged forms of AChE. Herein, we report a novel library of 4-amidophenol quinone methide precursors (QMP) that provide effective reactivation against multiple OP-inhibited forms of AChE in addition to resurrecting the aged form of AChE after exposure to a pesticide or some phosphoramidates. Furthermore, these QMP compounds also reactivate OP-inhibited butyrylcholinesterase (BChE) which is an in vivo, endogenous scavenger of OP compounds. The in vitro efficacies of these QMP compounds were tested for reactivation and resurrection of soluble forms of human AChE and BChE and for reactivation of cholinesterases within human blood as well as blood and brain samples from a humanized mouse model. We identify compound 10c as a lead candidate due to its broad-scope efficacy against multiple OP compounds as well as both cholinesterases. With methylphosphonates, compound 10c (250 µM, 1 h) shows >60% recovered activity from OEt-inhibited AChE in human blood as well as mouse blood and brain, thus highlighting its potential for future in vivo analysis. For 10c, the effective concentration (EC50) is less than 25 µM for reactivation of three different methylphosphonate-inhibited forms of AChE, with a maximum reactivation yield above 80%. Similarly, for OP-inhibited BChE, 10c has EC50 values that are less than 150 µM for two different methylphosphonate compounds. Furthermore, an in vitro kinetic analysis show that 10c has a 2.2- and 92.1-fold superior reactivation efficiency against OEt-inhibited and OiBu-inhibited AChE, respectively, when compared to an oxime control. In addition to 10c being a potent reactivator of AChE and BChE, we also show that 10c is capable of resurrecting (ethyl paraoxon)-aged AChE, which is another current limitation of oximes.

Redefine photoprotection: Sun protection beyond sunburn.

Excessive exposure to ultraviolet (UV) light leads to acute and chronic UV damage and is the main risk factor for the development of skin cancer. In most countries with western lifestyle, the topical application of sunscreens on UV-exposed skin areas is by far the most frequently used preventive measure against sunburn. Further than preventing sunburns, increasing numbers of consumers are appreciating sunscreens with a medium- to high-level sun protective factor (SPF) as basis for sustainable-skin ageing or skin cancer prevention programs. However, recent investigations indicate that clinically significant DNA damages as well as a lasting impairment of cutaneous immunosurveillance already occur far below the standard of one minimal erythema dose (MED) sunburn level, which contributes to the current discussion of the clinical value of high-protective SPF values. Ex vivo investigations on human skin showed that the application of SPF30 reduces DNA damage for a day long sun exposure (24 MED) drastically by about 53% but is significantly surpassed by SPF100 reducing DNA damage by approx. 73%. Further analysis on different SPF protection levels in UV-exposed cell culture assays focusing on IL-18, cell vitality and cis/trans-urocanic acid support these findings. Whereas SPF30 and SPF50+ sunscreens already offer a solid UVB cover for most indications, our results indicate that SPF100 provides significant additional protection against mutagenic (non-apoptotic-) DNA damage and functional impairment of the cutaneous immunosurveillance and therefore qualifies as an optimized sunscreen for specifically vulnerable patient groups such as immunosuppressed patients, or skin cancer patients.

Placental Lesions Associated With Stillbirth by Gestational Age, as Related to Cause of Death: Follow-Up Results From the Stillbirth Collaborative Research Network.

BACKGROUND: We previously identified placental lesions associated with stillbirths of varying gestational ages (GA) using advanced feature analysis. We further investigated the relationships between placental lesions and cause of death in stillbirths within these GA ranges. METHODS: Using data from the Stillbirth Collaborative Research Network, we derived a sample of stillbirths who underwent placental examination and Initial Causes of Fetal Death (INCODE) evaluation for determining cause of death. We then compared the rates of causes of death within and among GA ranges (extreme preterm stillbirth [PTSB] [<28 weeks], early PTSB [28-336/7 weeks], late PTSB [34-366/7 weeks], term stillbirth [≥37 weeks]) according to the presence of these lesions. RESULTS: We evaluated 352 stillbirths. In extreme PTSB, obstetric complications and infections were associated with acute funisitis. In early PTSB, uteroplacental insufficiency was associated with parenchymal infarcts. In term stillbirth (vs early PTSB), increased syncytial knots were associated with umbilical cord causes and infection. CONCLUSIONS: Placental lesions of high importance in distinguishing stillbirths at different GAs are associated with specific causes of death. This information is important in relating the presence of placental lesions and fetal death and in helping to understand etiologies of stillbirths at different GAs.

Neuroprotection of low dose carbon monoxide in Parkinson's disease models commensurate with the reduced risk of Parkinson's among smokers.

Paradoxically, cigarette smoking is associated with a reduced risk of Parkinson's disease (PD). This led us to hypothesize that carbon monoxide (CO) levels, which are constitutively but modestly elevated in smokers, might contribute to neuroprotection. Using rodent models of PD based on α-synuclein (αSyn) accumulation and oxidative stress, we show that low-dose CO mitigates neurodegeneration and reduces αSyn pathology. Oral CO administration activated signaling cascades mediated by heme oxygenase-1 (HO-1), which have been implicated in limiting oxidative stress, and in promoting αSyn degradation, thereby conferring neuroprotection. Consistent with a neuroprotective effect of smoking, HO-1 levels in cerebrospinal fluid were higher in human smokers compared to nonsmokers. Moreover, in PD brain samples, HO-1 levels were higher in neurons without αSyn pathology. Thus, CO in rodent PD models reduces pathology and increases oxidative stress responses, phenocopying possible protective effects of smoking evident in PD patients. These data highlight the potential for low-dose CO modulated pathways to slow symptom onset and limit pathology in PD patients.

'Doing school food!': a practical toolkit for adopting a whole school food approach.

AIMS: The dietary intake and reported eating behaviours of adolescents in the UK are a public health concern. Schools are identified as an ideal 'place' setting to promote health and improve young peoples' nutrition outcomes. A gap in the understanding of how healthy secondary school food policy can be implemented, sustainable and effective, may hamper progress to improving school food provision and nutrition education in the UK. Research was conducted to understand the factors which influence healthy school food provision and the adolescent's food choice to inform and develop a practical framework for schools. METHODS: This research involves the development of a practical toolkit which synthesises evidence generated from a mixed methods study and a systematic review. This was informed by an exploration of the secondary school food environment as a potentially 'obesogenic' setting, the effectiveness of school food interventions and policy in Europe and UK, included young people's (11-18 years of age) eating behaviours and priorities in food choice. A pragmatic approach was taken in the integration of evidence, using ecological and behaviour change theory, and joint display principles. RESULT: A six-phase practical toolkit is presented, guided by 'What Good Looks Like' and 'Whole Systems Approach to Obesity' principles which can be used to translate the evidence from this research into good school food practice. CONCLUSION: Improving secondary school food provision across the school day and having a coherent whole school food approach to healthy eating have the potential to significantly improve a young person's food choice, therefore impacting the nutrient intake of adolescents in the UK. This toolkit helps working towards operationalising this idea.

Combination HIV prevention during pregnancy and the post-partum period in Malawi and Zambia: a mathematical modelling analysis.

INTRODUCTION: Despite widespread success in reducing vertical HIV transmission, most antenatal care (ANC) programmes in eastern and southern Africa have not emphasized primary prevention of maternal HIV acquisition during pregnancy and lactation/breastfeeding. We hypothesized that combination HIV prevention interventions initiated alongside ANC could substantially reduce maternal HIV incidence. METHODS: We constructed a multi-state model describing male-to-female HIV transmission in steady heterosexual partnerships during pregnancy and lactation/breastfeeding, with initial conditions based on population distribution estimates for Malawi and Zambia in 2020. We modelled individual and joint increases in three HIV prevention strategies at or soon after ANC initiation: (1) HIV testing of male partners, resulting in HIV diagnosis and less condomless sex among those with previously undiagnosed HIV; (2) initiation (or re-initiation) of suppressive antiretroviral therapy (ART) for male partners with diagnosed but unsuppressed HIV; and (3) adherent pre-exposure prophylaxis (PrEP) for HIV-negative female ANC patients with HIV-diagnosed or unknown-status male partners. We estimated the percentage of within-couple, male-to-female HIV transmissions that could be averted during pregnancy and lactation/breastfeeding with these strategies, relative to base-case conditions in which 45% of undiagnosed male partners become newly HIV diagnosed via testing, 75% of male partners with diagnosed but unsuppressed HIV initiate/re-initiate ART and 0% of female ANC patients start PrEP. RESULTS: Increasing uptake of any single strategy by 20 percentage points above base-case levels averted 10%-11% of maternal HIV acquisitions during pregnancy and lactation/breastfeeding in the model. Joint uptake increases of 20 percentage points in two interventions averted an estimated 19%-23% of transmissions, and with a 20-percentage-point increase in uptake of all three interventions, 29% were averted. Strategies achieving 95% male testing, 90% male ART initiation/re-initiation and 40% female PrEP use reduced incident infections by 45%. CONCLUSIONS: Combination HIV prevention strategies provided alongside ANC and sustained through the post-partum period could substantially reduce maternal HIV incidence during pregnancy and lactation/breastfeeding in eastern and southern Africa.

The response of aquatic ecosystems to the interactive effects of stratospheric ozone depletion, UV radiation, and climate change.

Variations in stratospheric ozone and changes in the aquatic environment by climate change and human activity are modifying the exposure of aquatic ecosystems to UV radiation. These shifts in exposure have consequences for the distributions of species, biogeochemical cycles, and services provided by aquatic ecosystems. This Quadrennial Assessment presents the latest knowledge on the multi-faceted interactions between the effects of UV irradiation and climate change, and other anthropogenic activities, and how these conditions are changing aquatic ecosystems. Climate change results in variations in the depth of mixing, the thickness of ice cover, the duration of ice-free conditions and inputs of dissolved organic matter, all of which can either increase or decrease exposure to UV radiation. Anthropogenic activities release oil, UV filters in sunscreens, and microplastics into the aquatic environment that are then modified by UV radiation, frequently amplifying adverse effects on aquatic organisms and their environments. The impacts of these changes in combination with factors such as warming and ocean acidification are considered for aquatic micro-organisms, macroalgae, plants, and animals (floating, swimming, and attached). Minimising the disruptive consequences of these effects on critical services provided by the world's rivers, lakes and oceans (freshwater supply, recreation, transport, and food security) will not only require continued adherence to the Montreal Protocol but also a wider inclusion of solar UV radiation and its effects in studies and/or models of aquatic ecosystems under conditions of the future global climate.

Semantic modeling of cell damage prediction: a machine learning approach at human-level performance in dermatology.

Machine learning is transforming the field of histopathology. Especially in classification related tasks, there have been many successful applications of deep learning already. Yet, in tasks that rely on regression and many niche applications, the domain lacks cohesive procedures that are adapted to the learning processes of neural networks. In this work, we investigate cell damage in whole slide images of the epidermis. A common way for pathologists to annotate a score, characterizing the degree of damage for these samples, is the ratio between healthy and unhealthy nuclei. The annotation procedure of these scores, however, is expensive and prone to be noisy among pathologists. We propose a new measure of damage, that is the total area of damage, relative to the total area of the epidermis. In this work, we present results of regression and segmentation models, predicting both scores on a curated and public dataset. We have acquired the dataset in collaborative efforts with medical professionals. Our study resulted in a comprehensive evaluation of the proposed damage metrics in the epidermis, with recommendations, emphasizing practical relevance for real world applications.

Thirty-Day Outcomes of Young and Middle-Aged Adults Admitted with Severe COVID-19 in Uganda: A Retrospective Cohort Study.

Background: There is scarcity of data regarding young and middle-aged adults hospitalized with severe Corona Virus Disease 2019 (COVID-19) in Africa. In this study, we describe the clinical characteristics and 30-day survival among adults aged 18 to 49 years admitted with severe COVID-19 in Uganda. Methods: We reviewed treatment records of patients admitted with severe COVID-19 across five COVID-19 treatment units (CTU) in Uganda. We included individuals aged 18 to 49 years, who had a positive test or met the clinical criteria for COVID-19. We defined severe COVID-19 as having an oxygen saturation <94%, lung infiltrates >50% on imaging and presence of a co-morbidity that required admission in the CTU. Our main outcome was the 30-day survival from the time of admission. We used a Cox proportional hazards model to determine the factors associated with 30-day survival at a 5% level of significance. Results: Of the 246 patient files reviewed, 50.8% (n = 125) were male, the mean ± (standard deviation) age was 39 ± 8 years, majority presented with cough, 85.8% (n = 211) and median C-reactive protein (interquartile range) was 48 (47.5, 178.8) mg/L. The 30-day mortality was 23.9% (59/246). At admission, anemia (hazard ratio (HR): 3.00, 95% confidence interval (CI), 1.32-6.82; p = 0.009) and altered mental state (GCS <15) (HR: 6.89, 95% CI: 1.48-32.08, p = 0.014) were significant predictors of 30-day mortality. Conclusion: There was a high 30-day mortality among young and middle-aged adults with severe COVID-19 in Uganda. Early recognition and targeted management of anemia and altered consciousness are needed to improve clinical outcomes.