Organ-On-A-Chip: An Emerging Research Platform.

In drug development, conventional preclinical and clinical testing stages rely on cell cultures and animal experiments, but these methods may fall short of fully representing human biology. To overcome this limitation, the emergence of organ-on-a-chip (OOC) technology has sparked interest as a transformative approach in drug testing research. By closely replicating human organ responses to external signals, OOC devices hold immense potential in revolutionizing drug efficacy and safety predictions. This review focuses on the advancements, applications, and prospects of OOC devices in drug testing. Based on the latest advances in the field of OOC systems and their clinical applications, this review reflects the effectiveness of OOC devices in replacing human volunteers in certain clinical studies. This review underscores the critical role of OOC technology in transforming drug testing methodologies.

Selection and adaptation in human migration.

This article reviews the ways migration shapes human biology. This includes the physiological and genetic, but also socio-cultural aspects such as organization, behavior, and culture. Across disciplines I highlight the multiple levels of cultural and genetic selection whereby individuals and groups adapt to pressures along a migration timeline: the origin, transit, and destination. Generally, the evidence suggests that selective pressures and adaptations occur at the individual, family, and community levels. Consequently, across levels there are negotiations, interactions, and feedbacks that shape migration outcomes and the trajectory of evolutionary change. The rise and persistence of migration-relevant adaptations emerges as a central question, including the maintenance of cumulative culture adaptations, the persistence of "cultures of migration," as well as the individual-level physiological and cognitive adaptations applied to successful transit and settlement in novel environments.

Higher-Order Clicker Questions Engage Students and Prepare Them for Higher-Order Thinking Activities.

Previous research has shown that the use of clickers in the classroom enhances student engagement. However, few studies have investigated how the type of clicker question may influence learning outcomes. To explore this, we compared the effects of lower-order cognitive skill (LOCS) and higher-order cognitive skill (HOCS) clicker questions on later exam performance in a biology course. During class time, students were presented with clicker questions directly related to unit content. Half of the content units were taught with LOCS, the other half with HOCS. To ensure that type of content did not influence results, the cognitive level of the clicker questions was counterbalanced across two semesters. The exams included a mix of LOCS and HOCS for each content unit. We also investigated the possible moderating effects of student perceptions on the relationship between type of clicker question and exam performance using student surveys. We found that using HOCS clicker questions significantly affects student learning. Practice with HOCS clicker questions improved performance on LOCS exam questions but not on HOCS exam questions. Students ranked lecture with clickers as a preferred and most helpful teaching methodology. Overall, these results suggest that practice with HOCS questions is engaging and gives students practice recalling content to "solve" a problem, thereby encoding low-level information and preparing them for higher-order thinking activities.

A growth area: A review of the value of clinical studies of child growth for palaeopathology.

Studies of living children demonstrate that early life stress impacts linear growth outcomes. Stresses affecting linear growth may also impact later life health outcomes, including increased cardiometabolic disease risk. Palaeopathologists also assess the growth of children recovered from bioarchaeological contexts. Early life stresses are inferred to affect linear growth outcomes, and measurements of skeletal linear dimensions alongside other bioarchaeological information may indicate the types of challenges faced by past groups. In clinical settings, the impacts of stress on growing children are typically measured by examining height. Palaeopathologists are limited to examining bone dimensions directly and must grapple with incomplete pictures of childhood experiences that may affect growth. Palaeopathologists may use clinical growth studies to inform observations among past children; however, there may be issues with this approach. Here, we review the relationship between contemporary and palaeopathological studies of child and adolescent growth. We identify approaches to help bridge the gap between palaeopathological and biomedical growth studies. We advocate for: the creation of bone-specific growth reference information using medical imaging and greater examination of limb proportions; the inclusion of children from different global regions and life circumstances in contemporary bone growth studies; and greater collaboration and dialogue between palaeopathologists and clinicians as new studies are designed to assess linear growth past and present. We advocate for building stronger bridges between these fields to improve interpretations of growth patterns across human history and to potentially improve interventions for children living and growing today.

Embracing complexity in biomaterials design.

Animate materials, man-made materials behaving like living systems, are attracting enormous interest across a range of sectors, from construction and transport industry to medicine. In this leading opinion article, we propose that embracing complexity in biomaterials design offers untapped opportunities to create biomaterials with innovative life-like properties that extend their capabilities and unleash new paradigms in medical treatment.

The Ratón Pérez collection: Modern deciduous human teeth at the Centro Nacional de Investigación sobre la Evolución Humana (Burgos, Spain).

OBJECTIVES: The aim of this report is to present the large deciduous tooth collection of identified children that is housed at the National Research Center on Human Evolution (CENIEH) in Burgos, Spain. METHODS: Yearly, members of the Dental Anthropology Group of the CENIEH are in charge of collecting the teeth and registering all the relevant information from the donors at the time of collection. In compliance with Spanish Law 14/2007 of July 3, 2007, on Biomedical Research (BOE-A-2007-12945), all individuals are guaranteed anonymity and confidentiality. When the donor hands in the tooth, they fill out a Donor Information Form and sign the Informed Consent Form. At the same time, another person completes the data label for the transparent polyethylene zip lock bag where the tooth is temporarily stored. All teeth are then transferred to the CENIEH Restoration lab, where the specialists apply the same protocol as for the fossil remains. RESULTS: Although the sample is still growing, from the first collection campaign in 2014 to date it comprises 2977 teeth of children whose ages of tooth loss are between 2 and 15 years. Each tooth is associated with basic information of the individuals and their parents and grandparents (sex, date, and place of birth, ancestry, country of residence), as well as important data about early life history (pregnancy duration, breastfeeding, bottle-feeding) and other relevant information provided by the donors (such as if they are twins, dental loss, or dental extraction). CONCLUSIONS: Due to the scarcity of deciduous dental samples available, the Ratón Pérez collection represents a highly valuable sample for a wide range of disciplines such as forensic, dental, and anthropological fields among others.

Effects of human variation on foot and ankle pain in rural Madagascar.

OBJECTIVES: Foot and ankle dysfunction in barefoot/minimally shod populations remains understudied. Although factors affecting musculoskeletal pain in Western populations are well-studied, little is known about how types of work, gender, and body shape influence bone and joint health in non-Western and minimally shod communities. This study examines the effect of human variation on locomotor disability in an agrarian community in Madagascar. MATERIALS AND METHODS: Foot measurements were collected along with height, weight, age, and self-report data on daily activity and foot and ankle pain from 41 male and 48 female adults. A short form revised foot function index (FFI-R), that measures functional disability related to foot pain, was calculated. Raw and normalized foot measurements were compared by gender and used in a multiple linear regression model to determine predictors of FFI-R. RESULTS: Compared to men, women reported higher FFI-R scores (p = 0.014), spent more time on their feet (p = 0.019), and had higher BMIs (p = 0.0001). For their weight, women had significantly smaller and narrower feet than men. Bimalleolar breadth (p = 0.0005) and foot length (p = 0.0223) standardized by height, time spent on feet (p = 0.0102), ankle circumference standardized by weight (p = 0.0316), and age (p = 0.0090) were significant predictors of FFI-R score. DISCUSSION: Our findings suggest that human variation in anatomical and behavioral patterns serve as significant explanations for increased foot and ankle pain in women in this non-Western rural population. Foot and ankle pain were prevalent at similar levels to those in industrialized populations, indicating that research should continue to examine its effect on similar barefoot/minimally shod communities.

Jóvenes universitarios estilos de vida y biología humana: ¿Predisponen al desarrollo de enfermedad cardiovascular? / Young university students: lifestyles and human biology: ¿Do they predispose to the development of cardiovascular disease? / Jovens estudantes universitários: estilos de vida e biologia humana: ¿Eles predispõem ao desenvolvimento de doenças cardiovasculares?

INTRODUCCIÓN: Las enfermedades cardiovasculares han despertado interés en los últimos años por su alta incidencia a nivel mundial, generando 17,9 millones de muertes a nivel global, a pesar de que estas patológicas tienen poca prevalencia en poblaciones jóvenes, se sabe que desde edades tempranas se van produciendo cambios estructurales y funcionales en la red vascular y cardiaca derivados de conductas inadecuadas en salud relacionadas al estilo vida y aspectos biológicos propios de cada individuo. OBJETIVO: La investigación tiene como objetivo determinar los estilos de vida y los aspectos biológicos de los estudiantes de enfermería que pueden influir en el desarrollo de enfermedad cardiovascular. Metodología: Investigación cuantitativa descriptiva de corte transversal, con un muestreo a conveniencia donde participaron 100 estudiantes, se utilizaron instrumentos validados y estandarizados como el CEVJU-II, SISCO-SV-21 y datos de valoración física y bioquímica sanguínea. RESULTADOS: La edad promedio de los estudiantes fue de 21 años, en su mayoría población femenina. Los estudiantes presentaron conductas no saludables en los estilos de vida: actividad física, alimentación, sueño, consumo de alcohol, cigarro y drogas ilegales, y estrés moderado. El principal antecedente familiar fue la hipertensión arterial, sin embargo, las alteraciones antropométricas, presión arterial, lípidos y glucosa sanguínea no tuvieron altas prevalencias. CONCLUSIONES: Se concluye que a pesar de que la mayoría de los jóvenes universitarios mantienen conductas no saludables en los estilos de vida, estos comportamientos a edades tempranas no se manifestaban en cambios antropométricos y bioquímicos, lo que reduce el riesgo de presentar enfermedades cardiovasculares a futuro.

INTRODUCTION: Cardiovascular diseases have aroused interest in recent years due to their high incidence worldwide, generating 17.9 million deaths globally. Even though these pathological diseases have a slightprevalence in young populations, it is known that they are producing structural and functional changes in the vascular and cardiac network from an early age. These arederived from inappropriate health behaviors related to the lifestyle and biological aspects of everyone. AIM:The research aims to determine nursing students' lifestyles and biological elements that can influence the development of cardiovascular disease. METHODOLOGY: a cross-sectional descriptive quantitative studywas carried out, with a convenience sampling where 100 students participated, validated and standardized instruments such as CEVJU-II, SISCO-SV-21,and blood physical and biochemical assessment data were used. Results:The average age of the students was 21 years old, mostly female population. The students presented unhealthy behaviors intheir lifestyles: physical activity, eating, sleeping, consumption of alcohol, cigarettes,and illegal drugs, and moderate stress. The main family history was arterial hypertension;however, anthropometric alterations, blood pressure, lipids,and blood glucose did not have a high prevalence. CONCLUSIONS:This allows us to conclude that even though most young university students maintain unhealthy lifestyles, these behaviors at an early age were not manifested in anthropometric and biochemical changes, which reduces the risk of developing cardiovascular diseases in the future.

INTRODUÇÃO: As doenças cardiovasculares têm despertado interesse nos últimos anos devido à sua alta incidência mundial, gerando 17,9 milhões de mortes globalmente, apesar de essas doenças patológicas terem pouca prevalência em populações jovens, sabe-se que desde cedo estão produzindo alterações estruturais e funcionais na rede vascular e cardíaca derivada de comportamentos inadequados à saúde relacionados ao estilo de vida e aspectos biológicos de cada indivíduo. OBJETIVO: A pesquisa tem por objetivodeterminar os estilos de vida e aspectos biológicos de estudantes de enfermagem que podem influenciar no desenvolvimento de doenças cardiovasculares. METODOLOGIA: pesquisa quantitativa, descritiva transversal, com uma amostra de conveniência em que participaram 100 alunos, foram utilizados instrumentos validados e padronizados como o CEVJU-II, SISCO-SV-21 e dados de avaliação física e bioquímica do sangue. RESULTADOS: A idade média dos alunos era de 21 anos, em sua maioria população feminina. Os alunos apresentaram comportamentos não saudáveis no estilo de vida: atividade física, alimentação, sono, consumo de álcool, cigarro e drogas ilícitas e estresse moderado. Oprincipal antecedentefamiliar foihipertensão arterial, porém alterações antropométricas, pressão arterial, lipídios e glicemia não tiveram prevalências elevadas. CONCLUSÕES: Isso nos permite concluir que apesar de a maioria dos jovens universitários manter comportamentos não saudáveis em seus estilos de vida, esses comportamentos em uma idade precoce não se manifestaram em alterações antropométricas e bioquímicas, o que reduz o risco de desenvolver doenças cardiovasculares no futuro.

Underlying dyslipidemia postpartum in women with a recent GDM pregnancy who develop type 2 diabetes.

Approximately, 35% of women with Gestational Diabetes (GDM) progress to Type 2 Diabetes (T2D) within 10 years. However, links between GDM and T2D are not well understood. We used a well-characterised GDM prospective cohort of 1035 women following up to 8 years postpartum. Lipidomics profiling covering >1000 lipids was performed on fasting plasma samples from participants 6-9 week postpartum (171 incident T2D vs. 179 controls). We discovered 311 lipids positively and 70 lipids negatively associated with T2D risk. The upregulation of glycerolipid metabolism involving triacylglycerol and diacylglycerol biosynthesis suggested activated lipid storage before diabetes onset. In contrast, decreased sphingomyelines, hexosylceramide and lactosylceramide indicated impaired sphingolipid metabolism. Additionally, a lipid signature was identified to effectively predict future diabetes risk. These findings demonstrate an underlying dyslipidemia during the early postpartum in those GDM women who progress to T2D and suggest endogenous lipogenesis may be a driving force for future diabetes onset.

Balancing excitation and inhibition in the autistic brain.

A metric called the Hurst exponent could be a useful biomarker for studies exploring brain differences between men and women with autism spectrum disorder.

Intrinsic excitation-inhibition imbalance affects medial prefrontal cortex differently in autistic men versus women.

Excitation-inhibition (E:I) imbalance is theorized as an important pathophysiological mechanism in autism. Autism affects males more frequently than females and sex-related mechanisms (e.g., X-linked genes, androgen hormones) can influence E:I balance. This suggests that E:I imbalance may affect autism differently in males versus females. With a combination of in-silico modeling and in-vivo chemogenetic manipulations in mice, we first show that a time-series metric estimated from fMRI BOLD signal, the Hurst exponent (H), can be an index for underlying change in the synaptic E:I ratio. In autism we find that H is reduced, indicating increased excitation, in the medial prefrontal cortex (MPFC) of autistic males but not females. Increasingly intact MPFC H is also associated with heightened ability to behaviorally camouflage social-communicative difficulties, but only in autistic females. This work suggests that H in BOLD can index synaptic E:I ratio and that E:I imbalance affects autistic males and females differently.

Autism is a condition that is usually diagnosed early in life that affects how a person communicates and socializes, and is often characterized by repetitive behaviors. One key theory of autism is that it reflects an imbalance in levels of excitation and inhibition in the brain. Excitatory signals are those that make other brain cells more likely to become active; inhibitory signals have the opposite effect. In non-autistic individuals, inhibitory activity outweighs excitatory activity. In people with autism, by contrast, an increase in excitatory activity is believed to produce an imbalance in excitation and inhibition. Most of the evidence to support this excitation-inhibition imbalance theory has come from studies of rare mutations that cause autism. Many of these mutations occur on the sex chromosomes or are influenced by androgen hormones (hormones that usually play a role on typically male traits). However, most people with autism do not possess these particular mutations. It was thus unclear whether the theory could apply to everyone with autism or, for example, whether it may better apply to specific groups of individuals based on their sex or gender. This is especially important given that about four times as many men and boys compared to women and girls are diagnosed with autism. Trakoshis, Martínez-Cañada et al. have now found a way to ask whether any imbalance in excitation and inhibition in the brain occurs differently in men and women. Using computer modeling, they identified a signal in brain scans that corresponds to an imbalance of excitation and inhibition. After showing that the technique works to identify real increases in excitation in the brain scans of mice, Trakoshis, Martínez-Cañada et al. looked for this signal, or biomarker, in brain scans of people with and without autism. All the people in the study identified with the gender that matched the sex they were assigned at birth. The results revealed differences between the men and women with autism. Men with autism showed an imbalance in excitation and inhibition in specific 'social brain' regions including the medial prefrontal cortex, but women with autism did not. Notably, many of these brain regions are strongly affected by androgen hormones. Previous studies have found that women with autism are sometimes better at hiding or 'camouflaging' their difficulties when socializing or communicating than men with autism. Trakoshis, Martínez-Cañada et al. showed that the better a woman was at camouflaging her autism, the more her brain activity in this region resembled that of non-autistic women. Excitation-inhibition imbalance may thus affect specific brain regions involved in socializing and communication more in men who have autism than in women with the condition. Balanced excitation and inhibition in these brain areas may enable some women with autism to camouflage their difficulties socializing or communicating. Being able to detect imbalances in activity using standard brain imaging could be useful for clinical trials. Future studies could use this biomarker to monitor responses to drug treatments that aim to adjust the balance between excitation and inhibition.

Sensory restoration by epidural stimulation of the lateral spinal cord in upper-limb amputees.

Restoring somatosensory feedback to people with limb amputations is crucial to improve prosthetic control. Multiple studies have demonstrated that peripheral nerve stimulation and targeted reinnervation can provide somatotopically relevant sensory feedback. While effective, the surgical procedures required for these techniques remain a major barrier to translatability. Here, we demonstrate in four people with upper-limb amputation that epidural spinal cord stimulation (SCS), a common clinical technique to treat pain, evoked somatosensory percepts that were perceived as emanating from the missing arm and hand. Over up to 29 days, stimulation evoked sensory percepts in consistent locations in the missing hand regardless of time since amputation or level of amputation. Evoked sensations were occasionally described as naturalistic (e.g. touch or pressure), but were often paresthesias. Increasing stimulus amplitude increased the perceived intensity linearly, without increasing area of the sensations. These results demonstrate the potential of SCS as a tool to restore somatosensation after amputations.

Even some of the most advanced prosthetic arms lack an important feature: the ability to relay information about touch or pressure to the wearer. In fact, many people prefer to use simpler prostheses whose cables and harnesses pass on information about tension. However, recent studies suggest that electrical stimulation might give prosthesis users more sensation and better control. After an amputation, the nerves that used to deliver sensory information from the hand still exist above the injury. Stimulating these nerves can help to recreate sensations in the missing limb and improve the control of the prosthesis. Still, this stimulation requires complicated surgical interventions to implant electrodes in or around the nerves. Spinal cord stimulation ­ a technique where a small electrical device is inserted near the spinal cord to stimulate nerves ­ may be an easier alternative. This approach only requires a simple outpatient procedure, and it is routinely used to treat chronic pain conditions. Now, Chandrasekaran, Nanivadekar et al. show that spinal cord stimulation can produce the feeling of sensations in a person's missing hand or arm. In the experiments, four people who had an arm amputation underwent spinal cord stimulation over 29 days. During the stimulation, the participants reported feeling electrical buzzing, vibration, or pressure in their missing limb. Changing the strength of the electric signals delivered to the spinal cord altered the intensity of these sensations. The experiments are a step toward developing better prosthetics that restore some sensation. Further studies are now needed to determine whether spinal cord stimulation would allow people to perform sensory tasks with a prosthetic, for example handling an object that they cannot see.

Protective role of neuronal and lymphoid cannabinoid CB2 receptors in neuropathic pain.

Cannabinoid CB2 receptor (CB2) agonists are potential analgesics void of psychotropic effects. Peripheral immune cells, neurons and glia express CB2; however, the involvement of CB2 from these cells in neuropathic pain remains unresolved. We explored spontaneous neuropathic pain through on-demand self-administration of the selective CB2 agonist JWH133 in wild-type and knockout mice lacking CB2 in neurons, monocytes or constitutively. Operant self-administration reflected drug-taking to alleviate spontaneous pain, nociceptive and affective manifestations. While constitutive deletion of CB2 disrupted JWH133-taking behavior, this behavior was not modified in monocyte-specific CB2 knockouts and was increased in mice defective in neuronal CB2 knockouts suggestive of increased spontaneous pain. Interestingly, CB2-positive lymphocytes infiltrated the injured nerve and possible CB2transfer from immune cells to neurons was found. Lymphocyte CB2depletion also exacerbated JWH133 self-administration and inhibited antinociception. This work identifies a simultaneous activity of neuronal and lymphoid CB2that protects against spontaneous and evoked neuropathic pain.

Ovariectomy uncouples lifespan from metabolic health and reveals a sex-hormone-dependent role of hepatic mTORC2 in aging.

Inhibition of mTOR (mechanistic Target Of Rapamycin) signaling by rapamycin promotes healthspan and longevity more strongly in females than males, perhaps because inhibition of hepatic mTORC2 (mTOR Complex 2) specifically reduces the lifespan of males. Here, we demonstrate using gonadectomy that the sex-specific impact of reduced hepatic mTORC2 is not reversed by depletion of sex hormones. Intriguingly, we find that ovariectomy uncouples lifespan from metabolic health, with ovariectomized females having improved survival despite paradoxically having increased adiposity and decreased control of blood glucose levels. Further, ovariectomy unexpectedly promotes midlife survival of female mice lacking hepatic mTORC2, significantly increasing the survival of those mice that do not develop cancer. In addition to identifying a sex hormone-dependent role for hepatic mTORC2 in female longevity, our results demonstrate that metabolic health is not inextricably linked to lifespan in mammals, and highlight the importance of evaluating healthspan in mammalian longevity studies.

The identification of dual protective agents against cisplatin-induced oto- and nephrotoxicity using the zebrafish model.

Dose-limiting toxicities for cisplatin administration, including ototoxicity and nephrotoxicity, impact the clinical utility of this effective chemotherapy agent and lead to lifelong complications, particularly in pediatric cancer survivors. Using a two-pronged drug screen employing the zebrafish lateral line as an in vivo readout for ototoxicity and kidney cell-based nephrotoxicity assay, we screened 1280 compounds and identified 22 that were both oto- and nephroprotective. Of these, dopamine and L-mimosine, a plant-based amino acid active in the dopamine pathway, were further investigated. Dopamine and L-mimosine protected the hair cells in the zebrafish otic vesicle from cisplatin-induced damage and preserved zebrafish larval glomerular filtration. Importantly, these compounds did not abrogate the cytotoxic effects of cisplatin on human cancer cells. This study provides insights into the mechanisms underlying cisplatin-induced oto- and nephrotoxicity and compelling preclinical evidence for the potential utility of dopamine and L-mimosine in the safer administration of cisplatin.

Deciphering the neural signature of human cardiovascular regulation.

Cardiovascular regulation is integral to life. Animal studies have identified both neural and endocrine pathways, by which the central nervous system adjusts cardiac output and peripheral vascular resistance to changing physiological demands. The outflow of these pathways is coordinated by various central nervous regions based on afferent information from baroreceptors, chemoreceptors, nociceptors, and circulating hormones, and is modulated by physiologic and behavioural state. In humans, however, knowledge on central cardiovascular regulation below the cortical level is scarce. Here, we show using functional MRI (fMRI) that at least three hypothalamic subsystems are involved in cardiovascular regulation in humans. The rhythmic behaviour of these systems corresponds to high and low frequency oscillations typically seen in blood pressure and heart rate variability.

Stand up too fast and you know what happens next. You will feel faint as the blood rushes away from your head. Gravity pulls the blood into your legs, and your blood pressure drops. To correct this imbalance, the brain sends nerve impulses telling the heart to beat faster and the outer blood vessels to tighten. This is the autonomic nervous system at work. It is how the brain adjusts cardiac output, and quietly controls other internal organs in the body. It involves two key regions of the brain, the hypothalamus and the brainstem, and stimulates smooth muscles and glands around the body. The cardiovascular system also responds to the demands of exercise, with the heart supplying fresh blood laden with oxygen and the blood clearing out waste materials as it flows around the body. Perhaps surprisingly, blood pressure and heart rate fluctuate even at rest. The heart beats faster when breathing in and slower when breathing out. People's blood pressure, the force that keeps blood moving through arteries, also oscillates in so-called Mayer waves that last about 10 seconds. Much of the current understanding of the inner workings of the cardiovascular system ­ and how it is regulated by the brain ­ stems from animal experiments. This is because few attempts have been made to simultaneously measure how a person's brain and cardiovascular system work with enough detail to see how brain waves and cardiac oscillations might interact. To achieve this, Manuel et al. have now measured the brain activity, pulse and blood pressure of twenty-two healthy people while they were lying down in an MRI machine. This revealed that three distinct parts of the hypothalamus regulate cardiovascular output in humans. These 'subsystems' communicate with each other and with the lower brainstem, which sits beneath the hypothalamus. Manuel et al. also observed that the rhythmic activity of these subsystems runs in sync with oscillations typically seen in heart rate and blood pressure. With this work, Manuel et al. have shown that it is feasible to measure different systems of cardiovascular control in humans. In time, with further experiments using this new approach, the understanding of chronic high blood pressure and heart failure may improve.

Does the human placenta express the canonical cell entry mediators for SARS-CoV-2?

The pandemic of coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has affected more than 10 million people, including pregnant women. To date, no consistent evidence for the vertical transmission of SARS-CoV-2 exists. The novel coronavirus canonically utilizes the angiotensin-converting enzyme 2 (ACE2) receptor and the serine protease TMPRSS2 for cell entry. Herein, building upon our previous single-cell study (Pique-Regi et al., 2019), another study, and new single-cell/nuclei RNA-sequencing data, we investigated the expression of ACE2 and TMPRSS2 throughout pregnancy in the placenta as well as in third-trimester chorioamniotic membranes. We report that co-transcription of ACE2 and TMPRSS2 is negligible in the placenta, thus not a likely path of vertical transmission for SARS-CoV-2. By contrast, receptors for Zika virus and cytomegalovirus, which cause congenital infections, are highly expressed by placental cell types. These data show that the placenta minimally expresses the canonical cell-entry mediators for SARS-CoV-2.

Concentration-dependent mortality of chloroquine in overdose.

Hydroxychloroquine and chloroquine are used extensively in malaria and rheumatological conditions, and now in COVID-19 prevention and treatment. Although generally safe they are potentially lethal in overdose. In-vitro data suggest that high concentrations and thus high doses are needed for COVID-19 infections, but as yet there is no convincing evidence of clinical efficacy. Bayesian regression models were fitted to survival outcomes and electrocardiograph QRS durations from 302 prospectively studied French patients who had taken intentional chloroquine overdoses, of whom 33 died (11%), and 16 healthy volunteers who took 620 mg base chloroquine single doses. Whole blood concentrations of 13.5 µmol/L (95% credible interval 10.1-17.7) were associated with 1% mortality. Prolongation of ventricular depolarization is concentration-dependent with a QRS duration >150 msec independently highly predictive of mortality in chloroquine self-poisoning. Pharmacokinetic modeling predicts that most high dose regimens trialled in COVID-19 are unlikely to cause serious cardiovascular toxicity.

Hydroxychloroquine and chloroquine are closely-related drugs used for the treatment of malaria and rheumatological conditions, such as lupus. Laboratory tests have indicated that these drugs could also be used against the virus that causes COVID-19. Given the urgent need, these drugs have been fast-tracked into large-scale clinical trials, bypassing the usual stages that would provide estimates for suitable dosage. The dosage is a critical factor in a clinical trial: too low and the drug will not have an effect, too high and the side effects may counteract any potential benefits. Laboratory tests suggest that higher doses of chloroquine or hydroxychloroquine are needed for treating COVID-19 compared to malaria or lupus. However, there are concerns about the high doses used in some trials, as the drugs can have lethal side effects. Indeed, chloroquine has been used extensively in suicide attempts, particularly in France. To address these concerns, Watson et al. set out to determine the highest dosage of chloroquine (and thus of hydroxychloroquine, approximately) that does not cause unacceptable side effects. First, data was analysed regarding the concentration of chloroquine in the blood of 302 patients who had intentionally overdosed on the drug, since this concentration is tightly correlated with their risk of death. Watson et al. used a statistical model to calculate the maximal chloroquine concentration in a person's blood associated with a one per cent risk of death. This is taken to be the threshold above which any potential benefit of chloroquine treatment would be outweighed by the possibility of lethal toxicity. Watson et al. also estimated the relationship between chloroquine concentrations and changes in electrocardiogram patterns, which record the electrical activity of the heart. This makes it possible to determine whether a high dose of chloroquine has led to dangerous levels in the blood. Using a mathematical model of how chloroquine is metabolised, Watson et al. predicted that most of the trials that tested chloroquine as a treatment for COVID-19 did not reach the calculated threshold concentration. An exception was the CloroCovid-19 trial in Brazil, which was stopped early because people in the higher dosage group suffered more heart problems and died in greater numbers than those in the lower dosage group. Two large randomised trials, RECOVERY and SOLIDARITY, have shown no benefit of hydroxychloroquine or chloroquine in the treatment of COVID-19, changing clinical practice worldwide. Both of these trials used high doses resulting in higher hydroxychloroquine or chloroquine concentrations than normally observed in the treatment of malaria or rheumatological conditions. The results from Watson et al demonstrate that the lack of benefit seen in these two large clinical trials is not due to the drug dosage being too high.

Moving the human biology program from face-to-face to online delivery mode in the time of COVID-19.

Following the COVID-19 lockdown, the BSc in Human Biology Program of the University of Nicosia switched from face-to-face to online delivery mode. Herein we describe how we identified and managed the challenges that arose to successfully complete the Semester.