Children initially hospitalized with severe anaemia in Africa are at high risk of readmission or death within 6 months after discharge. No intervention strategy specifically protects children during the post-discharge period. Recent evidence from Malawi shows that 3 months of post-discharge malaria chemoprevention (PMC) with monthly treatment with artemether-lumefantrine in children with severe malarial anaemia prevented 31% of deaths and readmissions. While a confirmatory multi-centre trial for PMC with dihydroartemisinin-piperaquine is on going in Kenya and Uganda, there is a need to design and evaluate an effective delivery strategy for this promising intervention.This is a cluster-randomized trial with 5 arms, each representing a unique PMC delivery strategy. Convalescent children aged less than 5 years and weighing more than 5 kg admitted with severe anaemia and clinically stable are included. All eligible children will receive dihydroartemisinin-piperaquine at 2, 6 and 10 weeks after discharge either: 1) in the community without an SMS reminder; 2) in the community with an SMS reminder; 3) in the community with a community health worker reminder; 4) at the hospital with an SMS reminder; or 5) at the hospital without an SMS reminder. For community-based strategies , mothers will be given all the PMC doses at the time of discharge while for hospital-based strategies (4 and 5) mothers will be required to visit the hospital each month. Each arm will consist of 25 clusters with an average of 3 children per cluster giving approximately 75 children and will be followed up for 15 weeks. The primary outcome measure is uptake of complete courses of PMC drugs.The proposed study will help to identify the most effective, cost-effective, acceptable and feasible strategy for delivering malaria chemoprevention for post-discharge management of severe anaemia in under-five children in the Malawian context. This information is important for policy decision in the quest for new strategies for malaria control in children in similar contexts.NCT02721420. Protocol registered on 29 March 2016.The study was not retrospectively registered but there was a delay between date of submission and the date it first became available on the registry.ClinicalTrials.gov:  Severe anaemia is a reduction in haemoglobin (Hb) concentration below 5 g/dL or haematocrit below 15%. Globally, 43% of children have anaemia and in Africa 3.6% have severe anaemia –6. A casBy 18 months post discharge, 10.2% of children with severe anaemia were re-admitted with rebound severe anaemia and 12.6% had died, which is nine times higher than the mortality in community-based, age matched children with mild anaemia. High rates of post-discharge morbidity and mortality have also been reported in western Kenya and Uganda, where 36.5% of children aged less than 5 years admitted with severe anaemia died after 18 months of follow up .Previous observational studies in western Kenya and a recent intervention study in a high transmission areas in Malawi showed that malaria in the post-discharge period is an important contributor responsible for a slow haematological recovery, rebound severe anaemia and morbidity , 5, 7. MStandard treatment guidelines for severe anaemia in many countries in sub-Saharan Africa consists of a blood transfusion combined with presumptive intravenous anti-malarial treatment (quinine or artesunate) plus antibiotics if bacterial infections are suspected. Once children have stabilized and can be switched to oral treatment, they receive a 3-day treatment course with artemisinin-based combination therapy (ACT), usually artemether-lumefantrine (AL). Children are often discharged with a short course of iron and folate, typically with no scheduled follow-up . CreatinA study in Malawi showed that provision of 3 months of chemoprevention with 3 full treatment courses of artemether-lumefantrine (AL), given in-hospital for initial malaria episode and at 1 and 2 months post-discharge, prevented 41% of deaths or readmissions due to severe anaemia or severe malaria during a 6 months follow-up period , 11, 12.In the past two decades, most research on severe anaemia and severe malaria have focused on reducing in-hospital mortality. A major and potentially preventable component of the disease burden occurs after discharge from hospital and a proactive approach using PMC could offer substantial public health gains , and is Delivery of PMC to the target population will require new systems to be established that are sustainable and cost-effective. In contrast to IPT strategies in infants (IPTi) and pregnant women (IPTp), which are delivered through the expanded programme on immunization (EPI) and antenatal clinics, the delivery strategies for PMC are not yet in place. Some evidence shows that delivery of IPT to children (IPTc) through community health workers is feasible and well accepted in rural West Africa . In MalaThe primary objective of the trial is to determine the optimum PMC delivery strategy by comparing community-based versus health facility-based strategies in order to inform policy decision. Specifically we aim to compare PMC uptake (adherence) levels and safety between community-based versus health facility-based strategies. To determine and compare health system and family/household costs of delivering and receiving PMC using the alternative proposed strategies. To assess the feasibility and acceptability of delivering and receiving PMC in a typical Malawi health system setting. To determine whether SMS or Health Surveillance Assistant (HSA) reminder has additional benefit on PMC uptake (adherence) levels. To estimate the incremental cost-effectiveness and equity impact of the alternative delivery strategies.This is a single-centre open label cluster randomized clinical trial with 5-arms. A cluster represents a village, which is the smallest administrative unit and overseen by a village headman. A total of 1387 villages in the catchment areas of Zomba Central hospital in southern Malawi will be involved in this study.The study drug used in this trial is Eurartesim® manufactured by Sigma-Tau pharmaceuticals. This is a GMP certified co-formulated artemisin-based antimalarial combination, which contains 20 mg Dihydro-Artemesinin and 160 mg Piperaquine. It is administered according to body weight 2 (PMC-1), 6 (PMC-2) and 10 weeks (PMC-3) after discharge from hospital, each course for three consecutive days.Children aged 4 to 59 months admitted to Zomba central hospital with a diagnosis of severe anaemia either by haemoglobin of < 5 g/dl or clinically assessed as severely anaemic but clinically stable and have received all treatments according to the hospital standard of care are screened for inclusion in the trial at the time of discharge from hospital. Caretakers of children who meet the eligibility criteria are given general information about the trial and those who are interested are required to give written consent for the child to participate into the study.All children receive DHP and hence there are no placebo arms in this trial. However, children are randomized to receive PMC as follows:PMC drugs given at discharge without SMS reminder: The guardian receives all drugs for PMC-1, PMC-2 and PMC-3. They are instructed on how and when to give these drugs to the children when being discharged from hospital. The dates for each course are documented in the child’s health book.PMC drugs given at discharge with SMS reminders: The guardian receives all drugs for PMC-1, PMC-2 and PMC-3 and is instructed on how and when to give these drugs. Additionally they are reminded via SMS to give the drugs to the child one day before each treatment course is due.PMC drugs at discharge with Health Surveillance Assistant (HSA) reminders: The guardian receives all drugs for PMC-1, PMC-2 and PMC-3 and is instructed on how and when to give these drugs. Additionally, HSAs which are part of existing networks of community-based volunteers taking part in village health committees are reminded via SMS to go and remind the guardian to give the drugs to the child one day before each treatment course is due.PMC drugs collected from the hospital: At discharge, the guardian is instructed to return to the outpatient department (OPD) of the hospital each month to collect drugs for PMC-1, PMC-2 and PMC-3. They do not receive any form of reminder other than what has been documented in the child’s health card.PMC drugs at hospital with SMS reminders: At discharge, the guardian is requested to return to the OPD to collect drugs for PMC-1, PMC-2 and PMC-3. Additionally they will be reminded via SMS to come to the clinic to collect drugs one day before each treatment course is due.Figure Each pre-screened subject is assigned a pre-screening number in sequential order regardless of whether they fulfil the pre-screening eligibility criteria. After the child has recovered sufficiently, the caretaker is approached for further screening for eligibility. Caretakers of children who fulfil the eligibility criteria and who agree to participate in the research provide written informed consent before enrolling into the study. The study participant’s demographic data, relevant clinical information, including the previous and current medical history, and laboratory information is collected simultaneously. Furthermore, a physical and clinical examination is performed and captured on the enrolment case report forms (CRFs).The unit of randomization is villages within the catchment area of Zomba central hospital. 400 out of the 1387 villages were randomly selected and randomized to one of the study arms, where each arm represents a different implementation alternative. When a child is enrolled and all study procedures have been done, the study data officer enters the name of the village where the child resides into a pre-programed database and this automatically generates the study arm and study identification number. The participants and the study staff are aware of the study arm assigned. However, the study statistician who will perform the final analyses will be blinded to the allocated treatment arm.Table The primary outcome is the level of uptake of PMC drugs which will be assessed by unannounced home visits after each course whereby pill counts will be done. Hundred percent uptake of PMC drugs will be defined as administration of all 3-day treatment courses (i.e. 9 doses), given at 2, 6 and 10 weeks after discharge from hospital. Sixty percent of PMC drugs are defined as administration of 6 or more (but less than 9) of the daily dosages out of the total of 9.30% of PMC drugs will be defined as administration of 3 or more (but less than 6) of the daily dosages out of the total of 9. Less than 30% of PMC drugs is defined as administration of less than 3 of the daily dosages out of the total of 9, given 2, 6 and 10 weeks after discharge.Study instruments include structured forms for clinical history, physical assessment, laboratory evaluations and clinical information collected on history of current and previous illnesses and hospital admissions is collected in addition to hospitalizations and mortality. For children who are hospitalized during the follow-up period, data is collected on the length of hospitalization, diagnosis, treatments provided, laboratory results, and participant outcomes. Physical examination and laboratory tests include: height, weight, mid-upper arm circumference, malaria rapid test results, blood slide results, parasitaemia level, and haemoglobin concentration. This will be used to assess all-cause mortality, incidence rate of all-cause hospital readmissions, incidence rate of readmissions due to severe anaemia (Hb < 5 g/dL) or severe malaria defined by the administration of parenteral Artesunate or Quinine, incidence rate of non-severe all-cause sick-child clinic visits, specifically incidence rate of clinic visit due to RDT/microscopy confirmed non-severe malaria during the study period.Information about expenses, resource and time use with open-ended fields for unanticipated findings and place for comments will be collected. Demographic information on children is collected including age, sex, while religion, village of residence and socioeconomic features of their household is also recorded as well as cost information for the economic evaluation. This will assess health provider’s cost of delivering the PMC services, caretakers’ cost of receiving the PMC services, incremental cost-effectiveness ratio (ICER) of PMC delivery strategies and equity impact by socioeconomic status of PMC delivery strategies on main and secondary outcomes.In addition there will be interview guides for in-depth interviews and focus group discussions with a selection of caretakers and health workers who have been involved in the PMC trial. This information will be used to assess the acceptability of PMC, adaptations to health workers’ working practices required to implement PMC, perceptions of implementing PMC through different delivery strategies, and recommendations on effective implementation.2 = 0.036. Assuming an intra-cluster correlation coefficient (ICC) of 0.1 and allowing for 10% loss-to-follow-up, a sample size of 25 clusters (villages) of an average of 3 children per village ) has 80% power to detect a 25% absolute increase in uptake from an estimated 50% in the OPD and delivery at home groups to 75% in the arms supported by SMS reminders (α = 0.05). The ICC of 0.1 is slightly more conservative than the ICC in a previous trial of delivery approaches for IPTc in the Gambia.The sample size calculation has been adjusted for the design effect using the coefficient of variation method in order to account for the Intra-cluster Correlations (ICC) , 16. We Data is collected and recorded by one of the trained study staff at the point of contact. Data is entered directly into computer tablets that will be pre-programmed and uploaded with electronic case report forms (eCRFs). The eCRFs have crosschecks for verification, validation and comply with Good Clinical Practices (GCP). These gadgets are connected to a desktop allowing data to be directly uploaded into a database.The percentage of children receiving PMC according to schedule in each arm will be obtained and compared between arms using relative risks (RR) and the 95% CI for the RR will be reported. The estimates of the RR will be adjusted for prognostic factors and potential confounding factors at baseline using log binomial or Poisson regression with adjustment for cluster effects. Using Cox regression, hazard ratios will be calculated for morbidity endpoints such as incidence of severe anaemia, severe malaria and all cause hospital re-admissions, for repeated events with robust standard error estimation methods to account for correlation between episodes within children. Incidence rates per child-year and absolute rate reductions will also be calculated.This protocol describes a study in which we will determine the optimum PMC delivery mechanism in a Malawian context by comparing community versus health facility based strategies. Presently in African health systems and particularly in Malawi, post-discharge health management systems are not in place, and there is need to assess a number of relevant strategies for effective delivery of PMC in a largely rural community that would typically benefit from this intervention.We postulate that this post-discharge care in the form of PMC may be delivered either in the community or at a health facility. The most likely scenario where the health care provider is least involved would be where mothers are given all the PMC drugs on discharge from hospital and allowed to administer the drugs on her own to the child (Arm 1). In recent years there has been successful disease control programs operationalizing more decentralized drug delivery programs in the community in low-income countries, making it a viable option for PMC. However as we postulate that the mother could forget to administer the PMC, we would like to test two different reminder systems. The first is through the use of SMS technology, which has been shown to be user-friendly and acceptable from our own pilot work (unpublished pilot study) and other current programs in Malawi (Arm 2 and 5).An alternate reminder system is the use of Health Surveillance Assistants (HSA). HSA are Ministry of Health (MoH) employees who are responsible for basic health promotion activities in the community. Ideally MoH strives to have one HSA for every 1000 people, but in reality they often cater for much larger populations and are usually over-burdened with many disease control programs. In some areas in rural Malawi there are Village Health committees, which are made up of voluntary members of the community. They work hand in hand with the HSA. We postulate that HSAs and where available village health volunteers (VHVs) are an option for reminding mothers to give PMC to their child (Arm 3).Another option for delivery of PMC is to request the mother or caretaker to return to the health care facility to collect the drugs for each treatment course (Arms 4 and 5). This is a plausible strategy as it is consistent with the management of chronic illness such as TB and HIV where drugs are routinely collected from a health facility by the patients. This would be an alternative strategy as part of EPI or management of other chronic illnesses e.g. chest follow up clinic.


Nitrogen is essential for all living species and may be taken up from the environment in different forms like nitrate or peptides. In plants, members of a transporter family named NPFs transport nitrate and peptides across biological membranes. NPFs are phylogenetically related to a family of peptide transporters (PTRs) or proton-coupled oligopeptide transporters (POTs) that are evolutionarily conserved in all organisms except in Archaea. POTs are present in low numbers in bacteria, algae and animals. NPFs have expanded in plants and evolved to transport a wide range of substrates including phytohormones and glucosinolates. Functional studies have shown that most NPFs, like POTs, operate as symporters with simultaneous inwardly directed movement of protons. Here we focus on four structural features of NPFs/POTs/PTRs that have been shown by structural and functional studies to be essential to proton-coupled symport transport. The first two features are implicated in proton binding and transport: a conserved motif named ExxER/K, located in the first transmembrane helix (TMH1) and a D/E residue in TMH7 that has been observed in some bacterial and algal transporters. The third and fourth features are two inter-helical salt bridges between residues on TMH1 and TMH7 or TMH4 and TMH10. To understand if the mechanism of transport is conserved in NPFs with the expansion to novel substrates, we collected NPFs sequences from 42 plant genomes. Sequence alignment revealed that the ExxER/K motif is not strictly conserved and its conservation level is different in the NPF subfamilies. The proton binding site on TMH7 is missing in all NPFs with the exception of two NPFs from moss. The two moss NPFs also have a positively charged amino acid on TMH1 that can form the salt bridge with the TMH7 negative residue. None of the other NPFs we examined harbor residues that can form the TMH1–TMH7 salt bridge. In contrast, the amino acids required to form the TMH4–TMH10 salt bridge are highly conserved in NPFs, with some exceptions. These results support the need for further biochemical and structural studies of individual NPFs for a better understanding of the transport mechanism in this family of transporters. Arabidopsis thaliana from a mutant that conferred resistance to the herbicide chlorate and resulted in a decreased nitrate uptake (NRT1/PTR Family)   . NPFs we Family) . Thus, Ae (TCDB) .Drosophila and Caenorhabditis elegans; four in humans). In algae, NRT1s are present in one or two copies, with some algae having none at all. In contrast, plant genomes contain a much larger number of NPFs, from as low as 20 members in the moss Physcomitrella patens to as high as 115 in Glycine max  revealed several new NPFs that were not included in the previous Mt3.5 sequence release, bringing the total number of NPFs to 92, as reported in To recover the NPF sequences, we used the locus identification numbers reported in Multiple sequence alignments of amino acid sequences were performed using the Clustal Omega program via the Web Services interface at the European Bioinformatics Institute (EMBL-EBI) . We remo4  with the first glutamic acid in the motif, Glu41, occupying the 11th position of the TMH1. Therefore, the motif is located slightly closer to the cytoplasmic side of the membrane. The ExxER/K motif in AtNPF6.3 is conserved and when Glu41, Glu44 or Arg45 were mutated to an alanine, a loss of both nitrate uptake activity was observed in yeast- and oocyte-based nitrate uptake essays  have a completely conserved ExxER/K motif  NPFs completely lack any chargeable amino acids in the TMH1 region that aligns with the motif.After aligning 2383 NPF sequences from 42 plants, we identified the ExxER/K motif in each transporter using the AtNPF6.3 sequence as a reference. To help correctly identify the TMH1 in multiple sequence alignment, we included two conserved glycine residues in positions -1 and -2 with respect to the first amino acid of the AtNPF6.3’s TMH1. Both glycine residues located N-terminal to the TMH1 are conserved in 1455 NPF sequences and at least one of the two glycine residues is conserved in all but 72 NPFs, allowing us to unambiguously identify the residues corresponding to TMH1 and the ExxER/K motif  are distributed into two distinct subfamilies, similar to what was observed for the NPF2 members from A. thaliana. The NPF2a subfamily contains a total of 94 transporters (including AtNPF2.1–2.7)  are located in a larger clade , and two (M. acuminata and A. comosus) belong to the Bromelliaceae family, that diverged from the grass family 100 million years ago. The O. sativa genome contains ten NPF7s, seven of which, belong to the NPF7a subfamily. Some OsNPF7a members have been studied. OsNPF7.2 was functionally characterized in oocytes and shown to be a low affinity nitrate transporter that is not pH dependent  are a highly diverse group of photosynthetic eukaryotes from which the terrestrial plant lineage emerged > 1 billion years ago and therefore are phylogenetically closely related to plants . The algChromochloris zofingiensis contains two NRT1s, while Chlorella variabilis NC64A and Coccomyxa subellipsoidea both contain one full and one partial NRT1; Bathycoccus prasinos, Chlamydomonas reinhardtii, Dunaliella salina, Ostreococcus lucimarinus, Ostreococcus tauri, and Volvox carteri have a unique NRT1; Micromonas pusilla sp. RCC299 contains one NRT1, while Micromonas pusilla sp. CCMP1545 does not contain any NRT1. None of the algal NRT1s has been functionally characterized so far.As previously reported, sequenced genomes from Chlorophytes contain one or two NRT1s, or none at all . ChromocB. prasinos, M. pusilla, O. lucimarinus and O. tauris, which are all Mamiellophyceae, a class of green algae. These latter NRT1s also have an arginine on TMH1 that can form the TMH1-TMH7 salt bridge with the TMH7 glutamate. When aligned with our collection of plant NPFs sequences, the Mamiellophyceae NRT1s form a distinct subgroup with two NPFs from the moss P. patens, PpatNPF8.5 and PpatNPF8.6 (Supplementary Figure Chargeable amino acids in the ExxER/K motif as well as the oppositely charged amino acids required to form the TMH4–TMH10 salt bridge are conserved in all algal NRT1s (Supplementary Table NPF transporters are part of the major facilitator superfamily of secondary active transporters and are phylogenetically related to POT, PTR, NRT1 transporters of bacteria, animals and algae . Among tIn this study, we analyzed 2383 NPF sequences from 42 plant genomes including those from monocot and eudicot land plants as well as aquatic plants. The NPFs were surveyed for sequence conservation of four structural features implicated in the proposed proton-driven transport mechanism: the chargeable amino acids in the ExxER/K motif on TMH1, the D/E residue on TMH7, and the oppositely charged amino acids responsible for forming the inter-helical salt bridges between TMH1 and TMH7 and between TMH4 and TMH10.A. thaliana members of the NPF2a subfamily have been functionally characterized and shown to be passive nitrate or chloride transporters implicated in root-to-shoot efflux (Our analysis shows that the chargeable amino acids of the ExxER/K motif are conserved in only 62% of plant NPFs (Table t efflux . We specA. thaliana, O. sativa, and Z. mays NPF7 transporters in this group that have been studied, with observations of proton-driven nitrate symport as well as proton-potassium antiport (Another interesting case is represented by the NPF7 subfamily. When we examined the sequences in this subfamily, we observed that most NPF7s completely lack chargeable amino acids in the ExxER/K motif. There is controversy over the biochemical activities displayed by the several antiport . Our datOverall, our results suggest there exists a correlation between the presence of an ExxER/K motif and secondary active transport; i.e., transport of a substrate driven by the concomitant transport of protons down their energetic gradient. NPF transporters lacking the ExxER/K motif have lost one of the key elements of the proposed mechanism for active transport and thus function as passive transporters.St, proton driven uptake was affected (The glutamate/aspartate residue located on TMH7 is available as a proton-binding site in the outward-open conformation in some bacterial POTs. Although this residue is not strictly conserved in bacterial POTs, when it was mutated in PepT1affected . The coraffected . AnalysiTwo sets of inter-helical salt bridges have been described in POTs that are important for the alternating-access mechanism. One salt bridge has been observed in the inward-open conformation between residues located on TMH1 and TMH7; a second salt bridge is predicted to form in the outward-open conformation between THM4 and THM10 Figure  Newstea. Amino aS. oneidensis, S. thermophilus, Y. enterocolica, and X. campestris (The difference in level of conservation of the residues involved in the formation of the two salt bridges is in agreement with the observation that the largest conformational change is from outward-open to occluded, rather than from occluded to inward-open . Thus, tmpestris , the TMHP. patens which are the only plant NPFs to harbor the residues forming the TMH1-TMH7 salt bridge (Supplementary Figure We examined the four structural features implicated in NPF/POT/PRT proton-driven substrate transport in algal NRT1 transporters and found that the TMH1 ExxER/K motif and the residues contributing to the TMH4–TMH10 salt bridge are strictly conserved in all algal NRT1s. In contrast, the glutamate on TMH1 and the residues contributing to the TMH1–TMH7 salt bridge are only conserved in NRT1s from Mamiellophyceae algae. These NRT1s align with two NPFs from None of the algal NRT1s has been functionally characterized so far, but based on the conservation of two essential structural features, we speculate that, most likely, the NRT1s actively transport substrate in a proton-driven symport mechanism. This is significant because it suggests that these features are ancient and that during algal evolution the mechanism of proton-driven transport has been preserved.NPFs, like POTs, PTRs, and NRT1s, belong to the MFS superfamily that comprises facilitators, symporters, and antiporters, which move substrates across membranes via facilitated diffusion, cotransport, or exchange, respectively . POTs haAnother question, not addressed in our study, is how these transporters evolved to be able to transport such a variety of substrates. So far no direct connection between the protein sequences and the substrate transported has been established, but as we learn more about this family of proteins we may in the future be able to predict which substrate each NPF can transport based on its sequence. More crystal structures are needed of NPFs bound to different substrates. In the meantime, structural modeling of NPFs can help identify important differences between NPFs belonging to different families and transporting different substrates.In summary, our analysis of NPF sequences together with the available functional studies suggest that NPFs are versatile transporters. As symporters, they evolved from their initial role of proton-driven nitrate transporters to transport a variety of substrates, potentially using the same mechanism. As they expanded they acquired new roles: some evolved to passively facilitate nitrate or chloride efflux blurring the distinction between a transporter and a channel; others seem to have evolved to function as proton/potassium antiporters. This appears unique to NPFs.We observed that while many NPFs in plants have maintained elements or structural features that are at the basis of a conserved mechanism for proton-powered substrate transport, a significant number of NPFs lack such elements. In particular, we found that some plants contain NPFs that lack these elements and are passive nitrate or chloride efflux transporters. Other NPFs lack these elements but can still actively transport protons, suggesting the evolution of a different and still unknown mechanism for proton binding and transport. Our genome survey of plant NPFs combined with results from structural studies of NPF/POT transporters makes the case for extending the investigation to NPFs transporters from different subfamilies and plants. Since the function and mechanisms of NPFs cannot yet be easily inferred by sequence similarity, additional biochemical and structural studies as well as investigations of expression patterns and subcellular localization are needed to unravel the fascinating evolution of this family of plant proteins. Finally, although we did not address substrate recognition, we make the case for additional structural studies on NPFs in complex with the variety of different substrates that this family of proteins can transport.AL collected and analyzed the NPF/PTR/POT/NRT1 sequences and crystal structures. NWM conducted the phylogenetic analysis. AL and RD wrote the manuscript. All authors read the manuscript and approved it.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Is the prevalence of depression in pregnancy increasing across 2 generations of the Avon Longitudinal Study of Parents and Children?In this 2-generation cohort study, evidence was found showing that depression in young pregnant women is higher today than in the 1990s.The findings highlight the need for increased support for young pregnant women to minimize the potentially far-reaching effects of depression on mothers, their children, and future generations. This cohort study uses data from the Avon Longitudinal Study of Parents and Children (ALSPAC) to compare rates of prenatal depression between women who were pregnant in 1990 to 1992 and a second generation of women who were pregnant in 2012 to 2016. Depression during pregnancy  is common and has important consequences for mother and child. Evidence suggests an increasing prevalence of depression, especially in young women. It is unknown whether this is reflected in an increasing prevalence of prenatal depression.To compare the prevalence of depression during pregnancy in today’s young mothers with their mothers’ generation.In a longitudinal cohort study, we compared prenatal depressive symptoms in 2 generations of women who participated in the Avon Longitudinal Study of Parents and Children. Participants were the original mothers (recruited when they were pregnant) and their female offspring, or female partners of male offspring, who became pregnant. Both groups were limited to the same age range (19-24 years). The first generation of pregnancies occurred in 1990 to 1992 (n = 2390) and the second in 2012 to 2016 (n = 180). In both generations, women were born in the same geographical area (southwest England).Depressed mood measured prenatally using the Edinburgh Postnatal Depression Scale in self-reported surveys in both generations. A score of 13 or greater on a scale of 0 to 30 indicated depressed mood.Of 2390 pregnant women in the first generation who were included in analysis , 408 (17%) had high depressive symptom scores (≥13). Of 180 pregnant women in the second generation who were included in the analysis , 45 (25%) had high depressive symptom scores. Having high depressive symptom scores was more common in the second generation of young pregnant women than in their mothers’ generation , with imputation for missing confounding variable data and adjustment for age, parity, education, smoking, and body mass index not substantially changing this difference. Results were essentially the same when analyses were restricted to the 66 mother-offspring pairs. Maternal prenatal depression was associated with daughters’ prenatal depression .In this unique study of 2 generations of women who answered identical questionnaires in pregnancy, evidence was found that depressed mood may be higher in young pregnant women today than in their mothers’ generation. Because of the multiple and diverse consequences of prenatal depression, an increase in prevalence has important implications for families, health care professionals, and society. Comparing population surveys using comparable tools to measure depression provides a more valid estimate of trends in depression prevalence; however, findings from such studies are inconsistent.11 One explanation for inconsistent findings is that the trends in prevalence of depression over time vary between different subgroups of the population, and studies vary in participant composition . Indeed, evidence from population surveys  suggests that depression in young women (aged 19-24 years) is increasing more than depression in other gender and age groups.11There is evidence from routine data and population surveys that psychiatric service use and antidepressant prescriptions have increased in recent years.We hypothesized that the increase of depression among young women will also be reflected during pregnancy. To our knowledge, this is the first study to compare prenatal depression prevalence in young women across time.13 In this analysis, ALSPAC-G0 participants are the original mothers (recruited when they were pregnant), and ALSPAC-G1 are female offspring participants, or female partners of male offspring participants, who became pregnant. The children of ALSPAC-G0 participants are now aged 23 to 25 years. In 2012 we began to recruit the next generation, ie, female ALSPAC-G1 offspring who became pregnant, female partners carrying offspring of male ALSPAC-G1, and any children of the original ALSPAC-G1 offspring. Depressive symptoms during pregnancy have been collected using identical methods in both ALSPAC-G0 participants and in the next generation of pregnancies in 2012 to 2016. This provides an opportunity to compare the levels of prenatal depression in contemporary young women with their mothers’ generation who were pregnant in the early 1990s.The Avon Longitudinal Study of Parents and Children (ALSPAC) is a prospective, multigenerational cohort that recruited pregnant women living in southwest England between 1990 and 1992 and has followed them, their partners, and their index children since then.We hypothesized that the frequency of prenatal depression would be higher in today’s sample of young pregnant mothers compared with rates in young women in the 1990s.13 and further information can be found at http://www.bristol.ac.uk/alspac/. Ethical approval for the study was obtained from the ALSPAC Law and Ethics Committee and South West – Central Bristol National Health Service Research Ethics Committee, and participants gave written informed consent. We followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline in writing this article.The ALSPAC-G0 group consisted of pregnant women whose delivery date fell between April 1, 1991, and December 31, 1992 (inclusive), and who resided in the county previously known as Avon in southwest England. Participants were recruited from 3 maternity units where every woman who attended prenatal clinics over a fixed period of time was invited, and most joined the study. The original participants totaled 14 541 pregnant women, of whom 13 988 had children alive at 1 year; these children are referred to as ALSPAC-G1. The G0 women, their partners, and their children (G1) have been followed since the early 1990s through questionnaires, detailed clinical assessments, and record linkage. Full details of the study have been previously reported,In 2012 we began recruiting and collecting data on the next generation, ALSPAC-G2, the children of the G1 participants and grandchildren of the originally recruited G0 women. At the time that we began the G2 study, we developed protocols for collecting data on any G1 participants who had become parents, were pregnant, or had a partner who was pregnant. As with the original study, we collected data on both parents (≥1 of whom was an ALSPAC-G1 participant) and their children.The recruitment of G2 participants is through an open cohort. At the start of the study in 2012, some G1 participants had already become parents, and their children were entered into the study at any time (from early pregnancy on). The analysis for this specific article includes only G1 women recruited during pregnancy; of the total 442 G1 women who have become pregnant or G1 men who have a partner who is pregnant or who have become a parent, 180 provided depression data during pregnancy and were therefore eligible for this study. There were also 66 G0-G1 mother-offspring pairs in which both G0 and G1 women were pregnant at an age of 19 to 24 years and both had complete pregnancy depression data.The focus of this study is on prenatal depression and therefore includes all G1 participants or their partners who were recruited during pregnancy between June 6, 2012, and December 31, 2016, and completed a depression measure at either of the pregnancy assessments (one at 18 weeks and the second at 32 weeks). Where women completed both assessments, we used the early pregnancy measure so that in all women we were using their first report of depression in pregnancy. We only included G0 mothers who were in the same age range as the G1 generation . The G1 participants, by definition of the ALSPAC initial recruitment, were born in Avon. Therefore, we also restricted the G0 sample to those born in Avon . Thus, our study uses data from the first pregnancy assessments of 2390 mothers from 1991 to 1992 (G0) and 180 mothers from 2012 to 2016 (G1), all of whom were aged 19 to 24 years at the time of pregnancy assessment, had the same measure of prenatal depression assessed at approximately the same time in pregnancy, and had been born in Avon .14 was used to measure levels of depression in both G0 and G1 mothers. The EPDS is a 10-item self-report measure designed to screen women for symptoms of depression both during and after pregnancy. High levels of depressive symptoms were defined as a score of 13 or greater on the EPDS, a threshold commonly used in practice and well validated with strong specificity and sensitivity against diagnostic tools.15 We also compared continuous symptom scores across generations.The Edinburgh Postnatal Depression Scale (EPDS)We collected information on characteristics that are known to be associated with prenatal depression and that might differ between generations or have changed over the last 25 years to see whether differences between the 2 groups might be explained by any of these. With the exception of weight and height, similar protocols were used to collect these data in both generations. Age (in years), educational attainment , smoking , and alcohol (any during pregnancy vs none) were obtained from questionnaires. Gestational age at the time of each assessment of depression was calculated from the gestational age at delivery and date of the assessment. In ALSPAC-G0 body mass index (BMI)  was calculated from the woman’s retrospective report of her prepregnancy weight and measured height in early pregnancy. In ALSPAC-G1 both maternal weight and height were measured in early pregnancy by researchers.Characteristics for the 2 groups are presented as percentages  or means (continuous variables). Differences in means or prevalence ratios with 95% confidence intervals were used to explore differences between generations. We used binary regression with a log-link function to estimate rate ratios comparing rates of depression in ALSPAC-G1 and ALSPAC-G0. We present unadjusted associations and associations adjusted for age, parity, education, smoking, alcohol, and BMI. Adjusted associations are presented separately for each characteristic to enable us to see the extent to which any of them explain any differences. We adjusted for gestational age when women completed the EPDS (early or late pregnancy).We also investigated whether prenatal depression in G1 participants was associated with their own mothers’ depression during pregnancy.In additional analyses we compared continuous mean scores and the unadjusted responses to each of the 10 items of the EPDS between the 2 groups of women to determine whether any differences in the overall score might be driven by specific symptoms of depression. We also repeated our main unadjusted analyses in the G0-G1 mother-offspring pairs only (n = 66). We also used multivariable multiple imputation to deal with missing covariable data in G1 as an additional sensitivity analysis , 408 (17%) had high depressive symptom scores (≥13). Of 180 G1 women included in the analysis , 45 (25%) had high depressive symptom scores. The vast majority of G1 pregnancies were original female ALSPAC participants (163 of 180 [90.5%]), with the remaining 17 (9.5%) being pregnant female partners of a male ALSPAC-G1 participant. Within our total sample, there were 66 mother-offspring pairs.Compared with their mothers’ generation, ALSPAC-G1 women were more likely to have achieved A-Levels and were less likely to smoke, but were more likely to take antidepressants . AlcoholMaternal (G0) prenatal depression was associated with daughter’s (G1) prenatal depression. Of G1 participants whose mothers were depressed in pregnancy, 54% were depressed themselves, compared with only 16% of G1 participants whose mothers were not depressed prenatally .P = .02) higher than scores in G0. The individual EPDS item scores all increased in G1 mothers, with the exception of unnecessary self-blame and lack of sense of humor, which were more common in ALSPAC-G0 participants, and considering self-harm, which was similar in both groups . Given that very young age at pregnancy is a risk factor for depression, this would suggest that, if anything, depression in G1 is underestimated and the increase could be greater.16 Comparatively, therefore, the ALSPAC-G1 participants may be having children at a younger age than their peers relative to their mothers’ generation, which may result in more social isolation or stigma and could be a potential source of unmeasured explanation for the difference. However, this would be a potential underlying mechanism for the increase in prenatal depression in young women rather than a source of confounding.There are additional differences between generations that we could not account for, which could explain the difference we have observed. For example, although both G0 and G1 women were in the same age range (19-24 years), the average age of motherhood today is higher than in the 1990s.3 However, to confirm any specificity, future studies would need to compare mother-daughter associations between depression at different timings and the extent to which the daughters’ prenatal depression was related to a continuation of depression before pregnancy as opposed to a prenatal onset. Given that depression at any timing is highly correlated, larger samples than we currently have available are needed to have sufficient statistical power to disentangle specific timing effects.3 If, however, a prenatal-specific association is confirmed in other samples, it may highlight a specific intergenerational risk of depression during pregnancy, with potential genetic, biological , or environmental mechanisms that require further investigation.17Using this unique data source, we also found that maternal (G0) depression during pregnancy was a strong risk factor for prenatal depression in the G1 women . This risk of intergenerational prenatal depression exceeds the unadjusted association for intergenerational depression at other time points in this sample  based on previous publications.18 The impact of such changes may be amplified when a woman becomes pregnant. This generation of young women has also experienced rapid change in technology, internet, and social media use, which has been associated with increased feelings of depression and social isolation and changes to social relationships.20The findings in this study mirror the more general increase in depression among young women that has been recently reported. If the increase in the prevalence of prenatal depression over the past 25 years is confirmed, it is important to understand the potential changes in society and lifestyle that may have contributed to the observed increase. Chronic stress, sleep deprivation, eating habits, sedentary lifestyle, and the fast pace of modern life may be contributing to an increasing prevalence of depression among young people generally.21 and inflexible work arrangements and work pressure are associated with greater depressive symptoms in mothers.22 Difficulties balancing work and home may be increasing, and this may be reflected by the increase of G1 women reporting “things are getting too much” compared with their mother’s generation (G0) in our sample (23 are also arguably greater today, adding further pressure to working mothers.Beyond the background mechanisms for increasing depression prevalence among young people, pregnant women are likely to face additional pressures. First, as compared with the 1990s, the proportion of mothers working has increased substantially,r sample . FinanciUsing a unique data source, we present evidence that depression in young pregnant women is higher today than in the 1990s. There are a number of plausible explanations for this phenomenon that deserve further investigation in future research to guide prevention and treatment. The findings highlight the need for increased screening and resources to support young pregnant women and minimize the potentially far-reaching impact of depression on mothers, their children, and future generations.


Positron emission tomography acquisition takes several minutes representing an image averaged over multiple breathing cycles. Therefore, in areas influenced by respiratory movement, PET-positive lesions occur larger, but less intensive than they actually are, resulting in false quantitative assessment. We developed a motion-correction algorithm based on 4D-CT without the need to adapt PET-acquisition.The algorithm is based on a full 3D iterative Richardson-Lucy-Deconvolution using a point-spread-function constructed using the motion information obtained from the 4D-CT. In a motion phantom study (3 different hot spheres in background activity), optimal parameters for the algorithm in terms of number of iterations and start image were estimated. Finally, the correction method was applied to 3 patient data sets. In phantom and patient data sets lesions were delineated and compared between motion corrected and uncorrected images for activity uptake and volume.Phantom studies showed best results for motion correction after 6 deconvolution steps or higher. In phantom studies, lesion volume improved up to 23% for the largest, 43% for the medium and 49% for the smallest sphere due to the correction algorithm. In patient data the correction resulted in a significant reduction of the tumor volume up to 33.3 % and an increase of the maximum and mean uptake of the lesion up to 62.1 and 19.8 % respectively.In conclusion, the proposed motion correction method showed good results in phantom data and a promising reduction of detected lesion volume and a consequently increasing activity uptake in three patients with lung lesions. Positron emission tomography (PET), especially in combination with computed tomography (CT) is gaining more and more influence in the diagnosis, staging, therapy planning and treatment response control in cancer patients –4. As imDifferent options have been proposed to overcome this issue. Respiratory gating (4D-CT or 4D-PET) is the most widely distributed and is meanwhile implemented in all commercial PET systems. This method is based on image sorting, providing different images for the different breathing states of the patient and can therefore lead to significant improvements in lesion quantification . But it More sophisticated approaches for motion correction were developed over the past years. Some of them correct during the reconstruction process, others using a line of response correction, or using 4D-PET acquisition. For the first two approaches to reconstruction, individual information about the scanner as detector geometry is required. In contrast, corrections in the image space do not require information about the hardware as the are based on the reconstructed images , 16. HowDeconvolution techniques have been widely applied in optical analysis and video sequence processing to restore the sharpness of images –20. The Direct inversion using Fourier-based methods would lead to amplification of noise and degradation in the restored image , 20. TheIn this study, we developed a motion-correction algorithm, which derives the motion information from 4D-CT data, often acquired in clinical workflows for radiation therapy treatment planning in the lung or upper abdominal organs. The motion information is then used to construct a 3D PSF to deconvolve the motion image using iterative Richardson-Lucy algorithm.In comparison with the static PET-phantom acquisition (without movement) the results after 6 deconvolution steps or higher showed the best conformity. We found no significant differences between the results using different start images. So, for final analysis the blurred (uncorrected) PET image was used as start image together with 6 iterations steps for the deconvolution. In phantom studies, lesion volume improved up to 23% for the largest, 43% for the medium and 49% for the smallest sphere due to the correction algorithm, a comparison between the static phantom and the corrected data set can be seen in Figure In patient data the detected lung lesion volume decreased between 5.6 and 15.6 % when using just the PSF in cranio-caudal direction and between 25.2 and 33.3 % when using the full 3D PSF for motion correction. Consequently, maximum uptake in the lesion showed an increase between 43.4 and 62.1 % and the mean uptake between 12.0 and 19.8 % when using the full 3D PSF. The details for each individual patient can be found in Table Respiratory motion degrades quantitative assessment of lesion volume and activity concentration in PET/CT data of tumors in the lung or the upper abdomen. While many approaches for motion correction are available as discussed in the introduction, the presented algorithm has some essential differences. This algorithm is using clinical 3D-PET images, so it can be applied to all images independent of the scanner type. No dynamic PET scan or special acquisition protocols, or external sensors fixed to the patient, are necessary, as all steps of the algorithm are performed in the image space using reconstructed PET data. The motion vector is obtained by 4D-CT images which are performed often in case of radiation therapy treatment planning. However, motion can also be extracted from other sources, e.g. MR or just from a two phase CT  or tracked by infrared cameras and markers. Also, movement from sources other than respiration can be corrected as far as motion information is available. Furthermore, the presented motion correction approach can be applied to any (molecular) image, as long as the motion information is given and it is not limited to PET, it also can be applied to single photon emission tomography images. This may even be through for small animal PET imaging as long as the motion vector can be assessed by 4D CT or MRI imaging or any other means of measurement.The presented CT-based motion correction method showed promising results in phantom and patient data. The real volume of the spheres placed in the phantom could be restored very well. In patient data we found significant reduction of lesion volume up to 33.3 % and consequently an increase in activity uptake of up to 62.1 %. We could also show that the deconvolution using the full 3D PSF showed better reduction in lesion volume and a larger increase in activity uptake of the lesions as the PSF just based on the cranio-caudal movement. This effect was especially seen in patient 2 and 3, in who a relevant movement in the anterior-posterior direction was detected. Therefore, we conclude that a PSF based on the full 3D movement should be applied.However, a drawback of the method is that a 4D- or cine CT is necessary, as long as no other method of motion detection is used, which means additional dose for the patient. Just two low-dose CTs are possible as well, one taken in end-expiration, the other in end-inspiration. Using actual low-dose protocols, the additional dose will be minimal. Finally, in case PET is used for radiation treatment planning, where precise quantification is of special importance, often a 4D-CT is performed anyway.In conclusion, the proposed motion correction method showed good results in phantom data and a promising reduction of detected lesion volume and a consequently increasing activity uptake in three patients with lung lesions.This algorithm is using the high spatial and temporal resolution CT data from a hybrid PET/CT for motion registration in 3D to correct the low spatial resolution PET data. The basic principle of this approach was already used by Ben-Ezra et al , using aTherefore, we implemented full 3D deconvolution of PET images with a PSF created by 4D-CT. In the proposed algorithm no changes in patient setting or acquisition protocol of the PET data have to be done. Therefore, the algorithm is also independent of the hardware specifications of the scanner and can even be applied retrospectively to PET data as long as a 4D-CT or any motion information is available for this patient.The next essential step after acquiring the data is the estimation of the individual motion and the motion modelling for correction. Naqa et al.  used a dThe end-inspiration and end-expiration CT data sets were obtained from the 4D-CT and movement between these two phases was detected using a commercial rigid registration algorithm included in the Mediso Interview Fusion software . As optimal motion correction of the tumor was the primary goal, for registration a bounding box around the tumor was drawn for optimal co-registration in this area. The motion vector was used as motion trajectory which can be transferred in a 3D PSF representing the whole motion.Naqa et al  found ouWe used the iterative Richardson-Lucy-Deconvolution-Algorithm using this CT-registration based PSF for deconvolution of the 3D-PET images:We assume the PSF to be constant  over the whole image. Therefore, rigid registration between each CT was used to obtain just one motion vector for the whole dataset.As starting image there are two different options available. First, we used an image which all pixels had the same constant value The algorithm was applied to phantom data using these two options of the starting image. Consequently for phantom data different iteration number (n=1 to 9) were used in the algorithm to assess the optimal number of iterations.st just in cranio-caudal direction with a linear PSF in this direction and 2nd the correction for which the PSF is based on the full-3D-trajectory estimated previously.Finally, the correction algorithm was applied to 3 patients’ data sets using the parameters which have been found to be optimal in phantom studies. For patient studies two corrections were performed, 1To show the feasibility of the developed algorithm, PET/CT-motion phantom measurements were performed using an extended CT-motion phantom, which is provided in the basic form without the fillable sphere attachments by Anzai  Figure . The pha


The CA2 region of the hippocampus is a somewhat obscure area lacking in an understanding of its form and function. Until recently, the CA2 has been thought of as merely an extension of the CA3, with some referring to it as the CA3a region. Recent investigations into this area have not only delineated the CA2, but also defined it as a region distinct from both CA1 and CA3, with a unique set of cortical inputs and outputs and contributions to cognitive processes. One such process that has been shown to depend on the CA2 is the ability to recognize a novel or familiar conspecific, known as social recognition memory. Here, we review these findings and discuss the parallels between CA2 dysfunction and social impairments. Social cognitive neuroscience is a burgeoning interdisciplinary field of research that aims to delineate the “why” and “how” of interactions between individuals. It aims to explore the relationship between cognitive processes and behavior in a social context. First described by One of the processes that is paramount to the structure and stability of relationship networks that define societies is that of social memory . Social The ability to recognize a familiar versus novel individual is the foundation on which social relationships are built. Memory for individual conspecifics is not only necessary to engage in meaningful relationships but is also required to express appropriate behavioral responses based on previous encounters . Social While social recognition is a common process across a variety of mammals, there are species and sex differences which may influence how it is expressed . StudiesSex-differences have also been reported to exist in social recognition processes. In a social recognition task, female rats were reported to spend less time investigating a conspecific juvenile compared to males, yet females displayed stronger remote social recognition than males . Based oEvidence suggests that the hippocampus is required for proper processing of social memories as data have shown that hippocampal lesions disrupt social recognition . Rats wiThe two major divisions of the hippocampus are the dorsal and the ventral hippocampus , each wiThe ventral hippocampus has been shown to be involved in emotional memory processes, like fear, and influences the fear memory processing of the amygdala, given that the ventral, but not the dorsal, hippocampus projects directly to the amygdala . The dorThe dentate gyrus  receivesThe ability to organize and separate spatial events from one another, allowing an organism to temporally remember one place as distinct from another, is largely mediated by the dentate gyrus . This spstratum pyramidale, the stratum lacunosum-moleculare, the stratum lucidum, the stratum oriens, and the stratum radiatum. The stratum pyramidale contains the cell bodies of pyramidal cells and various interneurons  has been widely accepted to be the cellular underpinning of synaptic plasticity, and memory acquisition, storage, and retrieval in the central nervous system . High-frno avail .A inhibitory currents were blocked using picrotoxin, yet all of these protocols consistently induced LTP in the CA1  imaging to compare cell ensembles in CA1, CA2, and CA3 subregions in mutant mouse lines lacking either NMDA receptors at the CA3 synapse (CA3-NR1 KO) or at the perforant path inputs from the entorhinal cortex to the dentate gyrus (DG-NR1 KO). This allowed the investigators to manipulate the quality of incoming information to CA2. CA3-NR1 KO leads to deficits in rapid encoding information and associative memory storage, making a familiar representation more novel, while DG-NR1 KO leads to deficits in context discrimination, making a novel representation more familiar  or the environment in which the conspecific was initially encountered could ostensibly create errors in recognition. Together with the temporal processing of information, the CA2 can be viewed as processing the general ‘when, where, and what’ aspects of social recognition.stratum pyramidale of CA2 in schizophrenic and manic-depressive patients compared to controls  light chain in CA2 pyramidal neurons, which blocked neurotransmission. To test the efficacy of this method, they co-expressed channelrhodopsin-2 (ChR2) with either TeNT or yellow fluorescent protein (YFP) using Cre-dependent AAVs. From there, they used whole-cell current clamp recordings to determine the strength of synaptic transmission from CA2 to CA1 pyramidal neurons. Focal photostimulation over a wide range of intensities delivered to CA1 stratum oriens and stratum radiatum regions evoked robust monosynaptic potentials in the CA1 pyramidal neurons in slices in which ChR2 was co-expressed with YFP in CA2 pyramidal neurons. Slices in which ChR2 was co-expressed with TeNT in CA2 pyramidal neurons produced little to no synaptic response in CA1 neurons when CA2 neurons were illuminated (Recent advancements in genetic manipulation techniques have allowed for investigations into the role of CA2 in social cognition in a more precise and sensitive manner. uminated .Given the efficacy of TeNT lesions, they then investigated the behavioral consequences of CA2 inactivation. A three-chamber social novelty test was used to compare performance between control mice, expressing YFP in CA2 pyramidal neurons, and CA2-TeNT mice. In this test, the amount of time that the experimental mouse spent interacting with a novel, unrelated mouse was compared to the time spent interacting with a familiar co-housed littermate in order to measure social recognition . While tA five-trial habituation/dishabituation social memory was used to confirm that CA2-inactivation resulted in impaired social memory. In this test, the experimental mouse was exposed to a stimulus mouse for four consecutive trials then introduced to a novel stimulus mouse on the fifth trial. The CA2-TeNT mice showed no significant habituation during the first four trials as evidenced by a lack of decreased exploration and no significant dishabituation to the novel mouse as shown by a lack of increased exploration . The CA2A three-chamber test of sociability was used to compare performance between CA2-YFP mice and CA2-TeNT mice. This test examined the normal preference of the experimental mouse for a chamber containing a littermate versus an empty chamber. Both the CA2-YFP and CA2-TeNT groups displayed a significant preference for the compartment containing their littermate, suggesting that CA2 inactivation did not alter sociability . In theiFollowing up to the work by The CA2 is a dynamic region with a composition and connectivity unique to the hippocampus, and not just an extension of the CA3, as was previously believed. Given that research into this region is a relatively new endeavor, the precise role of the CA2 is not fully understood. Nevertheless, burgeoning research into this area has established the role of CA2 in social memory processes, with a particular focus on social recognition, and as such, dysfunction in this area has been implicated in the social impairments common to a number of psychiatric diseases. Beyond these preliminary findings, little is known concerning the cellular pathways that regulate this brain region and how it mediates social recognition representations, while its contribution to neuropathologies is somewhat vague and inferential, at best. Further research into the cellular mechanisms that govern the CA2 may provide insight into the social deficits underlying certain neuropathologies, such as autism and schizophrenia, and potentially yield novel treatment strategies for these disorders.NT wrote the initial and revised versions of the manuscript. MH commented and edited the manuscript. Both authors approved the final manuscript for submission.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.